Activation of α-secretase cleavage


Address correspondence and reprint requests to Rolf Postina, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University Mainz, Johann-Joachim-Becherweg 30, 55128 Mainz, Germany. E-mail:


J. Neurochem. (2012) 120 (Suppl. 1), 46–54.


Alpha-secretase-mediated cleavage of the amyloid precursor protein (APP) releases the neuroprotective APP fragment sαAPP and prevents amyloid β peptide (Aβ) generation. Moreover, α-secretase-like cleavage of the Aβ transporter ‘receptor for advanced glycation end products’ counteracts the import of blood Aβ into the brain. Assuming that Aβ is responsible for the development of Alzheimer’s disease (AD), activation of α-secretase should be preventive. α-Secretase-mediated APP cleavage can be activated via several G protein-coupled receptors and receptor tyrosine kinases. Protein kinase C, mitogen-activated protein kinases, phosphatidylinositol 3-kinase, cAMP and calcium are activators of receptor-induced α-secretase cleavage. Selective targeting of receptor subtypes expressed in brain regions affected by AD appears reasonable. Therefore, the PACAP receptor PAC1 and possibly the serotonin 5-HT6 receptor subtype are promising targets. Activation of APP α-secretase cleavage also occurs upon blockade of cholesterol synthesis by statins or zaragozic acid A. Under physiological statin concentrations, the brain cholesterol content is not influenced. Statins likely inhibit Aβ production in the blood by α-secretase activation which is possibly sufficient to inhibit AD development. A disintegrin and metalloproteinase 10 (ADAM10) acts as α-secretase on APP. By targeting the nuclear retinoic acid receptor β, the expression of ADAM10 and non-amyloidogenic APP processing can be enhanced. Excessive activation of ADAM10 should be avoided because ADAM10 and also ADAM17 are not APP-specific. Both ADAM proteins cleave various substrates, and therefore have been associated with tumorigenesis and tumor progression.

Abbreviations used



Alzheimer′s disease


A disintegrin and metalloproteinase


amyloid precursor protein


blood–brain barrier




epidermal growth factor


exchange protein activated by cAMP


endoplasmic reticulum


extracellular signal-regulated kinase


G protein-coupled receptor


muscarinic actetylcholine receptor




pituitary adenylate cyclase-activating polypeptide


phosphatidylinositol 3-kinase


protein kinase C


phospholipase C


retinoic acid


receptor for advanced glycation end products


reversion-inducing cysteine-rich protein with Kazal motifs


receptor tyrosine kinase


alpha-secretase-released APP ectodomain


Nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1


tissue inhibitor of metalloproteinases

Oligomeric and aggregated amyloid β peptides (Aβ) are hallmarks of neurodegenerative disorders including Alzheimer′s disease (AD). The amyloid precursor protein (APP) serves as a source of neurotoxic Aβ when proteolytically processed by β-secretase BACE1 and γ-secretase complex. However, APP is also a substrate for α-secretase cleaving within the Aβ peptide region. α-Secretase-mediated cleavage of APP is neuroprotective for two reasons: the soluble α-secretase released APP ectodomain (sαAPP) possesses neurotrophic and neuroprotective properties and formation of toxic Aβ is prevented. A decrease in α-secretase-mediated APP processing may contribute to the development of AD, because lower levels of soluble APP were detected in the CSF of AD patients (Lannfelt et al. 1995; Sennvik et al. 2000).

In relation to AD development, α-secretase-like cleavage of receptor for advanced glycation end products (RAGE) is of additional interest. RAGE has been identified as Aβ transporter importing circulating blood Aβ across the blood–brain barrier into the brain (Mackic et al. 1998; Deane et al. 2003). Shedding of RAGE releases the Aβ binding domain and has been demonstrated to be mediated by A disintegrin and metalloproteinase 10 (ADAM10) and MMP9 (Zhang et al. 2008). Thus, the import of Aβ peptides into the brain should be prevented following RAGE shedding. Considering this, strategies to increase α-secretase-mediated processing of APP and RAGE may have therapeutic values for the treatment of Alzheimer’s disease. Today, strongest evidence is provided for the proteinase ADAM10 to conduct α-secretase-mediated APP and RAGE processing.

