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Keywords:

  • Alzheimer's disease;
  • cholesterol;
  • amyloid β-protein;
  • tau;
  • apolipoportein E;
  • GM1 ganglioside;
  • raft;
  • Niemann-Pick type C disease

Abstract

  1. Top of page
  2. Abstract
  3. CHOLESTEROL METABOLISM IN CNS
  4. CHOLESTEROL AND GENETIC RISK FACTORS FOR AD
  5. CHOLESTEROL AND AGING
  6. EPIDEMIOLOGICAL ASPECTS ON ASSOCIATION BETWEEN CHOLESTEROL AND AD
  7. Aβ CASCADE AND CHOLESTEROL
  8. TAUOPATHY AND CHOLESTEROL
  9. REFERENCES

Fundamental questions on the pathogenesis of Alzheimer's disease (AD) are how nontoxic, soluble amyloid β-protein (Aβ) is converted to its toxic, aggregated form and how functional tau is hyperphosphorylated to form neurofibrillary tangles. Growing evidence from recent biochemical and cell biological studies suggests that altered cholesterol metabolism in neurons may underlie such pathological processes. The possibility that cholesterol is a risk factor in the development of AD has also been supported by recent epidemiological studies. Based on this line of evidence, it is noteworthy to examine the potency of cholesterol-lowering medicine and/or diet in suppressing the development or the progression of AD. © 2002 Wiley-Liss, Inc.


CHOLESTEROL METABOLISM IN CNS

  1. Top of page
  2. Abstract
  3. CHOLESTEROL METABOLISM IN CNS
  4. CHOLESTEROL AND GENETIC RISK FACTORS FOR AD
  5. CHOLESTEROL AND AGING
  6. EPIDEMIOLOGICAL ASPECTS ON ASSOCIATION BETWEEN CHOLESTEROL AND AD
  7. Aβ CASCADE AND CHOLESTEROL
  8. TAUOPATHY AND CHOLESTEROL
  9. REFERENCES

The central nervous system (CNS) is very unique compared with other peripheral organs in regard to cholesterol metabolism and cholesterol requirements (Dietschy and Turley, 2001) for the following reasons: First, the CNS, which accounts for only 2% of the entire body mass, is very rich in cholesterol; i.e., about 25% of the total amount of unesterified cholesterol in the entire body is contained in the CNS. Second, the CNS is considered to be isolated from blood and other organs by a blood-brain barrier and it can obtain cholesterol via de novo synthesis. Thus, it is likely that cholesterol in the CNS is actively turned over among neurons and glial cells via apolipoproteins and their receptors. Third, cholesterol plays an essential role in synaptic plasticity (Koudinov and Koudinova, 2001; Mauch et al., 2001), one of the neuron-specific biological functions. However, notably, cholesterol unlike other major membrane lipids cannot be synthesized at neuronal terminals (Vance et al., 1994). Thus, it is likely that synaptic function depends on whether cholesterol is fully supplied from exogenous sources, i.e., uptake via lipoprotein receptors, and from endogenous sources, i.e., transport via axonal flow.

CHOLESTEROL AND GENETIC RISK FACTORS FOR AD

  1. Top of page
  2. Abstract
  3. CHOLESTEROL METABOLISM IN CNS
  4. CHOLESTEROL AND GENETIC RISK FACTORS FOR AD
  5. CHOLESTEROL AND AGING
  6. EPIDEMIOLOGICAL ASPECTS ON ASSOCIATION BETWEEN CHOLESTEROL AND AD
  7. Aβ CASCADE AND CHOLESTEROL
  8. TAUOPATHY AND CHOLESTEROL
  9. REFERENCES

