• glycosaminoglycans;
  • proteoglycan;
  • brain development;
  • Alzheimer's disease


  1. Top of page
  2. Abstract
  3. Introduction
  4. Structure of GAGs
  5. Structure of PG Core Proteins
  6. Function of PGS in the Brain
  7. Role of PGs in AD
  8. Conclusions
  9. References

Proteoglycans (PGs) are major components of the cell surface and extracellular matrix and play critical roles in development and maintenance of the central nervous system (CNS). PGs are a family of proteins, all of which contain a core protein to which glycosaminoglycan side chains are covalently attached. PGs possess diverse physiological roles, particularly in neural development, and are also implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). The main functions of PGs in the CNS are reviewed as are the roles of PGs in brain injury and in the development or treatment of AD. © 2013 IUBMB Life, 65(2)108–120, 2013.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Structure of GAGs
  5. Structure of PG Core Proteins
  6. Function of PGS in the Brain
  7. Role of PGs in AD
  8. Conclusions
  9. References

Proteoglycans (PGs) are a diverse family of macromolecules that consist of a core protein covalently attached to long carbohydrate chains known as glycosaminoglycans (GAGs). There are various types of GAGs, of which all are linear highly negatively charged complex carbohydrates composed of repeating disaccharide units. PGs are mainly located on the cell surface or in the extracellular matrix (ECM) and participate in many important biological processes (1). PGs participate in the regulation of brain development and are also involved in normal brain function. Recent studies suggest that PGs may also play key roles in neurodegenerative diseases such as Alzheimer's disease (AD). In this review, we focus on the role of PGs and GAGs on the development and maturation of the human brain, and on their role in the etiology of AD.

Structure of GAGs

  1. Top of page
  2. Abstract
  3. Introduction
  4. Structure of GAGs
  5. Structure of PG Core Proteins
  6. Function of PGS in the Brain
  7. Role of PGs in AD
  8. Conclusions
  9. References

GAGs can be classified into several types according to the structure of their carbohydrate chain. GAGs include heparin or heparan sulfate (HS), chondroitin sulfate (ChS), dermatan sulfate (DS), hyaluronan (HA), and keratan sulfate (KS) (2) (Fig. 1). Heparin is a linear polysaccharide with a repeating disaccharide unit of 1 [RIGHTWARDS ARROW] 4 linked uronic acid and glucosamine residues (GlcN). The GlcN residues are predominately N-sulfated (GlcNS) and the rest N-acetylated (GlcNAc) with a very minor portion unsubstituted (GlcNH) (2). The uronic acid predominantly consists of approximately 90% iduronic acid (IdoA) and 10% glucuronic acid (GlcA) (3). The 3- and 6-position of GlcN can either be sulfated or remain unsubstituted. In addition, the 2-position of uronic acid can be substituted with a sulfate group (3). The average sulfation of heparin is approximately 2.7 sulfate groups per disaccharide unit (4). The presence of sulfate groups and carboxyl groups makes heparin highly negatively charged, which is important for its biological properties. HS is a heparin analog and has a similar structure to heparin. The uronic acid residue of HS is mainly GlcA but also contains IdoA (Fig. 1A). The degree of sulfation of HS is much less than heparin with an average of approximately one sulfate group per disaccharide unit (5). In addition, heparin is predominantly synthesized in mast cells and basophils (6), while HS is expressed by almost all cell types (7).

thumbnail image

Figure 1. The structure of some repeating disaccharide units of common GAGs. Abbreviations: GlcA, glucuronic acid; GlcNAc, N-acetylglucosamine; GalNAc, N-acetylgalactosamine; Gal, galactose. Sulfate groups are shown in red. [Color figure can be viewed in the online issue, which is available at]

Download figure to PowerPoint

ChS and DS (also called ChS B) consist of a repeating disaccharide unit in which N-acetylgalactosamine (GalNAc) is attached to GlcA and IdoA, respectively (8) (Fig. 1B). ChS and DS can be sulfated to different degrees and at varying positions depending upon the tissue source. Sulfation at the 4- and 6-position of the GalNAc residue forms ChS A (Ch4S) and ChS C (Ch6S), respectively. The sulfation at the 2-position of GlcA and 6-position of GalNAc forms ChS D. ChS can also be sulfated at the 4- and 6-position of the GalNAc to form ChS E. DS has a sulfation group at the 2-position of the IdoA (8).

HA contains a repeating unit in which GlcNAc is β1 [RIGHTWARDS ARROW] 3 linked to GlcA (Fig. 1C). HA is not sulfated and does not attach to a core protein. In addition, HA is the only GAG which is synthesized on the cell surface (9). KS is a linear polymer containing a repeating disaccharide unit of GlcNAc and galactose with the sulfation occurring on the C6 position of both sugar residues (10) (Fig. 1D). KS can be further classified into three different types according to the tissue source or the different linkage between KS and the core protein (11, 12).

Structure of PG Core Proteins

  1. Top of page
  2. Abstract
  3. Introduction
  4. Structure of GAGs
  5. Structure of PG Core Proteins
  6. Function of PGS in the Brain
  7. Role of PGs in AD
  8. Conclusions
  9. References

GAGs are normally attached to core proteins to form a PG. HS, ChS, and DS chains are normally linked to serine residues on core proteins via a tetrasaccharide (xylose–galactose–galactose–uronic acid). KS is normally attached to serine or threonine residues to form an O-linked oligosaccharide or to asparagine residues to form an N-linked oligosaccharide (13).

Chondroitin Sulfate Proteoglycans

Chondroitin sulfate proteoglycans (CSPGs) are the most abundant PGs in the mammalian central nervous system (CNS). They can be classified into several subtypes. Members of the lectican family, including aggrecan (14), versican (15), neurocan (16), and brevican (17), are CSPG components of the ECM. Lecticans contain a core protein ranging in molecular mass from 80- to 400-kDa with globular domains at the N-terminal and C-terminal ends. Their amino acid sequences are highly homologous. The core proteins contain an N-terminal HA-binding domain which has important roles in the formation of ECM (18). In the C-terminal domain of the core protein, there are two epidermal growth factor (EGF)-like repeats, a C-type lectin domain and complement regulatory protein (CRP)-like domain (18). The central domain of the core proteins contains attachment sites for ChSs, and the numbers of potential ChSs attachment sites vary greatly among the lectican family members (18) (Fig. 2A).

thumbnail image

Figure 2. The structure of some major CNS CSPGs (A) and HSPGs (B). Abbreviations: GPI, glycosylphosphatidylinositol; HA, hyaluronan; Ig, immunoglobulin; EGF, epidermal growth factor; CRP, complement regulatory protein; CAH, carbonic anhydrase; FN, fibronectin. [Color figure can be viewed in the online issue, which is available at]

Download figure to PowerPoint

Phosphacan and receptor-type protein-tyrosine phosphatase β (RPTPβ) are typical CSPGs (19). RPTPβ is a transmembrane PG. Its core protein has an N-terminal carbonic anhydrase-like domain, followed by a fibronectin type III domain, a chondroitin sulfate attachment region, a transmembrane segment, and two intracellular tyrosine phosphatase domains (19). Phosphacan is a secreted CSPG and is generated by alternative splicing of RPTPβ mRNA. Phosphacan has the same structure as RPTPβ but lacks the two intracellular tyrosine phosphatase domains (20) (Fig. 2A). Alternative splicing of RPTPβ and phosphacan can generate a short form of both proteins that has fewer ChS attachment sites than the full-length forms.

Decorin and biglycan are small leucine-rich PGs that have a core protein containing leucine-rich repeats in the central region (21). The leucine-rich repeats usually account for the majority of the core protein sequence and are flanked by cysteine clusters that may form disufide bonds (21). The N-terminal region of decorin and biglycan contain one (decorin) or two (biglycan) ChS binding sites (19).

Melanoma-associated chondroitin sulfate proteoglycan (MCSP) or NG2 is a transmembrane CSPG that does not show significant sequence homology with other PGs (22). The expression of MCSP is developmentally regulated with the highest expression in immature, proliferating cells (22). MCSP has a large ectodomain, followed by a transmembrane region and short cytoplasmic domain. The ectodomain can be further divided into three domains: the globular N-terminal cysteine-containing domain that is stabilized by several disulfide bonds, the central serine–glycine-containing domain that contains the ChS attachment sites, and another cysteine-containing domain (23).

In addition to these typical CSPGs, several proteins such as neuroglycan C, thrombomodulin, and β-amyloid precursor protein (APP) can occasionally be modified to form a CSPG. Neuroglycan C, which is predominantly expressed in the brain, is a transmembrane glycoprotein that contains an EGF-like extracellular domain with ChS attachment sites located at the N-terminal region (24). Neuroglycan C can act as a PG with a single ChS chain attached during the development of CNS. However, in the mature CNS, it exists mainly in a non-PG form (25). APP can exist as a CSPG called appican, which is mainly expressed by glia (26). Appican is generated by splice removal of exon 15 of APP mRNA, which forms a glycosylation sequence and allows a single ChS chain attachment (27). The biological function of appican is unclear. However, some evidence suggests that the attachment of ChS to APP may affect the processing of APP to Aβ (28).

Heparan Sulfate Proteoglycans

Heparan sulfate proteoglycans (HSPGs) are present in all animal tissues. They contain different core proteins to which HS chains are attached. HSPGs can be classified into two types, cell-surface HSPGs and ECM HSPGs (29). The syndecan family includes four members (syndecan 1–4), which are the typical cell-surface HSPGs (30). All syndecan genes encode a protein with an N-terminal signal peptide, a large ectodomain, a transmembrane domain, and a comparatively short cytoplasmic tail (30). The HS attachment sites are located either at both the N-terminal and the C-terminal ends of the ectodomain (syndecan 1 and 3) or at the N-terminal end only (syndecan 2 and 4) (31) (Fig. 2B). The ectodomains of the syndecans have only a small amount of amino-acid-sequence homology, although the cytoplasmic domains are highly conserved (32). The ectodomain of syndecans can undergo proteolytic cleavage by sheddases to generate C-terminal fragments that can be further cleaved by the γ-secretase complex (33, 34).