The identification of ADAM10 as sheddase for APP and other cell surface proteins is reviewed in another contribution of this issue and will therefore not be discussed here. However, the readers should keep in mind that a strong and widespread activation of α-secretase appears unfavorable because processing of substrates like epidermal growth factor (EGF) ligands, may promote tumor growth (Horiuchi et al. 2007). When compensating the age-related slight loss of α-secretase activity, a well-balanced activation may be tolerated. For the treatment of AD, the spatial activation of α-secretase in affected brain areas seems desirable. In this review, I will discuss approaches for activation of the α-secretase ADAM10 and also strategies leading to increased α-secretase-mediated APP processing.

Introductory remarks to ADAM10

The metalloproteinase ADAM10 is expressed as a catalytically inactive precursor where the prodomain acts as an intrinsic inhibitor. Removal of the prodomain by furin-like proprotein convertases in the trans Golgi network results in activation of ADAM10 (Anders et al. 2001). After translocation to the cell surface, ADAM10 activity is controlled by endogenous inhibitors including tissue inhibitor of metalloproteinases-3 (TIMP-3) (Baker et al. 2002) and reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) (Muraguchi et al. 2007). In addition, the transport, maturation and activation of ADAM10 might be controlled by scaffolding proteins including tetraspanins (Yanez-Mo et al. 2011). Each of these steps is involved in regulation of mature ADAM10 bioavailability and presumably pharmacological intervention is possible at all these levels (Fig. 1).

Figure 1.

 The metalloproteinase ADAM10 cleaves APP and RAGE. Substrate cleavage is regulated at several levels. ADAM10 expression can be enhanced via the track: all trans-retinoic acid (RA), SIRT1 and resveratrol. ADAM10 activity is blocked by the endogenous inhibitors TIMP-1, TIMP-3 and RECK. Substrate conversion by ADAM10 is inhibited by high cholesterol levels and is enhanced under conditions of higher membrane fluidity. Cleavage of APP can be induced via several cell surface receptors and their signal transduction pathways. However, it is unclear whether this directly affects ADAM10 activity. Ectodomain shedding also seems to be regulated by scaffolding proteins such as tetraspanins and perhaps GPCRs. GPCR, G protein-coupled receptor; RTK, receptor tyrosine kinase; PKC, protein kinase C, MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase.

Modulation of ADAM10 gene transcription

In the ADAM10 promoter, Sp1, upstream stimulating factors (USF) and retinoic acid (RA)-responsive elements regulate ADAM10 expression (Prinzen et al. 2005). The ubiquitous transcription factors Sp1 and USF are absolutely essential for ADAM10 expression (Prinzen et al. 2005) and are also involved in regulation of APP expression (Kovacs et al. 1995; Querfurth et al. 1999). RA is an activator of ADAM10 gene transcription (Prinzen et al. 2005).

A multitude of transcription factor binding sites is always present in promoters of mammalian genes. Therefore, specific up-regulation of selected genes is challenging. However, about 4% of proven drugs target nuclear receptors and modulate gene expressions (Hopkins and Groom 2002), hence this strategy may also work in the treatment of AD. Insulin has been shown to activate Sp1 by inducing O-glycosylation and phosphorylation (Majumdar et al. 2006) and insulin-mediated up-regulation of fatty acid synthase requires binding of USF1 and USF2 transcription factors (Wang and Sul 1997). Epidemiological studies revealed a link between type 2 diabetes mellitus and an increased risk of developing AD. Altered insulin signaling may result in an imbalance of AD-related gene expression.

A direct and positive effect on AD pathology was shown following activation of RA nuclear receptors. Activation of ADAM10 gene transcription was achieved by acitretin, a drug used for treatment of psoriasis. Acitretin releases all-trans RA by interacting with the RA-binding protein; RA then activates nuclear RA receptors and ADAM10 gene expression. Intracerebral injection of acitretin reduced Aβ production in APP transgenic mice (Tippmann et al. 2009). In these experiments, acitretin likely promoted APP α-secretase cleavage.