To date, a number of genetic polymorphisms have been reported to be possibly related to the development of Alzheimer's disease (AD) as risk factors. Interestingly, they include a number of genes encoding proteins that are directly involved in the regulation of lipid metabolism: apolipoprotein E (APOE) is a representative gene that is a risk factor of AD (Strittmatter et al., 1993; Corder et al., 1993; Saunders et al., 1993; Poirier et al., 1993). Apolipoprotein E (apoE) is a major apolipoprotein in the CNS and plays a pivotal role in cholesterol redistribution in the CNS. Since the observation of a high frequency of one of the APOE alleles, ϵ4, in AD patients, apoE has attracted considerable attention. A great deal of effort has been made to clarify the pathogenic effect of one of the isoforms of apoE, apoE4, a gene product of the APOE allele ϵ4; however, it remains to be determined how these lipid-associated genes, including APOE, accelerate the pathogenesis of AD. We attempted to address this issue from the viewpoint of apoE-related regulation of cholesterol metabolism in the CNS. Previously, based on the finding that apoE4 causes neuronal apoptosis when endogenous cholesterol synthesis is suppressed, we hypothesized that the pathogenic effects of apoE were closely associated with its isoform-specific regulation of cholesterol metabolism of neurons (Michikawa and Yanagisawa, 1998). We subsequently investigated the possibility of apoE-isoform-specific regulation of cholesterol metabolism of neurons using culture systems and found that apoE induced the efflux of lipids, including cholesterol, from cultured neurons and actrocytes in an isoform-specific manner (Michikawa et al., 2000). Furthermore, we recently observed, in human APOE (APOE ϵ3 and APOE ϵ4) knock-in mice that the distribution of cholesterol in synaptic plasma membranes varies with the genotype of APOE: the level of cholesterol in the exofacial leaflet of the synaptic plasma membranes prepared from APOE ϵ4 knock-in mice increased approximately twofold compared with that from APOE ϵ3 knock-in mice (Hayashi et al., 2002). These lines of evidence suggest that apoE modulates the distribution and metabolism of cholesterol in neuronal membranes in an isoform-dependent manner, which may be relevant to apoE-related pathogenic effects on the development of AD.

CHOLESTEROL AND AGING

  1. Top of page
  2. Abstract
  3. CHOLESTEROL METABOLISM IN CNS
  4. CHOLESTEROL AND GENETIC RISK FACTORS FOR AD
  5. CHOLESTEROL AND AGING
  6. EPIDEMIOLOGICAL ASPECTS ON ASSOCIATION BETWEEN CHOLESTEROL AND AD
  7. Aβ CASCADE AND CHOLESTEROL
  8. TAUOPATHY AND CHOLESTEROL
  9. REFERENCES

Aging of the brain is the strongest risk factor in the development of AD. It remains to be determined how aging enhances the pathological processes of AD. In regard to cholesterol metabolism, it is generally accepted that endogenous synthesis of cholesterol decreases with age in various organs including the nervous system (Popplewell and Azhar, 1987; Goodrum, 1990; Stahlberg et al., 1991; Canedella and Shi, 1994). Thus, it is likely that neuronal viability depends on the exogenous supply of cholesterol via lipoprotein receptors with age. It is also noteworthy to observe an increase in the level of cholesterol in the exofacial leaflet of synaptic plasma membranes in aged mice (Igbavboa et al., 1996). Thus, it seems reasonable to assume that the effect of aging on the development of AD is associated with the alteration of cholesterol metabolism in later stages of life.

EPIDEMIOLOGICAL ASPECTS ON ASSOCIATION BETWEEN CHOLESTEROL AND AD

  1. Top of page
  2. Abstract
  3. CHOLESTEROL METABOLISM IN CNS
  4. CHOLESTEROL AND GENETIC RISK FACTORS FOR AD
  5. CHOLESTEROL AND AGING
  6. EPIDEMIOLOGICAL ASPECTS ON ASSOCIATION BETWEEN CHOLESTEROL AND AD
  7. Aβ CASCADE AND CHOLESTEROL
  8. TAUOPATHY AND CHOLESTEROL
  9. REFERENCES