Members of the glypican family are linked via glycosylphosphatidylinositol (GPI) anchors to the cell surface. There are six glypicans, with core proteins containing 550–580 amino-acid residues (35). The glypican genes encode proteins containing an N-terminal signal peptide and a C-terminal hydrophobic domain that is required for the linkage of HSPG to the GPI anchor (36). The HS attachment sites of glypicans are located mainly at the C-terminus of the core protein, close to the GPI anchor (35) (Fig. 2B). Most glypicans undergo proteolytic cleavage by a furin-like convertase which cleaves at the C-terminal end of the ectodomain, generating two subunits linked to each other by several disulfide bonds (37).

Perlecan (HSPG2) is a secreted basement membrane-associated HSPG (38). Perlecan consists of a large core protein with a molecular weight of approximately 470 kDa. Perlecan contains five distinct domains. The N-terminal (domain I) contains a sperm protein-enterokinase-agrin module which has HS attachment sites. Domain II contains four EGF-like domains. Domain III contains laminin-like α-chains including three laminin IV-like modules followed by three sets of laminin EGF-like repeats. The large domain IV contains 21 immunoglobulin-like repeats. Domain V of perlecan contains three laminin G-like domains followed by two sets of EGF-like domains. Additionally, domain V also contains HS attachment sites (39). Other ECM-located HSPGs that have also been identified including agrin (40), collagen XVIII (41), and the testican proteins (42).

Function of PGS in the Brain

  1. Top of page
  2. Abstract
  3. Introduction
  4. Structure of GAGs
  5. Structure of PG Core Proteins
  6. Function of PGS in the Brain
  7. Role of PGs in AD
  8. Conclusions
  9. References

Recent studies demonstrate that PGs have important roles in the developing and mature brain. PGs interact with growth factors and receptors, chemokines, morphogens, axon guidance molecules, and ECM proteins (43). In addition, PGs have important roles in brain injury and neural regeneration (44).

CSPGs and CNS Development

During brain development, CSPGs interact with various proteins and are closely associated with cell adhesion, cell migration, neurite formation and elongation, synaptogenesis, axon guidance, and barrier formation (45). During CNS maturation, changes occur in both the level and composition of CSPGs (46).

CSPGs have important roles in neural cell migration (47). CSPGs are predominantly located in the regions where neural crest cells do not migrate, suggesting that they play an important role in restricting cell migration (48). In support of this idea, it has been shown the inhibition of CSPG synthesis alters the migration patterns of neural crest cells (48). In vivo studies demonstrate that implantation of micromembrane-bound aggrecans into neural crest cell migration pathways can induce neural crest cells to spatiotemporally deviate from their normal migratory trajectory (49).

CSPGs can also act as barriers to axonal growth (50–53). Extending axons avoid tissues with high CSPG expression and chemical removal of the ChS chains from CSPGs abolishes this avoidance phenomenon, this suggests that CSPGs are associated with the growth-cone repulsion (50–53). In vitro, CSPGs are inhibitory to both cerebellar granule neuron and dorsal root ganglion axonal growth (54–56). Thus, CSPGs may participate in axonal guidance by restricting axonal extension of developing neurons (57).

Specific sulfation patterns of CSPG may affect axonal guidance in different ways. ChS sulfated at the 4-position (ChS A), but not at the 6-position (ChS C), is a negative guidance cue for growing axons. Knockdown of the ChS biosynthetic enzyme 4-O-sulfotransferase, which catalyzes 4-O sulfation of ChS, significantly enhances axonal growth (58). However, knockdown of 6-O-sulfotransferase, the enzyme responsible for 6-O sulfation of GalNAc residues of ChS, has no effect on axonal outgrowth (58).

In vitro and in vivo studies also suggest a role of CSPGs in axon guidance during the development of the visual system. Retinal axons can grow into a region which is normally repulsive to axons after treatment with the chondroitin ABC lyase (59). Moreover, CSPGs inhibit the elongation of retinal ganglion cell (RGC) axons and the expression of CSPGs is undetectable after RGC axon elongation in the retina is complete (60).

CSPGs, and in particular phosphacan, are mainly confined to regions of active cell proliferation, suggesting that they may be involved in regulating cell proliferation during development (61). This view is supported by the observation that ChS polysaccharides can promote the fibroblast growth factor (FGF)-2-mediated proliferation of neural stem or progenitor cells (62). In addition, CSPGs may be associated with axon myelination during CNS development. The expression of brevican coincides with the myelination of axon fibers (63) and a deficiency of brevican can cause a reorganization of the nodal matrices around the nodes of Ranvier of axons (64).

HSPGs and CNS Development

Many studies suggest an important role for HSPG in axon guidance and growth (65). The addition of exogenous HS or removal of HS can perturb the growth of pioneer axons in cultured cockroach embryos, causing axon defasciculation and growth in incorrect directions (66). HSPG can stimulate neurite outgrowth by binding to and activating proteins including APP (67–69), laminin (70), and FGF-2 (71). Moreover, in the Xenopus optic system, treatment with exogenous HS, or enzymic digestion of HSPGs, causes axons from the retina to bypass their primary target, the optic tectum (72, 73). Other studies have demonstrated that there are two distinct roles of HS in retinal axon guidance (74). First, HS is involved in axon sorting. Disturbing the synthesis of HS causes missorting of RGC axons in the optic tract (74). Second, HS is also associated with the path-finding of retinal axons to the tectum (74). Moreover, in C. elegans, syndecan-1 has an important role in midline axon guidance (75).

The role of HSPG in axon guidance has also been examined in transgenic mice. HS 2-O-sulfotransferase (HS2ST) and HS 6-O-sulfotransferase (HS6ST) are responsible for the 2-O sulfation of uronic acid residues and 6-O sulfation of GlcN residues in HS, respectively (76, 77). HS2ST or HS6ST-null mice can express HS with N-sulfation but completely lack 2-O-sulfation or 6-O-sulfation and show specific axon guidance defects at the optic chiasm (78).

Several lines of evidence suggest a role for PGs in mediating a neurite outgrowth promoting function of the APP of AD. APP contains two potential heparin-binding domains. Structurally, the N-terminal domain of APP is vaguely similar to cysteine-rich growth factors, suggesting that this region of APP could function as a growth factor in vivo (79). Mice lacking members of the APP family have severe abnormalities in brain development, indicating that APP-like proteins have some roles in brain development (80). PGs and core proteins of PGs can bind directly to APP (81–85). For example, heparin can bind to the N-terminal of APP (residues 96–110) (68). Mutagenesis of three basic residues within this sequence decreases the heparin-binding capacity, and a peptide homologous to this heparin-binding domain of APP can bind strongly to heparin (68). Other studies have identified another heparin-binding site in the APP sequence (residues 316–447) (86, 87). The binding of PGs to APP can influence the effect of APP on neurite outgrowth (68, 69, 88). The binding of APP to HSPG derived from the ECM may stimulate the effects of APP on neurite outgrowth, and a peptide homologous to the heparin-binding region of APP can block APP-induced neurite outgrowth (68).

There is evidence that HSPG may also participate in the proliferation of neuronal precursor cells during early brain development. Studies demonstrate that syndecan-1 and glypican-4 are most highly expressed during the time of peak proliferation in the developing brain and that they are localized to ventricular regions of the brain where precursor cells are proliferating (89). Further studies show that HS is required for the FGF-stimulated brain precursor cell proliferation (89). Knockout of HS2ST in mice also shows that HSPGs have a critical role in regulating cell proliferation during development of the cerebral cortex. Mice lacking HS2ST have a significant decrease of neuronal cell proliferation (90).

Function of PGs in Synaptogenesis and Synaptic Plasticity

Early studies demonstrated that HSPGs, and in particular agrin, are components of synapses (91, 92). Agrin is important for stabilizing the developing cholinergic synapse by inducing postsynaptic acetylcholinesterase receptor clusters (93). In cultured hippocampal neurons, increased levels of agrin precede synaptogenesis. In contrast, inhibition of agrin synthesis by antisense oligonucleotide treatment or by blocking agrin with a specific antibody leads to fewer functional synapses (94, 95). Moreover, in neuron cultures from agrin knockout mice, the lack of agrin reduces synaptogenesis and selectively affects excitatory but not inhibitory synapses (96, 97). In addition, recent evidence shows that agrin secreted by astrocytes could induce hippocampal neuron synapse formation in vitro (98). Other HSPGs may also have roles in synapse formation. For example, syndecan-2 has been reported to promote filopodia growth and dendritic spine formation through the neurofibromin-PKA-Ena/VASP pathway (99).

During postnatal development, various brain regions exhibit considerable plasticity that decreases as the CNS matures (100). CSPGs have important roles in regulating this plasticity. Perineuronal nets (PNNs) are highly condensed matrices surrounding the cell body and proximal dendrites of certain types of neurons and they contain a different composition of ChS chains than ECM (101). PNNs are mainly assembled with CSPGs including members of the lectican family, phosphacan, HA, tenascin-R, and link proteins (102). PNNs are thought to have important functions in restricting plasticity in the brain (103). For example, the organization of CSPGs into PNNs coincides with the termination of critical periods for plasticity (104). Sensory deprivation of rats or mice with dark rearing or whisker trimming results not only in a decreased number of PNNs but also in a delayed critical period (104, 105). Degradation of CSPG in PNNs by chondroitin ABC lyase leads to reactivation of experience-dependent plasticity in the adult rat visual cortex, suggesting an inhibitory role of CSPG in experience-dependent plasticity (104). Enzymic removal of ChS chains reduces both long-term potentiation (LTP) and long-term depression (LTD) in hippocampal slice cultures (106), while brevican- and neurocan-deficient mice show significant deficits in the maintenance of hippocampal LTP (107, 108). However, the mechanism underlying the effect of CSPGs on LTP and LTD is currently unknown.