The transcription factor RA receptor β, responsible for increasing ADAM10 expression, is regulated by nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1 (SIRT1). In APP-transgenic mice, over-expression of SIRT1 in the brain resulted in increased deacetylation of the RA receptor β, activation of ADAM10 transcription, diminished Aβ plaque formation and improved learning (Donmez et al. 2010). Caloric restriction resulting in induction of SIRT1 has been shown to attenuate Aβ brain amyloidosis in monkeys (Qin et al. 2006). Enzymatic activation of SIRT1 can be achieved by the red wine compound resveratrol and a resveratrol-enriched diet has reduced plaque pathology in an APP-transgenic AD mouse model (Karuppagounder et al. 2009). Resveratrol and other polyphenolic stilbenoid compounds have a wide range of neuroprotective properties (Richard et al. 2011) which in part may be mediated by transcriptional α-secretase activation.

Manipulation of ADAM10 translation, intracellular trafficking and maturation

Protein expression of the α-secretase ADAM10 is suppressed by the 444 nucleotides-comprising 5′-untranslated region of the ADAM10-mRNA. Deletion of the first half of ADAM10s 5′-untranslated region prevents mRNA secondary structure formation and enhances α-secretase activity in HEK 293 cells (Lammich et al. 2010). In primary hepatocellular carcinoma cells, the liver-specific microRNA-122 (miR-122) represses ADAM10 expression (Bai et al. 2009). It is unknown whether ADAM10 expression is controlled in other tissues by different miRNAs. Increasing ADAM10 expression by knocking down inhibitory miRNAs using the RNA interference technology is possible in cultured cells. However, we are far away from its application in humans.

The intracellular C-terminus of the ADAM10 protein contains a triple arginine repeat that serves as an endoplasmic reticulum (ER) retention signal. Mutagenesis of the middle arginine to alanine allowed trafficking of ADAM10 to the cell surface. SAP97, an identified C-terminal ADAM10 interaction partner was unable to modulate ER export of ADAM10 (Marcello et al. 2010). This suggests that other proteins are involved in regulation of the intracellular ADAM10 transport. Masking the ER-retention motive of ADAM10 or application of competing cell-penetrating peptides should allow ADAM10 to exit from the ER leading to increased α-secretase activity at the cell surface.

During passage through the trans-Golgi network, the prodomain of ADAM10 is cleaved off by proprotein convertases (Anders et al. 2001). It has been demonstrated that the prodomain of ADAM10 binds with high affinity to mature ADAM10 and inhibits its activity. This inhibitory effect seems to be unique for ADAM10 because the ADAM17 prodomain does not function in a similar way on mature ADAM17, and the ADAM10 prodomain also did not inhibit other ADAMs (Moss et al. 2007). Masking of the released ADAM10 prodomain should result in increased ADAM10 activity and is possibly achievable by immunization against the ADAM10 prodomain.

By a currently unknown mechanism, tetraspanin 12 enhances the maturation of ADAM10 leading to increased α-secretase cleavage of APP (Xu et al. 2009). Furthermore, an association of ADAM10 and tetraspanin 28 (CD81) has been demonstrated to regulate shedding of TNF-α and EGF (Arduise et al. 2008).

Tetraspanins comprise a family of proteins having four transmembrane domains. The N- and C-terminus as well as a loop are located in the cytosol and two loops are located extracellularly. In humans, 33 different structurally related tetraspanins are expressed and they are expected to serve as scaffolding platforms organizing compartmentalization of membrane proteins. Tetraspanins not only interact with ADAMs they are also recruiting ADAM substrates such as cell adhesion molecules and EGFR ligand proforms (Yanez-Mo et al. 2009). Association of tetraspanin 28 with the orphan heterotrimeric G protein-coupled receptor, GPR56, has also been demonstrated (Little et al. 2004). As activation of G protein-coupled receptors (GPCR) leads to increased α-secretase-mediated processing of APP and other ADAM substrates in many cases, modulation of tetraspanin networks via GPCRs is conceivable.