Since the relationship between the possession of the APOE ϵ4 allele and the prevalence of AD has been widely confirmed in various ethnic groups, the question of whether cholesterol metabolism is altered in patients with AD has been the focus of AD research. Jarvik et al. (1995) addressed this issue and they found that the potency of APOE ϵ4 allele in inducing the development of AD is dependent on age, sex, and the level of serum total cholesterol (TC): affected men with higher a level of serum TC and age under 80 years old had the highest frequency of the APOE ϵ4 allele. Hofman et al. (1997) investigated the prevalence of dementia including AD in relation to atherosclerosis for which hypercholesterolemia is an important risk factorThey found that all indicators of atherosclerosis were associated with AD (odds ratios 1.3–1.8) and vascular dementia (VD; odds ratios 1.9–3.2). Their results suggested that AD and VD have common risk factors, including hypercholesterolemia. Results of a longitudinal study of Notkola et al. (1998) suggested that elevation of the serum TC level in midlife can be a risk factor in the development of late-life AD. Kivipelto et al. (2001) also performed a similar study and concluded that there was a relationship between midlife hypercholesterolemia and the development of late-life mild cognitive impairment (MCI), a putative preclinical stage of AD (Kivipelto et al., 2001). In regard to the temporal profile of the serum TC level, Jarvik et al. (1995) and Notkola et al. (1998) reported that the serum TC level decreased after the individuals developed AD. In contrast, Lesser et al. (2001) reported that the levels of serum TC and low-density lipoprotein cholesterol in very old patients with AD were significantly higher than those of controls. It is generally accepted that serum TC levels are dependent on age, sex, and the APOE genotype. Evans et al. (2000) attempted to clarify the relationship between serum TC levels and the APOE genotype in individuals who developed AD. They found in their population-based study of elderly African Americans that elevation of serum TC levels was associated with the prevalence of AD in the non-APOE ϵ4-carrier group, whereas it was not associated with the prevalence of AD in the group carrying the APOE ϵ4 allele.

Recently, retrospective epidemiological studies have suggested that the use of a cholesterol-lowering drug potentially suppresses the development of AD (Wolozin et al., 2000; Jick et al., 2000). Wolozin et al. (2000) attempted to determine whether there would be lower prevalence of AD among individuals taking 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), which inhibit endogenous cholesterol synthesis, than among those who did not take the drug. They concluded that the use of statins, including lovastatin and pravastatin, potentially suppresses the development of AD. The results of these studies reveal that the development of AD could be safely suppressed using common medicines.

Aβ CASCADE AND CHOLESTEROL

  1. Top of page
  2. Abstract
  3. CHOLESTEROL METABOLISM IN CNS
  4. CHOLESTEROL AND GENETIC RISK FACTORS FOR AD
  5. CHOLESTEROL AND AGING
  6. EPIDEMIOLOGICAL ASPECTS ON ASSOCIATION BETWEEN CHOLESTEROL AND AD
  7. Aβ CASCADE AND CHOLESTEROL
  8. TAUOPATHY AND CHOLESTEROL
  9. REFERENCES

Aβ Generation and Cholesterol

It was previously suggested that processing of the amyloid precursor protein (APP) is modulated by the alteration in the cellular cholesterol level (Bodovitz and Klein, 1996; Racchi et al., 1997). Recently, growing evidence suggests that the generation of Aβ decreased with substantial suppression of de novo cholesterol synthesis (Simons et al., 1998). In regard to the molecular mechanism underlying cholesterol-dependent modulation in Aβ generation, one possibility is that β-cleavage of APP is directly affected by the alteration in cholesterol levels in neuronal membranes (Frears et al., 1999; Fassbender et al., 2001), and an alternative explanation is that intracellular trafficking of APP is shifted from the Aβ-generating pathway to the Aβ-nongenerating (nonamyloidogenic) pathway (Kojro et al., 2001). Recently, it has been also suggested that activity of acyl-coenzyme A (ACAT) regulates Aβ generation (Puglielli et al., 2001).

