The role of cholesterol in the biosynthesis of β-amyloid.

Frears, Emma R.; Stephens, David; Walters, Claire E.; Davies, H. W. E.; Austen, Brian

doi:10.1097/00001756-199906030-00014

Cited by 309 publications

(219 citation statements)

References 8 publications

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“…SFV protein uptake by almost all neurons was found in both groups. These results corroborate previous findings (36) that cholesterol-dependent A␤ production does not depend on the use of SFV systems.…”

Section: Resultssupporting

confidence: 92%

Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo

Faßbender

Simons

Bergmann

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

1,040

724

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Recent epidemiological studies show a strong reduction in the incidence of Alzheimer's disease in patients treated with cholesterol-lowering statins. Moreover, elevated A␤42 levels and the 4 allele of the lipid-carrier apolipoprotein E are regarded as risk factors for sporadic and familial Alzheimer's disease. Here we demonstrate that the widely used cholesterol-lowering drugs simvastatin and lovastatin reduce intracellular and extracellular levels of A␤42 and A␤40 peptides in primary cultures of hippocampal neurons and mixed cortical neurons. Likewise, guinea pigs treated with high doses of simvastatin showed a strong and reversible reduction of cerebral A␤42 and A␤40 levels in the cerebrospinal fluid and brain homogenate. These results suggest that lipids are playing an important role in the development of Alzheimer's disease. Lowered levels of A␤42 may provide the mechanism for the observed reduced incidence of dementia in statin-treated patients and may open up avenues for therapeutic interventions.A part from age, environmental factors have only slight influence on the incidence of Alzheimer's disease (AD). Very recently, two independent reports showed a strong decrease in the incidence of AD and dementia for patients that were treated with statins (1, 2). Both studies were retrospective, and statins were not given in any relation to dementia. Usually statins are prescribed for treatment of elevated serum cholesterol levels in patients. They reduce cholesterol levels by inhibiting the bottleneck enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. They are widely used drugs, well characterized and considered to be very safe for long-time treatment, and approved for use in elderly patients (3, 4).The 4 allele of the apolipoprotein E (apoE) is the major genetic risk factor for AD (5). Several lines of evidence indicate that apoE 4 and statins have a related influence on AD. The normal cellular function of apoE is uptake and delivery of lipids. The isoform apoE 4 correlates with an increased risk for atherosclerosis (6) and amyloid plaque formation (7). Moreover, elevated cholesterol uptake increases amyloid plaque formation or amyloid deposition (8,9). This correlation may be extended to A␤ production, since cellular cholesterol levels affect neuronal A␤ production in vitro (10). Initially, A␤ has been a focus of AD research, because it was found to be the major constituent of the amyloid plaque. It is unknown whether the amyloid plaque is actively involved in the neurodegenerative process in AD or instead is a consequence of the disease process. More recently, however, A␤ has been a focus of AD research not because of it presence in the amyloid plaque, but because an overproduction of a minor A␤ isoform, A␤42, is linked to all identified inherited forms of AD (11-13).A␤ is produced during normal cellular processing of the Alzheimer amyloid precursor protein (APP) (14) by ␤-secretase and ␥-secretase (15). While the majority of all A␤ isoforms produced is A␤40, Ϸ10% of total A␤ ...

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Section: Resultssupporting

confidence: 92%

Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo

Faßbender

Simons

Bergmann

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

1,040

724

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“…A␤ production is sensitive to cellular cholesterol levels in vitro and in vivo (34,35,54). To define the enzymatic requirements of cholesterol-dependent A␤ production we applied a set of APP and truncated APP constructs designed to reveal consecutive and independent activities of ␤-and ␥-secretase with modulated cholesterol levels.…”

Section: Discussionmentioning

confidence: 99%

“…BACE I has been shown to recycle between the TGN and the plasma membrane via endosomes (72), and cyclodextrin is known to reduce endocytosis (73). Therefore, the observed ␤-secretase inhibition may be due to inhibited endocytosis, whereas normal secretion remains intact (34,35,54), leaving BACE at the plasma membrane, a compartment of unfavorable pH for ␤-secretase cleavage. However, Kalvodova et al (39) showed that BACE activity is sensitive to cholesterol levels even in the absence of trafficking in vitro, which may indicate that removal of cholesterol from the membrane microenvironment of BACE I in the late secretory pathway may suffice to reduce its activity.…”

Section: Discussionmentioning

confidence: 99%

Independent Inhibition of Alzheimer Disease β- and γ-Secretase Cleavage by Lowered Cholesterol Levels