Function of PGs in CNS Injury

Lesions to the CNS induce the formation of glial scars that contain activated astrocytes, microglia, and oligodendrocyte precursors as well as PGs (44). Although glial scars can initiate the healing process and may play a protective role after the CNS injury, they may also have detrimental effects on axon regeneration (109). Direct evidence for this comes from the observation that axon extension is blocked by glial scars surrounding the lesion, while axons can grow normally along routes where the glial scar is absent (110). Several studies suggest that CSPG may be associated with the inhibitory effects of glial scars on axon growth (111). The level of CSPGs is upregulated around the lesion area soon after the CNS injury (112, 113). Inhibition of CSPG synthesis or removal of the ChS chains with chondroitin ABC lyase increases axon elongation over the scar surface in vitro (114, 115). In vivo, treatment with chondroitin ABC lyase promotes axon regeneration of dopaminergic neurons and enhances the regrowth of both sensory and motor axons after spinal cord injury (116–118).

Unlike CSPGs, the role of HSPG in response to CNS injury is largely unknown. Several studies demonstrate that the level of HSPGs within or surrounding the lesion core is upregulated following CNS injury (119–121). Other studies indicate that there is an increase in 2-O-sulfated HS and syndecan-1 in the injured adult rat brain (122). However, the role of these HSPGs following the CNS injury is unclear. HSPGs are important for the trophic effects of FGF-2 and FGF receptor 1 (FGFR1) (120, 121, 123), which suggests that HSPGs may have a supportive role in axon regeneration in the CNS lesion.

Recent evidence indicates that keratan sulfate proteoglycans (KSPGs) are associated with spinal cord lesions (124). KS-deficient mice exhibit better functional recovery after spinal cord injury (125). Overexpression of keratanase II (K-II), which can specifically degrade KS, promotes recovery of motor and sensory function and enhances axonal regeneration and sprouting after spinal cord injury in rats (126).

Role of PGs in AD

  1. Top of page
  2. Abstract
  3. Introduction
  4. Structure of GAGs
  5. Structure of PG Core Proteins
  6. Function of PGS in the Brain
  7. Role of PGs in AD
  8. Conclusions
  9. References

AD is an irreversible, progressive neurodegenerative disorder that is commonly found in the elderly population (127). AD is characterized pathologically by the presence of amyloid plaques, neurofibrillary tangles (NFTs), and congophilic amyloid angiopathy (CAA) in the brain (128, 129). The major component of the amyloid plaque and CAA is a polypeptide known as the β-amyloid protein (Aβ), which is generated from APP by the β-site APP cleaving enzyme-1 (BACE1) and γ-secretase (130–134) (Fig. 3).

thumbnail image

Figure 3. The major roles of GAGs in the Aβ pathology of AD. Figure shows that GAG can enhance Aβ aggregation (1), regulate BACE1 activity and level (2), inhibit Aβ uptake by microglia (3), bind to APP and stimulate neuronal growth (4), and suppress Aβ-induced neurotoxicity (5). [Color figure can be viewed in the online issue, which is available at]

Download figure to PowerPoint

PGs in AD Pathology

Several studies have shown that PGs are localized to amyloid plaques (135–138). HSPGs are present in amyloid plaques of the hippocampus in AD brain (139). Agrin, syndecan, glypican but not perlecan have been reported in amyloid plaques (135, 140, 141). Recent studies demonstrate that HSPGs are preferentially accumulated around the dense cores of amyloid plaques, but that they remain largely absent from diffuse plaques (142). CSPGs are also found in amyloid plaques (143) and immunocytochemical studies demonstrate that decorin is peripherally localized to amyloid deposits (144). PGs are also associated with CAA, which is formed by the deposition of Aβ in the walls of cerebral and leptomeningeal blood vessels. Several studies have reported that HSPGs are presented in CAA (135, 136, 138). Indeed, several HSPGs including glypican-1, syndecan-2, collagen XVIII, and agrin, but not syndecan-1, syndecan-3, and perlecan, are reported to be associated with CAA (141, 145, 146). PGs are also reported to be associated with the formation of NFTs. Agrin, syndecan, and glypican, but not perlecan, have been localized in association with NFTs (136, 137, 140). The CSPG decorin is also reported to be associated with NFTs (143, 144).

The overall level of PG in the brain may be altered in AD. Studies on postmortem tissue show that the level of PG is increased approximately 1.6-fold in the hippocampus of AD patients and 4.3-fold in the superior frontal gyrus compared to normal elderly subjects. HS is increased 9.3-fold in hippocampus and increased 6.6-fold in superior frontal gyrus (147). This increase may be a consequence of Aβ deposition because Aβ treatment can increase the expression of glypican-1 and syndecan-3 in glial culture (142). Infusion of Aβ40 into hippocampus leads to an accumulation of perlecan in microglia and macrophages at the Aβ infusion site (148). In addition, in Tg2576 mice which overexpress human APP, glypican-1 and syndecan-3 are found in glia associated with amyloid deposits proximal to the site of HS accumulation. This result is consistent with the finding that expression of HSPGs is elevated in neurons and glia of the brains of AD patients (137). The findings suggest that HSPGs codeposited with amyloid plaques may be derived from glia and that they may be produced in response to the accumulation of Aβ.

PGs may be associated with amyloid plaques because they bind directly to Aβ. Studies show that both HS chains and core proteins can bind to the N-terminal region of Aβ (149, 150). Within the N-terminal region, residues 13–16 may be critical for the interaction between Aβ and GAGs (151, 152). Binding of Aβ to GAGs is pH dependent. GAGs bind more strongly at acidic pH and more weakly at pH > 7.0 (153). Watson et al. (154) reported that heparin binds to fibrillar but not nonfibrillar Aβ, suggesting that the heparin–Aβ interaction depends on the conformation and aggregation state of Aβ rather than the primary sequence alone.

PGs may play a role in the aggregation or stabilization of Aβ amyloid. As GAGs can bind to Aβ, the effect of GAGs on Aβ aggregation has been investigated. Sulfated GAGs can enhance the aggregation of Aβ (151). PGs, including perlecan and agrin, can accelerate Aβ fibril formation and maintain the stability of the Aβ fibrils, and their effects on Aβ aggregation are mediated by the GAG chains (141, 155). The sulfate moieties of GAGs are critical for the enhancement of Aβ aggregation. Removal of the O-sulfate from heparin leads to a partial loss of the effect on Aβ aggregation, while complete deletion of sulfate groups results in a complete loss of enhancement of Aβ fibril formation (156). Other GAGs such as Ch4S and DS or the sulfated oligosaccharides, dextran sulfate, and pentosan polysulfate can also promote Aβ aggregation (156, 157). In addition, it has been shown that DS can promote the assembly of Aβ42 into stable fibrils, and DS-induced Aβ fibrils reportedly have little toxicity on neuroblastoma cells in vitro (158). These findings indicate that GAG-mediated neuroprotection is due to the sequestering of Aβ.

PGs may be associated with inhibition of Aβ degradation (139). In vitro studies demonstrate that both HSPGs and CSPGs can block the proteolytic degradation of fibrillar Aβ but not nonfibrillar forms when Aβ is treated with proteases (159), suggesting that PGs have an important role in the accumulation and persistence of amyloid plaques in AD. Moreover, other studies indicate that microglia can take up and degrade plaque-like deposits on culture dishes. However, addition of CSPG inhibits removal of Aβ deposits by microglia (160). These findings suggest that PGs in amyloid plaques may contribute to the resistance of amyloid plaques to degradation.

PGs can bind directly to tau which is the major protein component of NFTs (161). Under physiological conditions in vitro, sulfated GAG heparin can promote assembly of nonphosphorylated recombinant tau to paired helical-like filaments (PHFs) (162, 163). Several studies show that heparin can promote phosphorylation of tau by protein kinases, prevent tau from binding to microtubules, and induce rapid microtubule disassembly in a sulfation-dependent manner (162, 164). In addition, GAGs can induce a conformational change in tau and affect PHF conformation and PHF-tau solubilization (165, 166). These findings suggest that GAGs may be an important factor in the development of the neurofibrillary lesions in AD.

Role of PGs in APP Metabolism

In 1997, Leveugle et al. (167) first reported that heparin could dose-dependently increase BACE1 cleavage of APP in a human neuroblastoma cell line. In contrast, Scholefield et al. (168) reported that HS and heparin could bind to BACE1 and inhibit cleavage of APP in SHSY5Y neuroblastoma cells expressing APP with the Swedish mutation. The inhibitory effect of heparin on BACE1 was reported to be dependent on size and on the structure of the heparin. Scholefield et al. (168) found, in contrast to the results of Leveugle et al. (167), that treatment with heparin could reduce the production of sAPPβ and Aβ but that it had no effect on sAPPα. These findings suggested several possibilities for the role of GAGs in the regulation of BACE1 cleavage of APP. GAGs like HS could bind to BACE1 and thereby prevent the access of APP to the active site of BACE1. Alternatively, as GAGs interact with APP, it is possible that GAG–APP binding could sequester APP away from BACE1 and thereby prevent Aβ generation (169).

The conflict about whether GAGs stimulate or inhibit BACE1 was resolved in studies from our group (170) which showed that low concentrations (1 μg/mL) of heparin can stimulate recombinant human BACE1, while higher concentrations of heparin (10 or 100 μg/mL) inhibit BACE1 activity. Heparin could not activate the mature form (prosequence cleaved) of BACE1, although it interacted strongly with the zymogen form of BACE1 (proBACE1) and bound to a peptide homologous to the N-terminal pro sequence of BACE1 (170). These observations indicate that the prodomain is necessary for the activation effect of heparin on BACE1. Further investigations showed that effect of heparin on proBACE1 is dependent on the size, degree of sulfation, and carboxylation of GAG (171). More recently, our studies have shown that treatment with exogenous heparin or enoxaparin can decrease APP processing to Aβ by decreasing the level of BACE1 (172). These effects of GAGs on APP processing are both size- and sulfation-dependent (173). These findings suggest that it may be possible to design potent and specific GAG derivatives that act specifically to prevent AD-related disorders.