Aβ Aggregation and Cholesterol

The molecular mechanism underlying pathological aggregation of Aβ in an AD brain remains to be determined. In the case of familial AD, the generation of responsible genes is likely to enhance Aβ aggregation via increased generation of Aβ. However, no evidence of altered Aβ generation in sporadic AD, a major form of the disease, has been provided. Thus, it is reasonable to assume that Aβ aggregation in sporadic AD may be induced by an as yet unknown post-translational modification of Aβ and/or by an altered clearance mechanism. On this subject, we previously hypothesized that Aβ starts to be aggregated in the brain via its binding to a glycolipid molecule, GM1 ganglioside (Yanagisawa et al., 1995). Based on the unique molecular characteristics of the GM1 ganglioside-bound Aβ (GM1-Aβ), including its extremely high aggregation potential and altered immunoreactivity, we consider that Aβ adopts an altered conformation via binding to GM1 and accelerates aggregation of soluble Aβ by acting as a seed (Yanagisawa et al., 1995; Yanagisawa and Ihara, 1998). Recently, we attempted to clarify the molecular mechanism underlying generation of GM1-Aβ and found that the binding of Aβ to GM1 was markedly accelerated in a cholesterol-rich environment (Kakio et al., 2001). Furthermore, our study also suggested that cholesterol-dependent formation of GM1-Aβ is due to the formation of a GM1 “cluster” in membranes rich in cholesterol, and that soluble Aβ recognizes the GM1 “cluster” as a chemical receptor and binds to it (Kakio et al., 2001). Previously, it was reported that Aβ initially accumulated in the fractions with a lipid composition similar to that of lipid rafts in an animal model of AD (Sawamura et al., 2000). Furthermore, cholesterol-associated aggregation of Aβ was also observed in cultured cells, mimicking impaired cholesterol trafficking in Niemann-Pick type C disease (NPC), a genetic disorder of cholesterol trafficking (Yamazaki et al., 2001). Taken together with the results of previous in vitro studies (Mizuno et al., 1999; Yip et al., 2001), it is highly likely that membrane lipids, including cholesterol and ganglioside, are highly involved in the aggregation of soluble Aβ in AD brains.

Serum Cholesterol and Aβ Deposition in the Brain

The relationship between the degree of deposition of Aβ or formation of neuritic plaques in human brains and the serum cholesterol level has recently been investigated. Kuo et al. (1998) investigated the levels of cholesterol in the sera obtained postmortem and reported the following: first, a significant increase in the level of LDL cholesterol and a significant decrease in the level of HDL cholesterol in the serum of AD patients were observed. Second, the levels of serum TC and LDL cholesterol were positively correlated to the level of Aβ42, but not to that of Aβ40. In contrast, Launer et al. (2001) found a positive correlation between the level of late-life HDL cholesterol and the number of neocortical neuritic plaques. These inconsistent findings remain to be clarified in future studies.

In Vivo Experimental Studies on Aβ Generation and Deposition

The report by Sparks et al. (1994) was the first to suggest that a high-cholesterol diet potentially enhances the accumulation of Aβ in the brain. This possibility has been supported by recent observation. Refolo et al. (2000) reported that diet-induced hypercholesterolemia resulted in an increased level of deposition of Aβ in the brains of APP transgenic mice, with a positive correlation between the level of deposited Aβ and those of both plasma and CNS TC. Alternatively, Mori et al. (2001) recently reported that cholesterol was abnormally accumulated in mature but not in diffuse or immature plaques in human and APP transgenic mouse brains and suggested that cholesterol may play a role in the formation and progression of senile plaques. It is generally believed that cholesterol input into the CNS originates almost entirely from in situ synthesis of cholesterol; however, these lines of evidence may raise the possibility that cholesterol can be transferred from the plasma to the CNS.