Regulation of α-secretase by endogenous inhibitory proteins

TIMP-1 and TIMP-3 as well as RECK are endogenous inhibitors of ADAM10 and matrix-metalloproteinases. While TIMPs are secreted proteins, RECK is membrane-anchored by a glycosylphosphatidylinositol moiety.

In the mouse brain, RECK acts as a physiological inhibitor of ADAM10 regulating Notch signaling during cortical neurogenesis (Muraguchi et al. 2007). In the plasma membrane RECK and ADAM10 are mainly located in different microenvironments. As a glycosylphosphatidylinositol-anchored protein, RECK prefers cholesterol-rich domains whereas ADAM10 is located in cholesterol-poor phospholipid regions. This spatial separation of enzyme and inhibitor should be neutralized by reducing the cholesterol content of the plasma membrane and thus, ADAM10 should be inhibited more effectively by RECK. However, the opposite effect was observed: because of an increased expression of ADAM10, lovastatin-induced cholesterol depletion resulted in increased α-secretase cleavage of APP (Kojro et al. 2010).

Regulation of α-secretase by cell surface receptors

Distinct G protein-coupled receptors modulate either α-, β- or γ-secretase-mediated processing of APP; for a recent review see (Thathiah and De Strooper 2011).

In most cases, GPCR activation results in increased APP processing by α-secretase enzymatic activity. In some rare cases, by using either a selective inhibitor or expression analysis, the observed effects were attributed to either ADAM10 (Kojro et al. 2006) or ADAM17 (Caccamo et al. 2006). Critically viewed, the connection of GPCR activation and ADAM proteins has not been investigated to the necessary extent. Whereas the ADAM10 activity has been shown to be inducible via Ca2+ (Le Gall et al. 2009), ADAM17 can be stimulated by Ca2+ and phorbol esters (Horiuchi et al. 2007). Thus, by stimulation of GPCRs ADAM10 and/or ADAM17 activities can likely be induced. It is known that GPCR-induced activation of protein kinase C (PKC) (Buxbaum et al. 1992; Nitsch et al. 1992), mitogen-activated protein kinase and phosphatidylinositol 3-kinase (PI3K) (Kojro et al. 2006) stimulates non-amyloidogenic APP processing. Furthermore, cyclic AMP signaling can modulate APP processing by α-secretase (Robert et al. 2001). As stimulation of the serotonin 5-HT4 receptor induces shedding of APP by α-secretase in a cyclic AMP-dependent but protein kinase A-independent way, the exchange protein activated by cAMP (EPAC) could be involved in that process. It was found that EPAC-mediated activation of Rap1 regulates secretion of sαAPP (Maillet et al. 2003).

EPAC also modulates intracellular Ca2+ levels via different mechanisms including Rap2-mediated activation of phospholipase C-ε and opening of ryanodine receptor calcium channels in the endoplasmatic reticulum (Holz et al. 2006). Calcium has been demonstrated to be a key regulator of α-secretase ADAM10-mediated shedding of EGF receptor ligands (Horiuchi et al. 2007), chemokines (Hundhausen et al. 2007) and adhesion molecules (Schulz et al. 2008).

The C-terminus of ADAM10 is required for calcium induction of ADAM10 activity (Horiuchi et al. 2007). A putative PKC phosphorylation site and SH3 domains in the ADAM10 C-terminus are possibly involved in shedding activation (Ohtsu et al. 2006). Activation of most PKC isoforms requires Ca2+; however, there is no experimental evidence that the ADAM10 C-terminus is phosphorylated by PKC. The activity of ADAM17, another α-secretase candidate, has been shown to be regulated by extracellular signal-regulated kinase (ERK)-mediated phosphorylation (Diaz-Rodriguez et al. 2002). Thus, GPCR-induced phosphorylation of ADAM proteins may regulate APP processing.