GAGs in AD Therapy

The observations that GAGs bind to tau alter Aβ aggregation and clearance and inhibit production of Aβ suggest that they may have value as therapeutic agents for AD. Several studies have demonstrated that a low molecular weight (LMW) heparin, C3 or neuroparin, may have therapeutic potential for the treatment of AD (174). C3 is composed of 4–10 saccharides (approximately 2.1 kDa) and is derived from heparin by gamma irradiation (174). C3 can penetrate the blood-brain barrier (BBB) and has effects in the CNS (175). Initial studies show that oral or subcutaneous administration of C3 can prevent Aβ25–35-induced appearance of tau-2-immunoreacticity in the hippocampus of rats, suggesting that C3 may have potential to prevent abnormal tau protein formation in AD (176). Further studies in rats indicate that C3 also effectively reduces cholinergic damage induced by a cholinotoxin, AF64A, in a dose- and time-dependent manner (177, 178). In addition, injection of LMW heparin (enoxaparin or dalteparin), LMW anionic sulfonate, or sulfate compounds can arrest inflammation-associated amyloid deposits in mice (179, 180). Chronic subcutaneous administration of certoparin can prevent Aβ25–35-induced abnormal intracellular tau changes and reactive astrocytosis in rats (181).

In APP23 transgenic mice, peripheral administration of enoxaparin can reduce amyloid plaques and the level of Aβ in the brain of the mice (182). Injection of enoxaparin also significantly decreases the number of activated astrocytes surrounding amyloid deposits and reduces the Aβ-induced inflammatory response in the APP23 mouse brain (182). Recent studies demonstrate that administration of enoxaparin can improve cognition in APPswe/PS1dE9 mice and influence Aβ accumulation differently at different stages of amyloid plaque formation (183).

As GAGs can attenuate Aβ-induced inflammation in vitro and in vivo (178, 179, 183), prevent Aβ aggregation (179), lower Aβ generation and improve cognition in vivo (181, 182), and regulate the activity and level of BACE1 (167, 171), it seems logical to consider the possibility that GAGs may have therapeutic value for AD. Moreover, several lines of evidence also indicate that endogenous HS is involved in Aβ uptake by cells (184, 185). LMW GAGs can cross the BBB (174, 186). These observations suggest that GAGs could have multiple benefits for the treatment of AD (Fig. 3). However, further work is clearly needed to establish the value of GAGs for the treatment of AD. In particular, it will be important to establish whether many of the biochemical effects of GAGs that have been observed in cell culture systems can be translated into similar effects in vivo. To achieve sufficiently high levels of GAGs in the brain to obtain these effects will not be easy as the permeability of the BBB to LMW GAGs is poorly understood. Therefore, further studies in this important area seem warranted.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Structure of GAGs
  5. Structure of PG Core Proteins
  6. Function of PGS in the Brain
  7. Role of PGs in AD
  8. Conclusions
  9. References