TAUOPATHY AND CHOLESTEROL

  1. Top of page
  2. Abstract
  3. CHOLESTEROL METABOLISM IN CNS
  4. CHOLESTEROL AND GENETIC RISK FACTORS FOR AD
  5. CHOLESTEROL AND AGING
  6. EPIDEMIOLOGICAL ASPECTS ON ASSOCIATION BETWEEN CHOLESTEROL AND AD
  7. Aβ CASCADE AND CHOLESTEROL
  8. TAUOPATHY AND CHOLESTEROL
  9. REFERENCES

Phosphorylation of tau is a fundamental step in the formation of neurofibrillary tangle (NFT); however, little is known about the mechanism underlying accelerated phosphorylation of tau in an AD brain. It was reported that the brains of patients with NPC showed NFT formation (Auer et al., 1995; Suzuki et al., 1995). This finding led us to investigate in more detail the phosphorylation state of tau in NPC mutant mice and we found that tau in these mice was hyperphosphorylated in a site-specific manner, accompanied by activation of mitogen-activated protein kinase (MAPK; Sawamura et al., 2001). Taken together with a recent autopsy study, which showed accumulation of free cholesterol in tangle-bearing neurons (Distl et al., 2001), one may conclude that phosphorylation of tau is accelerated by the increase in the level of intracellular cholesterol. However, we also previously found that depletion of cholesterol from cultured neurons induced hyperphosphorylation of tau (Fan et al., 2001). Thus, phosphorylation of tau may not be dependent on the increase in the total amount of cellular cholesterol but rather on the alteration of an unknown intracellular signaling which is closely associated with the cellular cholesterol metabolism. In this context, it is noteworthy that aggregated or oligomeric Aβ, which is most likely generated before NFT formation, affects cholesterol metabolism of neurons (Liu et al., 1998; Michikawa et al., 2001). Recently we reported that oligomeric but not monomeric Aβ promotes cholesterol release from neuronal membranes (Michikawa et al., 2001). Notably, the oligomeric Aβ-associated lipid particle, unlike apoE-containing HDL, cannot be internalized into neurons, suggesting that cholesterol homeostasis of neurons exposed to oligomeric or aggregated Aβ for a long period of time is disrupted by the substantial loss of cholesterol from their surface.

Conclusions

Considerable attention has been focused in the past few years on the possible association between cholesterol metabolism of neurons and development of AD. However, we are still far from being able to understand how alteration in the level and/or distribution of intraneuronal cholesterol pathologically affects neurons, leading to the acceleration of AD-specific pathological processes. Furthermore, we lack definite information on whether too much or too little cholesterol is crucial to neurons. Previous studies suggested the following: first, generation and aggregation of Aβ are accelerated by an increase in the level of intraneuronal cholesterol; second, pathological phosphorylation of tau and impaired plasticity of synapses (Koudinov and Koudinova, 2001; Mauch et al., 2001) are associated with a reduced level and/or altered distribution of intraneuronal cholesterol. Based on these results, it may be possible to develop a hypothetical scheme as shown in Figure 1. Alternatively, it is well known that cholesterol is not uniformly distributed in plasma membranes including neuronal membranes (Wood et al., 1999). Thus, it may be required for future studies to investigate in more detail the neuronal regions exhibiting different cholesterol contents with regard to AD-related pathological processes.

thumbnail image

Figure 1. A hypothetical scheme showing a possible association between alteration in the level of cholesterol in neuronal membranes and the development of Alzheimer's disease (AD). Cholesterol in excessive amounts in membranes accelerates the generation and aggregation of amyloid β-protein (Aβ), resulting in the generation of oligomeric Aβ. The oligomeric Aβ causes cholesterol efflux from neuronal membranes, leading to substantial loss of cholesterol from neurons. Disruption of cholesterol homeostasis in neurons, induced by oligomeric Aβ, may lead to various pathological alterations, including hyperphosphorylation of tau and impairment of synaptic plasticity, which underlie neuronal death in AD. APP, amyloid precursor protein. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]

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REFERENCES

  1. Top of page
  2. Abstract
  3. CHOLESTEROL METABOLISM IN CNS
  4. CHOLESTEROL AND GENETIC RISK FACTORS FOR AD
  5. CHOLESTEROL AND AGING
  6. EPIDEMIOLOGICAL ASPECTS ON ASSOCIATION BETWEEN CHOLESTEROL AND AD
  7. Aβ CASCADE AND CHOLESTEROL
  8. TAUOPATHY AND CHOLESTEROL
  9. REFERENCES
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