Despite the unknown mechanism of GPCR-induced α-secretase processing of APP, its effectiveness in cellular and animal models suggests a therapeutic value for AD treatment. In AD, several GPCR-dependent neurotransmitter systems are impaired including cholinergic and neuropeptide signaling (Schliebs and Arendt 2006; Wu et al. 2006). Muscarinic actetylcholine receptors (mAChR) were first examples for GPCR-induced α-secretase activation. About 20 years ago, it was observed that carbachol induced, in a protein kinase-dependent way, the release of APP derivatives by activation of M1 and M3 muscarinic receptor subtypes (Nitsch et al. 1992). Deficiency of the M1 mAChR in a transgenic AD mouse model causes a decrease in α-secretase released sαAPP and an increase of amyloidogenic APP processing. Transgenic expression of the M1 mAChR on the M1 mAChR knock-out background rescued the observed phenotype, indicating that endogenous activation of the M1 mAChR is sufficient to shift APP processing towards the non-amyloidogenic route (Davis et al. 2010). As the M1 mAChR is expressed in the hippocampus and the cortex, areas affected by the AD pathology, its activation may counteract progression of AD. However, clinical studies with unselective muscarinic agonists but also with selective M1 agonists were discontinued due to a variety of intolerable side-effects (e.g. hypotension, sweating, bronchoconstriction).

Metabotropic glutamate receptor 1α stimulation has been described to increase the amount of secreted APP (Lee et al. 1995). However, recently it was shown that stimulation of group I metabotropic glutamate receptors with the selective agonist 3,5-dihydroxyphenylglycine stimulates both α- and β-secretase-mediated APP processing (Kim et al. 2010). Thus, it is questionable whether these GPCRs can be selectively modulated for α-secretase stimulation.

5-Hydroxytryptamine (5-HT), also known as serotonin, is a neurotransmitter of the gastrointestinal tract and of the CNS. Reduced levels of serotonin are causative for the development of depression in humans and a high percentage of AD patients suffers from depression. Fourteen different serotonin receptor subtypes, most of them GPCRs, are known to mediate the biological function of 5-HT. Stimulation of phospholipase C-coupled serotonin 5-HT2a and 5-HT2c receptors (Nitsch et al. 1996) enhances secretion of soluble APP. In addition, stimulation of the 5-HT4 receptor, which couples to adenylate cyclase, also induces shedding of APP by α-secretase in a cyclic AMP-dependent way (Robert et al. 2001; Cachard-Chastel et al. 2007). Among the 5-HT receptor subtypes, the 5-HT6 receptor is primarily specific for the CNS with strongest expression in the caudate nucleus and the hippocampus (Kohen et al. 1996). The effect of 5-HT6 receptor activation on APP processing has not been investigated so far. As the 5-HT6 receptor is also positively coupled to adenylate cyclase activation, a similar effect as described above for the 5-HT4 receptor subtype is conceivable. Modulation of 5-HT6 receptors influences several neurotransmitter levels. Although activation via specific agonists increases the GABA concentration in the brain (Schechter et al. 2008), the antagonistic blockade of 5-HT6 increases hippocampal levels of glutamate and norepinephrine (Dawson et al. 2001). The expression of the 5-HT6 receptor in the prefrontal cortex of AD patients was found to be decreased by 40% (Lorke et al. 2006). Therefore, for the treatment of AD, the agonistic stimulation of 5-HT6 receptors may compensate for the loss of reduced receptor levels. In rats treated with 5-HT6 receptor agonists, antidepressant and anxiolytic effects have been observed (Carr et al. 2011). Depressions and anxiety also occur in AD, and therefore, independent from its putative α-secretase-modulating activity, 5-HT6 receptor activation possibly affects behavior of AD patients.

Serotonin uptake inhibitors such as Escitalopram are used for the treatment of depressions. Perhaps these compounds will shift APP processing towards the non-amyloidogenic route by prolonging 5-HT receptor activation.

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has neurotrophic properties and modulates learning and memory (Uchida et al. 1996; Vaudry et al. 2009). In several AD transgenic mouse models as well as in the human AD temporal cortex, the expression of PACAP is down-regulated (Wu et al. 2006). From different PACAP receptor subtypes, the PAC1 receptor is predominantly expressed in the CNS (Spengler et al. 1993). Activation of the PAC1 receptor with either PACAP-27 or PACAP-38 had no effect on the expression of APP and putative α-secretases ADAM10 and ADAM17 but strongly induced α-secretase cleavage of APP (Kojro et al. 2006). By using specific protein kinase inhibitors, it was further shown that the extracellular-regulated kinases ERK1 and ERK2 and phosphatidylinositol 3-kinase mediate PACAP-induced α-secretase activation.