GAGs and PGs are major components of the cell membrane and ECM of the CNS. PGs and GAGs participate in a variety of functions such as brain development, plasticity, repair, and synaptogenesis. GAGs and PGs also have been reported to be involved in neurodegenerative diseases such as AD. The functions of PGs are dependent on the structure of the GAG chains attached to the core protein. Further investigations are needed to demonstrate the role of GAG structure on brain development and disorders. These investigations may help to answer how PGs function in the brain and may also contribute to the design and development of therapeutic agents for the treatment of neurodegenerative disease such as AD.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Structure of GAGs
  5. Structure of PG Core Proteins
  6. Function of PGS in the Brain
  7. Role of PGs in AD
  8. Conclusions
  9. References
  • 1
    Hardingham, T. E. and Fosang, A. J. ( 1992) Proteoglycans: many forms and many functions. FASEB J. 6, 861870.
  • 2
    Casu, B. ( 1985) Structure and biological activity of heparin. Adv. Carbohydr. Chem. Biochem. 43, 51134.
  • 3
    Hileman, R. E., Fromm, J. R., Weiler, J. M., and Linhardt, R. J. ( 1998) Glycosaminoglycan-protein interactions: definition of consensus sites in glycosaminoglycan binding proteins. Bioessays 20, 156167.
  • 4
    Linhardt, R. J., Ampofo, S. A., Fareed, J., Hoppensteadt, D., Mulliken, J. B., et al. ( 1992) Isolation and characterization of human heparin. Biochemistry 31, 1244112445.
  • 5
    Castillo, G. M., Cummings, J. A., Yang, W., Judge, M. E., Sheardown, M. J., et al. ( 1998) Sulfate content and specific glycosaminoglycan backbone of perlecan are critical for perlecan's enhancement of islet amyloid polypeptide (amylin) fibril formation. Diabetes 47, 612620.
  • 6
    Wedemeyer, J., Tsai, M., and Galli, S. J. ( 2000) Roles of mast cells and basophils in innate and acquired immunity. Curr. Opin. Immunol. 12, 624631.
  • 7
    Lindahl, U., Kusche-Gullberg, M., and Kjellen, L. ( 1998) Regulated diversity of heparan sulfate. J. Biol. Chem. 273, 2497924982.
  • 8
    Silbert, J. E. and Sugumaran, G. ( 2002) Biosynthesis of chondroitin/dermatan sulfate. IUBMB Life 54, 177186.
  • 9
    McDonald, J. A. and Camenisch, T. D. ( 2002) Hyaluronan: genetic insights into the complex biology of a simple polysaccharide. Glycoconj. J. 19, 331339.
  • 10
    Meyer, K., Linker, A., Davidson, E. A., and Weissmann, B. ( 1953) The mucopolysaccharides of bovine cornea. J. Biol. Chem. 205, 611616.
  • 11
    Krusius, T., Finne, J., Margolis, R. K., and Margolis, R. U. ( 1986) Identification of an O-glycosidic mannose-linked sialylated tetrasaccharide and keratan sulfate oligosaccharides in the chondroitin sulfate proteoglycan of brain. J. Biol. Chem. 261, 82378242.
  • 12
    Funderburgh, J. L. ( 2000) Keratan sulfate: structure, biosynthesis, and function. Glycobiology 10, 951958.
  • 13
    Small, D. H., Mok, S. S., Williamson, T. G., and Nurcombe, V. ( 1996) Role of proteoglycans in neural development, regeneration, and the aging brain, J. Neurochem. 67, 889899.
  • 14
    Doege, K. J., Sasaki, M., Kimura, T., and Yamada, Y. ( 1991) Complete coding sequence and deduced primary structure of the human cartilage large aggregating proteoglycan, aggrecan. Human-specific repeats, and additional alternatively spliced forms. J. Biol. Chem. 266, 894902.
  • 15
    Zimmermann, D. R. and Ruoslahti, E. ( 1989) Multiple domains of the large fibroblast proteoglycan. versican, EMBO J. 8, 29752981.
  • 16
    Rauch, U., Karthikeyan, L., Maurel, P., Margolis, R. U., and Margolis, R. K. ( 1992) Cloning and primary structure of neurocan, a developmentally regulated, aggregating chondroitin sulfate proteoglycan of brain. J. Biol. Chem. 267, 1953619547.
  • 17
    Yamada, H., Watanabe, K., Shimonaka, M., and Yamaguchi, Y. ( 1994) Molecular cloning of brevican, a novel brain proteoglycan of the aggrecan/versican family. J. Biol. Chem. 269, 1011910126.
  • 18
    Yamaguchi, Y. ( 2000) Lecticans: organizers of the brain extracellular matrix. Cell. Mol. Life Sci. 57, 276289.
  • 19
    Galtrey, C. M. and Fawcett, J. W. ( 2007) The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. Brain Res. Rev. 54, 118.
  • 20
    Maurel, P., Rauch, U., Flad, M., Margolis, R. K., and Margolis, R. U. ( 1994) Phosphacan, a chondroitin sulfate proteoglycan of brain that interacts with neurons and neural cell-adhesion molecules, is an extracellular variant of a receptor-type protein tyrosine phosphatase. Proc. Natl. Acad. Sci. USA 91, 25122516.
  • 21
    Hocking, A. M., Shinomura, T., and McQuillan, D. J. ( 1998) Leucine-rich repeat glycoproteins of the extracellular matrix. Matrix Biol. 17, 119.
  • 22
    Nishiyama, A., Dahlin, K. J., Prince, J. T., Johnstone, S. R., and Stallcup, W. B. ( 1991) The primary structure of NG2, a novel membrane-spanning proteoglycan. J. Cell Biol. 114, 359371.
  • 23
    Staub, E., Hinzmann, B., and Rosenthal, A. ( 2002) A novel repeat in the melanoma-associated chondroitin sulfate proteoglycan defines a new protein family. FEBS Lett. 527, 114118.
  • 24
    Watanabe, E., Maeda, N., Matsui, F., Kushima, Y., Noda, M., et al. ( 1995) Neuroglycan C, a novel membrane-spanning chondroitin sulfate proteoglycan that is restricted to the brain. J. Biol. Chem. 270, 2687626882.
  • 25
    Aono, S., Keino, H., Ono, T., Yasuda, Y., Tokita, Y., et al. ( 2000) Genomic organization and expression pattern of mouse neuroglycan C in the cerebellar development. J. Biol. Chem. 275, 337342.
  • 26
    Shioi, J., Pangalos, M. N., Ripellino, J. A., Vassilacopoulou, D., Mytilineou, C., et al. ( 1995) The Alzheimer amyloid precursor proteoglycan (appican) is present in brain and is produced by astrocytes but not by neurons in primary neural cultures. J. Biol. Chem. 270, 1183911844.
  • 27
    Pangalos, M. N., Efthimiopoulos, S., Shioi, J., and Robakis, N. K. ( 1995) The chondroitin sulfate attachment site of appican is formed by splicing out exon 15 of the amyloid precursor gene. J. Biol. Chem. 270, 1038810391.
  • 28
    Shioi, J., Anderson, J. P., Ripellino, J. A., and Robakis, N. K. ( 1992) Chondroitin sulfate proteoglycan form of the Alzheimer's beta-amyloid precursor. J. Biol. Chem. 267, 1381913822.
  • 29
    Dreyfuss, J. L., Regatieri, C. V., Jarrouge, T. R., Cavalheiro, R. P., Sampaio, L. O., et al. ( 2009) Heparan sulfate proteoglycans: structure, protein interactions and cell signaling. An. Acad. Bras. Cienc. 81, 409429.
  • 30
    Bernfield, M., Kokenyesi, R., Kato, M., Hinkes, M. T., Spring, J., et al. ( 1992) Biology of the syndecans: a family of transmembrane heparan sulfate proteoglycans. Annu. Rev. Cell Biol. 8, 365393.
  • 31
    Elenius, K. and Jalkanen, M. ( 1994) Function of the syndecans—a family of cell surface proteoglycans. J. Cell Sci. 107 ( Pt 11), 29752982.
  • 32
    David, G. ( 1993) Integral membrane heparan sulfate proteoglycans. FASEB J. 7, 10231030.
  • 33
    Schulz, J. G., Annaert, W., Vandekerckhove, J., Zimmermann, P., De Strooper, B., et al. ( 2003) Syndecan 3 intramembrane proteolysis is presenilin/gamma-secretase-dependent and modulates cytosolic signaling. J. Biol. Chem. 278, 4865148657.
  • 34
    Fitzgerald, M. L., Wang, Z., Park, P. W., Murphy, G., and Bernfield, M. ( 2000) Shedding of syndecan-1 and −4 ectodomains is regulated by multiple signaling pathways and mediated by a TIMP-3-sensitive metalloproteinase. J. Cell Biol. 148, 811824.
  • 35
    Filmus, J., Capurro, M., and Rast, J. ( 2008) Glypicans. Genome Biol. 9, 224.
  • 36
    De Cat, B. and David, G. ( 2001) Developmental roles of the glypicans. Semin. Cell. Dev. Biol. 12, 117125.
  • 37
    De Cat, B., Muyldermans, S. Y., Coomans, C., Degeest, G., Vanderschueren, B., et al. ( 2003) Processing by proprotein convertases is required for glypican-3 modulation of cell survival, Wnt signaling, and gastrulation movements. J. Cell Biol. 163, 625635.
  • 38
    Iozzo, R. V., Cohen, I. R., Grassel, S., and Murdoch, A. D. ( 1994) The biology of perlecan: the multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices. Biochem. J. 302 ( Pt 3), 625639.
  • 39
    Kirn-Safran, C., Farach-Carson, M. C., and Carson, D. D. ( 2009) Multifunctionality of extracellular and cell surface heparan sulfate proteoglycans. Cell. Mol. Life Sci. 66, 34213434.
  • 40
    Winzen, U., Cole, G. J., and Halfter, W. ( 2003) Agrin is a chimeric proteoglycan with the attachment sites for heparan sulfate/chondroitin sulfate located in two multiple serine-glycine clusters. J. Biol. Chem. 278, 3010630114.
  • 41
    Iozzo, R. V. ( 2005) Basement membrane proteoglycans: from cellar to ceiling. Nat. Rev. Mol. Cell. Biol. 6, 646656.
  • 42
    Alliel, P. M., Perin, J. P., Jolles, P., and Bonnet, F. J. ( 1993) Testican, a multidomain testicular proteoglycan resembling modulators of cell social behaviour. Eur. J. Biochem. 214, 347350.
  • 43
    Maeda, N., Ishii, M., Nishimura, K., and Kamimura, K. ( 2011) Functions of chondroitin sulfate and heparan sulfate in the developing brain. Neurochem. Res. 36, 12281240.
  • 44
    Properzi, F. and Fawcett, J. W. ( 2004) Proteoglycans and brain repair. News Physiol. Sci. 19, 3338.
  • 45
    Carulli, D., Laabs, T., Geller, H. M., and Fawcett, J. W. ( 2005) Chondroitin sulfate proteoglycans in neural development and regeneration. Curr. Opin. Neurobiol. 15, 116120.
  • 46
    Meyer-Puttlitz, B., Milev, P., Junker, E., Zimmer, I., Margolis, R. U., et al. ( 1995) Chondroitin sulfate and chondroitin/keratan sulfate proteoglycans of nervous tissue: developmental changes of neurocan and phosphacan. J. Neurochem. 65, 23272337.
  • 47
    Perris, R. and Perissinotto, D. ( 2000) Role of the extracellular matrix during neural crest cell migration. Mech. Dev. 95, 321.
  • 48
    Kubota, Y., Morita, T., Kusakabe, M., Sakakura, T., and Ito, K. ( 1999) Spatial and temporal changes in chondroitin sulfate distribution in the sclerotome play an essential role in the formation of migration patterns of mouse neural crest cells. Dev. Dyn. 214, 5565.
  • 49
    Perissinotto, D., Iacopetti, P., Bellina, I., Doliana, R., Colombatti, A., et al. ( 2000) Avian neural crest cell migration is diversely regulated by the two major hyaluronan-binding proteoglycans PG-M/versican and aggrecan. Development 127, 28232842.
  • 50
    Landolt, R. M., Vaughan, L., Winterhalter, K. H., and Zimmermann, D. R. ( 1995) Versican is selectively expressed in embryonic tissues that act as barriers to neural crest cell migration and axon outgrowth. Development 121, 23032312.
  • 51
    Oakley, R. A. and Tosney, K. W. ( 1991) Peanut agglutinin and chondroitin-6-sulfate are molecular markers for tissues that act as barriers to axon advance in the avian embryo. Dev. Biol. 147, 187206.
  • 52
    Oakley, R. A., Lasky, C. J., Erickson, C. A., and Tosney, K. W. ( 1994) Glycoconjugates mark a transient barrier to neural crest migration in the chicken embryo. Development 120, 103114.
  • 53
    Ring, C., Hassell, J., and Halfter, W. ( 1996) Expression pattern of collagen IX and potential role in the segmentation of the peripheral nervous system. Dev. Biol. 180, 4153.
  • 54
    Snow, D. M., Lemmon, V., Carrino, D. A., Caplan, A. I., and Silver, J. ( 1990) Sulfated proteoglycans in astroglial barriers inhibit neurite outgrowth in vitro. Exp. Neurol. 109, 111130.
  • 55
    Fichard, A., Verna, J. M., Olivares, J., and Saxod, R. ( 1991) Involvement of a chondroitin sulfate proteoglycan in the avoidance of chick epidermis by dorsal root ganglia fibers: a study using beta-D-xyloside. Dev. Biol. 148, 19.
  • 56
    Verna, J. M., Fichard, A., and Saxod, R. ( 1989) Influence of glycosaminoglycans on neurite morphology and outgrowth patterns in vitro. Int. J. Dev. Neurosci. 7, 389399.
  • 57
    Dou, C. L. and Levine, J. M. ( 1994) Inhibition of neurite growth by the NG2 chondroitin sulfate proteoglycan. J. Neurosci. 14, 76167628.
  • 58
    Wang, H., Katagiri, Y., McCann, T. E., Unsworth, E., Goldsmith, P., et al. ( 2008) Chondroitin-4-sulfation negatively regulates axonal guidance and growth. J. Cell Sci. 121, 30833091.
  • 59
    Brittis, P. A., Canning, D. R., and Silver, J. ( 1992) Chondroitin sulfate as a regulator of neuronal patterning in the retina. Science 255, 733736.
  • 60
    Snow, D. M., Watanabe, M., Letourneau, P. C., and Silver, J. ( 1991) A chondroitin sulfate proteoglycan may influence the direction of retinal ganglion cell outgrowth. Development 113, 14731485.
  • 61
    Engel, M., Maurel, P., Margolis, R. U., and Margolis, R. K. ( 1996) Chondroitin sulfate proteoglycans in the developing central nervous system. I. Cellular sites of synthesis of neurocan and phosphacan. J. Comp. Neurol. 366, 3443.
  • 62
    Ida, M., Shuo, T., Hirano, K., Tokita, Y., Nakanishi, K., et al. ( 2006) Identification and functions of chondroitin sulfate in the milieu of neural stem cells. J. Biol. Chem. 281, 59825991.
  • 63
    Ogawa, T., Hagihara, K., Suzuki, M., and Yamaguchi, Y. ( 2001) Brevican in the developing hippocampal fimbria: differential expression in myelinating oligodendrocytes and adult astrocytes suggests a dual role for brevican in central nervous system fiber tract development. J. Comp. Neurol. 432, 285295.
  • 64
    Bekku, Y., Rauch, U., Ninomiya, Y., and Oohashi, T. ( 2009) Brevican distinctively assembles extracellular components at the large diameter nodes of Ranvier in the CNS. J. Neurochem. 108, 12661276.
  • 65
    Holt, C. E. and Dickson, B. J. ( 2005) Sugar codes for axons? Neuron 46, 169172.
  • 66
    Wang, L. and Denburg, J. L. ( 1992) A role for proteoglycans in the guidance of a subset of pioneer axons in cultured embryos of the cockroach. Neuron 8, 701714.
  • 67
    Gurwitz, D. and Cunningham, D. D. ( 1990) Neurite outgrowth activity of protease nexin-1 on neuroblastoma cells requires thrombin inhibition. J. Cell. Physiol. 142, 155162.
  • 68
    Small, D. H., Nurcombe, V., Reed, G., Clarris, H., Moir, R., et al. ( 1994) A heparin-binding domain in the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth. J. Neurosci. 14, 21172127.
  • 69
    Williamson, T. G., Nurcombe, V., Beyreuther, K., Masters, C. L., and Small, D. H. ( 1995) Affinity purification of proteoglycans that bind to the amyloid protein precursor of Alzheimer's disease. J. Neurochem. 65, 22012208.
  • 70
    Bronner-Fraser, M. and Lallier, T. ( 1988) A monoclonal antibody against a laminin-heparan sulfate proteoglycan complex perturbs cranial neural crest migration in vivo. J. Cell Biol. 106, 13211329.
  • 71
    Walicke, P. A. ( 1988) Interactions between basic fibroblast growth factor (FGF) and glycosoaminoglycans in promoting neurite outgrowth. Exp. Neurol. 102, 144148.
  • 72
    Walz, A., McFarlane, S., Brickman, Y. G., Nurcombe, V., Bartlett, P. F., et al. ( 1997) Essential role of heparan sulfates in axon navigation and targeting in the developing visual system. Development 124, 24212430.
  • 73
    Irie, A., Yates, E. A., Turnbull, J. E., and Holt, C. E. ( 2002) Specific heparan sulfate structures involved in retinal axon targeting. Development 129, 6170.
  • 74
    Lee, J. S., von der Hardt, S., Rusch, M. A., Stringer, S. E., Stickney, H. L., et al. ( 2004) Axon sorting in the optic tract requires HSPG synthesis by ext2 (dackel) and extl3 (boxer). Neuron 44, 947960.
  • 75
    Rhiner, C., Gysi, S., Frohli, E., Hengartner, M. O., and Hajnal, A. ( 2005) Syndecan regulates cell migration and axon guidance in C. elegans. Development 132, 46214633.
  • 76
    Habuchi, H., Kobayashi, M., and Kimata, K. ( 1998) Molecular characterization and expression of heparan-sulfate 6-sulfotransferase. Complete cDNA cloning in human and partial cloning in Chinese hamster ovary cells. J. Biol. Chem. 273, 92089213.
  • 77
    Bai, X. and Esko, J. D. ( 1996) An animal cell mutant defective in heparan sulfate hexuronic acid 2-O-sulfation. J. Biol. Chem. 271, 1771117717.
  • 78
    Pratt, T., Conway, C. D., Tian, N. M., Price, D. J., and Mason, J. O. ( 2006) Heparan sulphation patterns generated by specific heparan sulfotransferase enzymes direct distinct aspects of retinal axon guidance at the optic chiasm. J. Neurosci. 26, 69116923.
  • 79
    Rossjohn, J., Cappai, R., Feil, S. C., Henry, A., McKinstry, W. J., et al. ( 1999) Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein. Nat. Struct. Biol. 6, 327331.
  • 80
    Herms, J., Anliker, B., Heber, S., Ring, S., Fuhrmann, M., et al. ( 2004) Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members. EMBO J. 23, 41064115.
  • 81
    Small, D. H., Nurcombe, V., Moir, R., Michaelson, S., Monard, D., et al. ( 1992) Association and release of the amyloid protein precursor of Alzheimer's disease from chick brain extracellular matrix. J. Neurosci. 12, 41434150.
  • 82
    Narindrasorasak, S., Lowery, D., Gonzalez-DeWhitt, P., Poorman, R. A., Greenberg, B., et al. ( 1991) High affinity interactions between the Alzheimer's beta-amyloid precursor proteins and the basement membrane form of heparan sulfate proteoglycan. J. Biol. Chem. 266, 1287812883.
  • 83
    Narindrasorasak, S., Lowery, D. E., Altman, R. A., Gonzalez-DeWhitt, P. A., Greenberg, B. D., et al. ( 1992) Characterization of high affinity binding between laminin and Alzheimer's disease amyloid precursor proteins. Lab. Invest. 67, 643652.
  • 84
    Schubert, D., LaCorbiere, M., Saitoh, T., and Cole, G. ( 1989) Characterization of an amyloid beta precursor protein that binds heparin and contains tyrosine sulfate. Proc Natl Acad Sci USA 86, 20662069.
  • 85
    Schubert, D., Jin, L. W., Saitoh, T., and Cole, G. ( 1989) The regulation of amyloid beta protein precursor secretion and its modulatory role in cell adhesion. Neuron 3, 689694.
  • 86
    Clarris, H. J., Cappai, R., Heffernan, D., Beyreuther, K., Masters, C. L., et al. ( 1997) Identification of heparin-binding domains in the amyloid precursor protein of Alzheimer's disease by deletion mutagenesis and peptide mapping. J. Neurochem. 68, 11641172.
  • 87
    Mok, S. S., Sberna, G., Heffernan, D., Cappai, R., Galatis, D., et al. ( 1997) Expression and analysis of heparin-binding regions of the amyloid precursor protein of Alzheimer's disease. FEBS Lett. 415, 303307.
  • 88
    Williamson, T. G., Mok, S. S., Henry, A., Cappai, R., Lander, A. D., et al. ( 1996) Secreted glypican binds to the amyloid precursor protein of Alzheimer's disease (APP) and inhibits APP-induced neurite outgrowth. J. Biol. Chem. 271, 3121531221.
  • 89
    Ford-Perriss, M., Turner, K., Guimond, S., Apedaile, A., Haubeck, H. D., et al. ( 2003) Localisation of specific heparan sulfate proteoglycans during the proliferative phase of brain development. Dev. Dyn. 227, 170184.
  • 90
    McLaughlin, D., Karlsson, F., Tian, N., Pratt, T., Bullock, S. L., et al. ( 2003) Specific modification of heparan sulphate is required for normal cerebral cortical development. Mech. Dev. 120, 14811488.
  • 91
    Nitkin, R. M., Smith, M. A., Magill, C., Fallon, J. R., Yao, Y. M., et al. ( 1987) Identification of agrin, a synaptic organizing protein from Torpedo electric organ. J. Cell Biol. 105, 24712478.
  • 92
    Reist, N. E., Magill, C., and McMahan, U. J. ( 1987) Agrin-like molecules at synaptic sites in normal, denervated, and damaged skeletal muscles. J. Cell Biol. 105, 24572469.
  • 93
    Herbst, R. and Burden, S. J. ( 2000) The juxtamembrane region of MuSK has a critical role in agrin-mediated signaling. EMBO J. 19, 6777.
  • 94
    Ferreira, A. ( 1999) Abnormal synapse formation in agrin-depleted hippocampal neurons. J. Cell Sci. 112 ( Pt 24), 47294738.
  • 95