In therapeutic applications, the disadvantages of large neuropeptides such as PACAP are instability in blood and poor blood–brain barrier (BBB) penetration. However, the BBB and systemic side effects of drug action can be bypassed by intranasal administration of drugs (Born et al. 2002; Hanson and Frey 2007). By using this approach, the impact of PACAP on APP processing and gene expression was analyzed in an AD mouse model (Rat et al. 2011). In the brain of PACAP-treated mice, the amount of sαAPP was significantly increased suggesting α-secretase activation. The expression of the brain-derived neurotrophic factor, the anti-apoptotic Bcl-2 protein and the Aβ-degrading enzyme neprilysin were increased. Interestingly, the expression of endogenous PACAP and PAC1 receptors was also increased in PACAP-treated mice. The latter observation is of particular importance since it suggests that impaired PACAP/PAC1 signaling, as observed in AD brains, can be regenerated by intranasal PACAP delivery. In PACAP-treated mice, the expression of Aβ transporter RAGE was found to be decreased. PACAP also improved cognitive functions in treated mice. All these data suggest that PACAP exerts neuroprotective effects in multiple ways, including via activation of α-secretase-mediated APP processing.

GABA is an inhibitory neurotransmitter in the CNS and in the spinal cord. The biological action of GABA is mediated by two different receptor types: GABAA receptors (ion channels) and GABAB receptors (GPCRs). Activation of GABAA receptors leads to influx of Cl into neurons. Several studies showed a link between GABAA receptor signaling and protection against Aβ–mediated neurotoxicity (Louzada et al. 2004; Lee et al. 2005). Etazolate, an allosteric activator of the GABAA receptor, activates α-secretase processing of APP in rat cortical neurons and in guinea pig brains (Marcade et al. 2008). A clinical phase II trial with etazolate has been completed, but results have not been communicated yet.

Some direct links between AD and type 2 diabetes mellitus have been described and impaired insulin signaling has been implicated in AD development, for review see (Kojro and Postina 2009). Insulin-induced PI3K signaling stimulates α-secretase-mediated APP processing (Solano et al. 2000). The shedding of Klotho, another ADAM10 substrate, is also inducible via insulin (Chen et al. 2007). Memory enhancing properties of intranasal-applied insulin have been described in AD patients (Reger et al. 2008; Stein et al. 2011). PI3K activity can be induced via GPCRs and receptor tyrosine kinases such as the insulin receptor. Furthermore, the activity of PI3K is up-regulated by calcium calmodulin binding (Joyal et al. 1997). Thus, it is possible that calcium signaling is the main regulator of α-secretase activation.

Activation of α-secretase by protein kinase C

Protein kinase C (PKC) is a known activator of α-secretase (Hung et al. 1993). Classical PKC isoforms are activated by the second messenger molecules Ca2+ and diacylglycerol (DAG) which are generated via phospholipase C (PLC). PLCβ is an effector in GPCR signaling and PLCγ is linked to receptor tyrosine kinase (RTK) signaling. Therefore, PKC can be activated via GPCRs and RTKs.

Independently from receptor-mediated activation, PKC can also be induced by DAG-mimetics such as phorbol 12,13-dibutyrate or phorbol 12-myristate 13-acetate. Both compounds were found to induce α-secretase-mediated cleavage of APP (Hung et al. 1993). However, because of their tumor growth-promoting properties, they are not suitable as therapeutic agents. Another class of PKC activators, the bryostatins, inhibit tumor growth and are potential anti-cancer drugs.

Bryostatins comprise a family of marine natural macrocyclic polyketides which are able to occupy the DAG binding motive of PKC (Pettit et al. 1982). Bryostatin-1 was shown to affect behavior and cognition in rats (Sun and Alkon 2005). In an AD mouse, Bryostatin-1 significantly increased the amount of sαAPP and reduced Aβ peptide levels (Etcheberrigaray et al. 2004). The beneficial effect of Bryostatin-1 in AD mice was attributed to PKCε activation (Hongpaisan et al. 2011). PKCε belongs to the class of novel PKCs which are Ca2+-independent but require DAG or Bryostatin for translocation to the cell membrane.