    Bose, C. M., Qiu, D., Bergamaschi, A., Gravante, B., Bossi, M., et al. ( 2000) Agrin controls synaptic differentiation in hippocampal neurons. J. Neurosci. 20, 90869095.
  • 96
    Gingras, J., Rassadi, S., Cooper, E., and Ferns, M. ( 2002) Agrin plays an organizing role in the formation of sympathetic synapses. J. Cell. Biol. 158, 11091118.
  • 97
    Ksiazek, I., Burkhardt, C., Lin, S., Seddik, R., Maj, M., et al. ( 2007) Synapse loss in cortex of agrin-deficient mice after genetic rescue of perinatal death. J. Neurosci. 27, 71837195.
  • 98
    Tournell, C. E., Bergstrom, R. A., and Ferreira, A. ( 2006) Progesterone-induced agrin expression in astrocytes modulates glia-neuron interactions leading to synapse formation. Neuroscience 141, 13271338.
  • 99
    Lin, Y. L., Lei, Y. T., Hong, C. J., and Hsueh, Y. P. ( 2007) Syndecan-2 induces filopodia and dendritic spine formation via the neurofibromin-PKA-Ena/VASP pathway. J. Cell Biol. 177, 829841.
  • 100
    Berardi, N., Pizzorusso, T., and Maffei, L. ( 2000) Critical periods during sensory development. Curr. Opin. Neurobiol. 10, 138145.
  • 101
    Deepa, S. S., Carulli, D., Galtrey, C., Rhodes, K., Fukuda, J., et al. ( 2006) Composition of perineuronal net extracellular matrix in rat brain: a different disaccharide composition for the net-associated proteoglycans. J. Biol. Chem. 281, 1778917800.
  • 102
    Kwok, J. C., Carulli, D., and Fawcett, J. W. ( 2010) In vitro modeling of perineuronal nets: hyaluronan synthase and link protein are necessary for their formation and integrity. J. Neurochem. 114, 14471459.
  • 103
    Wang, D. and Fawcett, J. ( 2012) The perineuronal net and the control of CNS plasticity. Cell Tissue Res. 349, 147160.
  • 104
    Pizzorusso, T., Medini, P., Berardi, N., Chierzi, S., Fawcett, J. W., et al. ( 2002) Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298, 12481251.
  • 105
    McRae, P. A., Rocco, M. M., Kelly, G., Brumberg, J. C., and Matthews, R. T. ( 2007) Sensory deprivation alters aggrecan and perineuronal net expression in the mouse barrel cortex. J. Neurosci. 27, 54055413.
  • 106
    Bukalo, O., Schachner, M., and Dityatev, A. ( 2001) Modification of extracellular matrix by enzymatic removal of chondroitin sulfate and by lack of tenascin-R differentially affects several forms of synaptic plasticity in the hippocampus. Neuroscience 104, 359369.
  • 107
    Zhou, X. H., Brakebusch, C., Matthies, H., Oohashi, T., Hirsch, E., et al. ( 2001) Neurocan is dispensable for brain development. Mol. Cell. Biol. 21, 59705978.
  • 108
    Brakebusch, C., Seidenbecher, C. I., Asztely, F., Rauch, U., Matthies, H., et al. ( 2002) Brevican-deficient mice display impaired hippocampal CA1 long-term potentiation but show no obvious deficits in learning and memory. Mol. Cell. Biol. 22, 74177427.
  • 109
    Rolls, A., Shechter, R., and Schwartz, M. ( 2009) The bright side of the glial scar in CNS repair. Nat. Rev. Neurosci. 10, 235241.
  • 110
    Davies, S. J., Goucher, D. R., Doller, C., and Silver, J. ( 1999) Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J. Neurosci. 19, 58105822.
  • 111
    Asher, R. A., Morgenstern, D. A., Moon, L. D., and Fawcett, J. W. ( 2001) Chondroitin sulphate proteoglycans: inhibitory components of the glial scar. Prog. Brain Res. 132, 611619.
  • 112
    Levine, J. M. ( 1994) Increased expression of the NG2 chondroitin-sulfate proteoglycan after brain injury. J. Neurosci. 14, 47164730.
  • 113
    Harris, N. G., Carmichael, S. T., Hovda, D. A., and Sutton, R. L. ( 2009) Traumatic brain injury results in disparate regions of chondroitin sulfate proteoglycan expression that are temporally limited. J. Neurosci. Res. 87, 29372950.
  • 114
    McKeon, R. J., Hoke, A., and Silver, J. ( 1995) Injury-induced proteoglycans inhibit the potential for laminin-mediated axon growth on astrocytic scars. Exp. Neurol. 136, 3243.
  • 115
    Smith-Thomas, L. C., Stevens, J., Fok-Seang, J., Faissner, A., Rogers, J. H., et al. ( 1995) Increased axon regeneration in astrocytes grown in the presence of proteoglycan synthesis inhibitors. J. Cell Sci. 108 ( Pt 3), 13071315.
  • 116
    Moon, L. D., Asher, R. A., Rhodes, K. E., and Fawcett, J. W. ( 2001) Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nat. Neurosci. 4, 465466.
  • 117
    Bradbury, E. J., Moon, L. D., Popat, R. J., King, V. R., Bennett, G. S., et al. ( 2002) Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636640.
  • 118
    Yick, L. W., Cheung, P. T., So, K. F., and Wu, W. ( 2003) Axonal regeneration of Clarke's neurons beyond the spinal cord injury scar after treatment with chondroitinase ABC. Exp. Neurol. 182, 160168.
  • 119
    Moon, L. D., Asher, R. A., Rhodes, K. E., and Fawcett, J. W. ( 2002) Relationship between sprouting axons, proteoglycans and glial cells following unilateral nigrostriatal axotomy in the adult rat. Neuroscience 109, 101117.
  • 120
    Iseki, K., Hagino, S., Mori, T., Zhang, Y., Yokoya, S., et al. ( 2002) Increased syndecan expression by pleiotrophin and FGF receptor-expressing astrocytes in injured brain tissue. Glia 39, 19.
  • 121
    Hagino, S., Iseki, K., Mori, T., Zhang, Y., Sakai, N., et al. ( 2003) Expression pattern of glypican-1 mRNA after brain injury in mice. Neurosci. Lett. 349, 2932.
  • 122
    Properzi, F., Lin, R., Kwok, J., Naidu, M., van Kuppevelt, T. H., et al. ( 2008) Heparan sulphate proteoglycans in glia and in the normal and injured CNS: expression of sulphotransferases and changes in sulphation. Eur. J. Neurosci. 27, 593604.
  • 123
    Leadbeater, W. E., Gonzalez, A. M., Logaras, N., Berry, M., Turnbull, J. E., et al. ( 2006) Intracellular trafficking in neurones and glia of fibroblast growth factor-2, fibroblast growth factor receptor 1 and heparan sulphate proteoglycans in the injured adult rat cerebral cortex. J. Neurochem. 96, 11891200.
  • 124
    Hilton, B. J., Lang, B. T., and Cregg, J. M. ( 2012) Keratan sulfate proteoglycans in plasticity and recovery after spinal cord injury. J. Neurosci. 32, 43314333.
  • 125
    Ito, Z., Sakamoto, K., Imagama, S., Matsuyama, Y., Zhang, H., et al. ( 2010) N-acetylglucosamine 6-O-sulfotransferase-1-deficient mice show better functional recovery after spinal cord injury. J. Neurosci. 30, 59375947.
  • 126
    Imagama, S., Sakamoto, K., Tauchi, R., Shinjo, R., Ohgomori, T., et al. ( 2011) Keratan sulfate restricts neural plasticity after spinal cord injury. J. Neurosci. 31, 1709117102.
  • 127
    Ferri, C. P., Prince, M., Brayne, C., Brodaty, H., Fratiglioni, L., et al. ( 2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366, 21122117.
  • 128
    Kidd, M. ( 1964) Alzheimer's Disease—an electron microscopical study. Brain 87, 307320.
  • 129
    Terry, R. D., Gonatas, N. K., and Weiss, M. ( 1964) Ultrastructural studies in Alzheimer's presenile dementia. Am. J. Pathol. 44, 269297.
  • 130
    Glenner, G. G. and Wong, C. W. ( 1984) Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120, 885890.
  • 131
    Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., et al. ( 1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. USA 82, 42454249.
  • 132
    Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. M., Masters, C. L., et al. ( 1987) The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733736.
  • 133
    Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., et al. ( 1999) Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286, 735741.
  • 134
    Haass, C., Schlossmacher, M. G., Hung, A. Y., Vigo-Pelfrey, C., Mellon, A., et al. ( 1992) Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359, 322325.
  • 135
    Snow, A. D., Mar, H., Nochlin, D., Kimata, K., Kato, M., et al. ( 1988) The presence of heparan sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer's disease. Am. J. Pathol. 133, 456463.
  • 136
    Snow, A. D., Mar, H., Nochlin, D., Sekiguchi, R. T., Kimata, K., et al. ( 1990) Early accumulation of heparan sulfate in neurons and in the beta-amyloid protein-containing lesions of Alzheimer's disease and Down's syndrome. Am. J. Pathol. 137, 12531270.
  • 137
    Su, J. H., Cummings, B. J., and Cotman, C. W. ( 1992) Localization of heparan sulfate glycosaminoglycan and proteoglycan core protein in aged brain and Alzheimer's disease. Neuroscience 51, 801813.
  • 138
    Perlmutter, L. S., Chui, H. C., Saperia, D., and Athanikar, J. ( 1990) Microangiopathy and the colocalization of heparan sulfate proteoglycan with amyloid in senile plaques of Alzheimer's disease. Brain Res. 508, 1319.
  • 139
    Snow, A. D., Sekiguchi, R. T., Nochlin, D., Kalaria, R. N., and Kimata, K. ( 1994) Heparan sulfate proteoglycan in diffuse plaques of hippocampus but not of cerebellum in Alzheimer's disease brain. Am. J. Pathol. 144, 337347.
  • 140
    Verbeek, M. M., Otte-Holler, I., van den Born, J., van den Heuvel, L. P., David, G., et al. ( 1999) Agrin is a major heparan sulfate proteoglycan accumulating in Alzheimer's disease brain. Am. J. Pathol. 155, 21152125.
  • 141
    Cotman, S. L., Halfter, W., and Cole, G. J. ( 2000) Agrin binds to beta-amyloid (Abeta), accelerates abeta fibril formation, and is localized to Abeta deposits in Alzheimer's disease brain. Mol. Cell. Neurosci. 15, 183198.
  • 142
    O'Callaghan, P., Sandwall, E., Li, J. P., Yu, H., Ravid, R., et al. ( 2008) Heparan sulfate accumulation with Abeta deposits in Alzheimer's disease and Tg2576 mice is contributed by glial cells. Brain Pathol. 18, 548561.
  • 143
    DeWitt, D. A., Silver, J., Canning, D. R., and Perry, G. ( 1993) Chondroitin sulfate proteoglycans are associated with the lesions of Alzheimer's disease. Exp. Neurol. 121, 149152.
  • 144
    Snow, A. D., Mar, H., Nochlin, D., Kresse, H., and Wight, T. N. ( 1992) Peripheral distribution of dermatan sulfate proteoglycans (decorin) in amyloid-containing plaques and their presence in neurofibrillary tangles of Alzheimer's disease. J. Histochem. Cytochem. 40, 105113.