Bryostatin-1 is currently being tested in various clinical cancer studies, and a clinical trial for AD is in preparation ( Following intravenous infusion, a low concentration of Bryostatin-1 passes the BBB (Zhang et al. 1996). For the treatment of AD, the availability of this α-secretase activator in the brain should be improved.

Activation of α-secretase by blockade of cholesterol biosynthesis

Biochemical and epidemiological studies reveal a link between cholesterol levels, Aβ production, and the development of AD. In several clinical studies, increased cholesterol levels were found in the blood of AD patients (Lehtonen and Luutonen 1986; Czech et al. 1994; Jarvik et al. 1995). Based on the relationship between cholesterol and AD, it was hypothesized that cholesterol-lowering drugs such as HMG-CoA reductase inhibitors have therapeutic potential in the prevention and treatment of AD.

Statin treatment activates α-secretase-mediated APP cleavage and reduces Aβ peptide levels (Fassbender et al. 2001; Kojro et al. 2001). In animal studies, it was shown that a cholesterol-rich diet accelerates Aβ deposition in the brain and the opposite effect was observed following treatment with cholesterol-lowering drugs (Refolo et al. 2000; Sparks et al. 2000; Fassbender et al. 2001). Statins influence both, cholesterol biosynthesis and protein isoprenylation. Recently, it was demonstrated that specific blockade of cholesterol synthesis by a squalene synthase inhibitor is sufficient for α-secretase activation (Kojro et al. 2010). The effect of cholesterol depletion on activation of α-secretase-mediated APP processing can mechanistically be explained by increased membrane fluidity and impaired internalization of APP (Kojro et al. 2001). In accordance with this, it was shown that increasing membrane fluidity by unsaturated free fatty acids increases ADAM-mediated substrate cleavage but does not activate ADAM enzymatic activity directly (Reiss et al. 2011). Thus, the higher rate of substrate cleavage appears to be caused by a more frequent colocalization of membrane-bound proteinase and substrate.

Activation of APP α-secretase cleavage by blockade of cholesterol synthesis requires a strong reduction of the cellular cholesterol level. The statin concentrations used for reduction of high blood cholesterol in humans do not modify the brain cholesterol content and therefore, most likely, do not modulate APP processing in the brain. Amyloidogenic, as well as non-amyloidogenic APP processing is by far not restricted to the brain and occurs throughout the body. Therefore, Aβ is also present in blood. In aged monkeys, blood-derived Aβ was found in brain AD lesions, indicating that circulating Aβ crosses the BBB (Mackic et al. 2002) via RAGE (Deane et al. 2003). Reduction of Aβ production in the blood by activation of α-secretase via reduction of cholesterol is likely sufficient for treating AD.


According to the amyloid hypothesis, increased amounts of Aβ peptides contribute to the development of AD (Hardy and Selkoe 2002). Aβ peptides are generated in the amyloidogenic pathway of APP processing by sequential proteolysis by β- and γ-secretases. In the alternative non-amyloidogenic APP processing pathway, α-secretase cleaves within the Aβ peptide-region and prevents generation of Aβ. Increasing the α-secretase-mediated processing of APP is therefore a therapeutic option for the treatment of AD. Non-amyloidogenic APP processing is inducible by activation of various cell surface-located receptors including GPCRs, RTKs and ion channels. Receptor-induced PKC, mitogen-activated protein kinases, PI3 kinase and calcium signaling have been shown to contribute to α-secretase activation. Since various substrates have been assigned to α-secretase-like cleavage events, putative side-effects of α-secretase activators should be considered. Activation of α-secretase cleavage should ideally occur in brain areas affected in AD. This is possibly achievable by targeting of locally expressed receptors such as the 5-HT6 or PAC1 receptor.


I thank Drs Elzbieta Kojro and Gerald Gimpl for critically reading and commenting on the manuscript.

Conflict of interest

The author declares no conflict of interests.