  • 145
    van Horssen, J., Otte-Holler, I., David, G., Maat-Schieman, M. L., van den Heuvel, L. P., et al. ( 2001) Heparan sulfate proteoglycan expression in cerebrovascular amyloid beta deposits in Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis (Dutch) brains. Acta Neuropathol. 102, 604614.
  • 146
    van Horssen, J., Wilhelmus, M. M., Heljasvaara, R., Pihlajaniemi, T., Wesseling, P., et al. ( 2002) Collagen XVIII: a novel heparan sulfate proteoglycan associated with vascular amyloid depositions and senile plaques in Alzheimer's disease brains. Brain Pathol. 12, 456462.
  • 147
    Shimizu, H., Ghazizadeh, M., Sato, S., Oguro, T., and Kawanami, O. ( 2009) Interaction between beta-amyloid protein and heparan sulfate proteoglycans from the cerebral capillary basement membrane in Alzheimer's disease. J. Clin. Neurosci. 16, 277282.
  • 148
    Miller, J. D., Cummings, J., Maresh, G. A., Walker, D. G., Castillo, G. M., et al. ( 1997) Localization of perlecan (or a perlecan-related macromolecule) to isolated microglia in vitro and to microglia/macrophages following infusion of beta-amyloid protein into rodent hippocampus. Glia 21, 228243.
  • 149
    Buee, L., Ding, W., Delacourte, A., and Fillit, H. ( 1993) Binding of secreted human neuroblastoma proteoglycans to the Alzheimer's amyloid A4 peptide. Brain Res. 601, 154163.
  • 150
    Buee, L., Ding, W., Anderson, J. P., Narindrasorasak, S., Kisilevsky, R., et al. ( 1993) Binding of vascular heparan sulfate proteoglycan to Alzheimer's amyloid precursor protein is mediated in part by the N-terminal region of A4 peptide. Brain Res. 627, 199204.
  • 151
    Fraser, P. E., Nguyen, J. T., Chin, D. T., and Kirschner, D. A. ( 1992) Effects of sulfate ions on Alzheimer beta/A4 peptide assemblies: implications for amyloid fibril-proteoglycan interactions. J. Neurochem. 59, 15311540.
  • 152
    McLaurin, J. and Fraser, P. E. ( 2000) Effect of amino-acid substitutions on Alzheimer's amyloid-beta peptide-glycosaminoglycan interactions. Eur. J. Biochem. 267, 63536361.
  • 153
    Brunden, K. R., Richter-Cook, N. J., Chaturvedi, N., and Frederickson, R. C. ( 1993) pH-dependent binding of synthetic beta-amyloid peptides to glycosaminoglycans. J. Neurochem. 61, 21472154.
  • 154
    Watson, D. J., Lander, A. D., and Selkoe, D. J. ( 1997) Heparin-binding properties of the amyloidogenic peptides Abeta and amylin. Dependence on aggregation state and inhibition by Congo red. J. Biol. Chem. 272, 3161731624.
  • 155
    Castillo, G. M., Ngo, C., Cummings, J., Wight, T. N., and Snow, A. D. ( 1997) Perlecan binds to the beta-amyloid proteins (A beta) of Alzheimer's disease, accelerates A beta fibril formation, and maintains A beta fibril stability. J. Neurochem. 69, 24522465.
  • 156
    Castillo, G. M., Lukito, W., Wight, T. N., and Snow, A. D. ( 1999) The sulfate moieties of glycosaminoglycans are critical for the enhancement of beta-amyloid protein fibril formation. J. Neurochem. 72, 16811687.
  • 157
    Fraser, P. E., Darabie, A. A., and McLaurin, J. A. ( 2001) Amyloid-beta interactions with chondroitin sulfate-derived monosaccharides and disaccharides. Implications for drug development. J. Biol. Chem. 276, 64126419.
  • 158
    Bravo, R., Arimon, M., Valle-Delgado, J. J., Garcia, R., Durany, N., et al. ( 2008) Sulfated polysaccharides promote the assembly of amyloid beta(1–42) peptide into stable fibrils of reduced cytotoxicity. J. Biol. Chem. 283, 3247132483.
  • 159
    Gupta-Bansal, R., Frederickson, R. C., and Brunden, K. R. ( 1995) Proteoglycan-mediated inhibition of A beta proteolysis. A potential cause of senile plaque accumulation. J. Biol. Chem. 270, 1866618671.
  • 160
    Shaffer, L. M., Dority, M. D., Gupta-Bansal, R., Frederickson, R. C., Younkin, S. G., et al. ( 1995) Amyloid beta protein (A beta) removal by neuroglial cells in culture. Neurobiol. Aging 16, 737745.
  • 161
    Delacourte, A. and Defossez, A. ( 1986) Alzheimer's disease: tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments. J. Neurol. Sci. 76, 173186.
  • 162
    Goedert, M., Jakes, R., Spillantini, M. G., Hasegawa, M., Smith, M. J., et al. ( 1996) Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383, 550553.
  • 163
    Perez, M., Valpuesta, J. M., Medina, M., Montejo de Garcini, E., and Avila, J. ( 1996) Polymerization of tau into filaments in the presence of heparin: the minimal sequence required for tau-tau interaction. J. Neurochem. 67, 11831190.
  • 164
    Hasegawa, M., Crowther, R. A., Jakes, R., and Goedert, M. ( 1997) Alzheimer-like changes in microtubule-associated protein Tau induced by sulfated glycosaminoglycans. Inhibition of microtubule binding, stimulation of phosphorylation, and filament assembly depend on the degree of sulfation. J. Biol. Chem. 272, 3311833124.
  • 165
    Hernandez, F., Perez, M., Lucas, J. J., and Avila, J. ( 2002) Sulfo-glycosaminoglycan content affects PHF-tau solubility and allows the identification of different types of PHFs. Brain Res. 935, 6572.
  • 166
    Paudel, H. K. and Li, W. ( 1999) Heparin-induced conformational change in microtubule-associated protein Tau as detected by chemical cross-linking and phosphopeptide mapping. J. Biol. Chem. 274, 80298038.
  • 167
    Leveugle, B., Ding, W., Durkin, J. T., Mistretta, S., Eisle, J., et al. ( 1997) Heparin promotes beta-secretase cleavage of the Alzheimer's amyloid precursor protein. Neurochem. Int. 30, 543548.
  • 168
    Scholefield, Z., Yates, E. A., Wayne, G., Amour, A., McDowell, W., et al. ( 2003) Heparan sulfate regulates amyloid precursor protein processing by BACE1, the Alzheimer's beta-secretase. J. Cell Biol. 163, 97107.
  • 169
    Patey, S. J., Yates, E. A., and Turnbull, J. E. ( 2005) Novel heparan sulphate analogues: inhibition of beta-secretase cleavage of amyloid precursor protein. Biochem. Soc. Trans. 33, 11161118.
  • 170
    Beckman, M., Holsinger, R. M., and Small, D. H. ( 2006) Heparin activates beta-secretase (BACE1) of Alzheimer's disease and increases autocatalysis of the enzyme. Biochemistry 45, 67036714.
  • 171
    Klaver, D. W., Wilce, M. C., Gasperini, R., Freeman, C., Juliano, J. P., et al. ( 2010) Glycosaminoglycan-induced activation of the beta-secretase (BACE1) of Alzheimer's disease. J. Neurochem. 112, 15521561.
  • 172
    Cui, H., Hung, A. C., Klaver, D. W., Suzuki, T., Freeman, C., et al. ( 2011) Effects of heparin and enoxaparin on APP processing and Abeta production in primary cortical neurons from Tg2576 mice. PLoS One 6, e23007.
  • 173
    Cui, H., Hung, A. C., Freeman, C., Narkowicz, C., Jacobson, G. A., et al. ( 2012) Size and sulfation are critical for the effect of heparin on APP processing and Abeta production. J Neurochem. 123, 447457.
  • 174
    Dudas, B., Rose, M., Cornelli, U., Pavlovich, A., and Hanin, I. ( 2008) Neuroprotective properties of glycosaminoglycans: potential treatment for neurodegenerative disorders. Neurodegener. Dis. 5, 200205.
  • 175
    Ma, Q., Dudas, B., Hejna, M., Cornelli, U., Lee, J. M., et al. ( 2002) The blood-brain barrier accessibility of a heparin-derived oligosaccharides C3. Thromb. Res. 105, 447453.
  • 176
    Dudas, B., Cornelli, U., Lee, J. M., Hejna, M. J., Walzer, M., et al. ( 2002) Oral and subcutaneous administration of the glycosaminoglycan C3 attenuates Abeta(25–35)-induced abnormal tau protein immunoreactivity in rat brain. Neurobiol. Aging 23, 97104.
  • 177
    Rose, M., Dudas, B., Cornelli, U., and Hanin, I. ( 2003) Protective effect of the heparin-derived oligosaccharide C3, on AF64A-induced cholinergic lesion in rats. Neurobiol. Aging 24, 481490.
  • 178
    Rose, M., Dudas, B., Cornelli, U., and Hanin, I. ( 2004) Glycosaminoglycan C3 protects against AF64A-induced cholinotoxicity in a dose-dependent and time-dependent manner. Brain Res. 1015, 96102.
  • 179
    Zhu, H., Yu, J., and Kindy, M. S. ( 2001) Inhibition of amyloidosis using low-molecular-weight heparins. Mol. Med. 7, 517522.
  • 180
    Kisilevsky, R., Lemieux, L. J., Fraser, P. E., Kong, X., Hultin, P. G., et al. ( 1995) Arresting amyloidosis in vivo using small-molecule anionic sulphonates or sulphates: implications for Alzheimer's disease. Nat. Med. 1, 143148.
  • 181
    Walzer, M., Lorens, S., Hejna, M., Fareed, J., Hanin, I., et al. ( 2002) Low molecular weight glycosaminoglycan blockade of beta-amyloid induced neuropathology. Eur. J. Pharmacol. 445, 211220.
  • 182
    Bergamaschini, L., Rossi, E., Storini, C., Pizzimenti, S., Distaso, M., et al. ( 2004) Peripheral treatment with enoxaparin, a low molecular weight heparin, reduces plaques and beta-amyloid accumulation in a mouse model of Alzheimer's disease. J. Neurosci. 24, 41814186.
  • 183
    Timmer, N. M., van Dijk, L., van der Zee, C. E., Kiliaan, A., de Waal, R. M., et al. ( 2010) Enoxaparin treatment administered at both early and late stages of amyloid beta deposition improves cognition of APPswe/PS1dE9 mice with differential effects on brain A beta levels. Neurobiol. Dis. 40, 340347.
  • 184
    Bergamaschini, L., Donarini, C., Rossi, E., De Luigi, A., Vergani, C., et al. ( 2002) Heparin attenuates cytotoxic and inflammatory activity of Alzheimer amyloid-beta in vitro. Neurobiol. Aging 23, 531536.
  • 185
    Sandwall, E., O'Callaghan, P., Zhang, X., Lindahl, U., Lannfelt, L., et al. ( 2010) Heparan sulfate mediates amyloid-beta internalization and cytotoxicity. Glycobiology 20, 533541.
  • 186
    Kanekiyo, T., Zhang, J., Liu, Q., Liu, C. C., Zhang, L., et al. ( 2011) Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake. J. Neurosci. 31, 16441651.
  • 187
    Leveugle, B., Ding, W., Laurence, F., Dehouck, M. P., Scanameo, A., et al. ( 1998) Heparin oligosaccharides that pass the blood-brain barrier inhibit beta-amyloid precursor protein secretion and heparin binding to beta-amyloid peptide. J. Neurochem. 70, 736744.