Grimm

Tomic

et al. 2008

Journal of Biological Chemistry

120

107

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The major molecular risk factor for Alzheimer disease so far identified is the amyloidogenic peptide A␤ 42 . In addition, growing evidence suggests a role of cholesterol in Alzheimer disease pathology and A␤ generation. However, the cellular mechanism of lipid-dependent A␤ production remains unclear. Here we describe that the two enzymatic activities responsible for A␤ production, ␤-secretase and ␥-secretase, are inhibited in parallel by cholesterol reduction. Importantly, our data indicate that cholesterol depletion within the cellular context inhibits both secretases additively and independently from each other. This is unexpected because the ␤-secretase ␤-site amyloid precursor protein cleaving enzyme and the presenilin-containing ␥-secretase complex are structurally different from each other, and these enzymes are apparently located in different subcellular compartments. The parallel and additive inhibition has obvious consequences for therapeutic research and may indicate an intrinsic cross-talk between Alzheimer disease-related amyloid precursor protein processing, amyloid precursor protein function, and lipid biology.A␤ peptides are the main proteinaceous component of Alzheimer disease amyloid plaques. A␤ is derived from posttranslational cleavage of the amyloid precursor protein (APP). Cleavage of APP by BACE I (1) at the N terminus of the A␤ sequence generates a C-terminal fragment (C99) that includes the entire A␤ sequence. In mouse cortical neurons BACE I is essential for APP ␤-cleavage (2). A second proteolytic activity termed ␥-secretase cleaves APP at the C-terminal end of the A␤ sequence, releasing A␤ 40 and A␤ 42 during normal cellular metabolism of APP (3, 4). A fraction of APP is processed by the ␣-secretase pathway in which APP is cleaved within the A␤ region thus precluding A␤ formation. However, neurons predominately use the ␤-secretory pathway at the expense of the ␣-secretory pathway to process APP (5). Moreover, neurons produce significant amounts of intracellular A␤ in vivo and in vitro (6 -8). A specific feature of ␥-secretase is that it is capable of cleaving APP only after a major part of the APP luminal domain is removed. Under normal circumstances it is therefore not possible to assay ␥-secretase activity directly.Analyses of APP-FAD mutations (9) as well as of PS-FAD mutations (10) have corroborated the assumption that a small increase in A␤ 42 levels causes AD (11). The subcellular activities of both ␤-and ␥-secretase have been extensively studied. Processing of APP to A␤ differs for different intracellular compartments (12) and depends among others on the interaction of membrane composition and the APP transmembrane domain (13). Variable amounts of ␤-secretase activity were found along the secretory pathway starting in the ER/intermediate compartment, post-Golgi vesicles, TGN, and endosomes (14, 15). In contrast, ␥-secretase activity was found to be prominent in the ER, TGN, and plasma membrane and to produce different A␤ isoforms in different compartments (reviewed by Hartmann (...

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“…Numerous studies using immortalized and primary cell lines [83][84][85] have demonstrated that increased cholesterol levels can increase the activity of the ␤-secretase pathway, leading to an accumulation of A␤ and A␤ 1-42 peptides, with a resulting increase in formation of extracellular amyloid deposits. Moreover, it has recently been demonstrated that cholesterol is capable of modulating the production of mature glycosylated APP.…”

Section: Cholesterol Homeostasis In Neurodegenerative Conditionsmentioning

confidence: 99%

Brain Cholesterol: Long Secret Life Behind a Barrier

Björkhem

Meaney

2004

ATVB

881

732

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Abstract-Although an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Approximately 25% of the total amount of the cholesterol present in humans is localized to this organ, most of it present in myelin. Almost all brain cholesterol is a product of local synthesis, with the blood-brain barrier efficiently protecting it from exchange with lipoprotein cholesterol in the circulation. Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation. Under steady-state conditions, most of the de novo synthesis of cholesterol in the brain appears to be balanced by excretion of the cytochrome P-450 -generated oxysterol 24S-hydroxycholesterol. This oxysterol is capable of escaping the recycling mechanism and traversing the blood-brain barrier. Cholesterol levels and cholesterol turnover are affected in neurodegenerating disorders, and the capacity for cholesterol transport and recycling in the brain seems to be of importance for the development of such diseases. The possibility has been discussed that administration of inhibitors of cholesterol synthesis may reduce the prevalence of Alzheimer disease. No firm conclusions can, however, be drawn from the studies presented thus far.In the present review, the most recent advances in our understanding of cholesterol turnover in the brain is discussed. Key Words: brain cholesterol Ⅲ blood-brain barrier Ⅲ cholesterol 24S-hydroxylase Ⅲ Alzheimer disease Ⅲ statins H ighly sophisticated regulatory systems have evolved for the maintenance of cholesterol homeostasis in the body. There is a distinct difference between the situation in the central nervous system and that in most other extrahepatic tissues. Outside the brain, the cellular needs for cholesterol is covered by de novo synthesis and by cellular uptake of lipoprotein cholesterol from the circulation. In the brain, the blood-brain barrier effectively prevents uptake from the circulation, and de novo synthesis is responsible for practically all cholesterol present in this organ. The independence of the isolated pool of cholesterol in the brain is likely to reflect a high need for constancy in the cholesterol content of membrane and myelin, a constancy that would be difficult to keep if brain cholesterol had been exchangeable with lipoprotein cholesterol.The importance of cholesterol in the nervous system was recognized as early as 1834, when Couerbe's observations lead him to regard cholesterol as un element principal of the nervous system. 1 Despite concerted efforts in the interim, it is only during the past few decades that the brain has begun to surrender the secrets of the behavior of one of its most abundant lipids.In the present brief review, we summarize the basal characteristics of brain cholesterol and some recent findings with respect to homeostasis of this compound in the brain. Emphasis is put on the newly described relation betwee...

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The role of cholesterol in the biosynthesis of β-amyloid.

Cited by 309 publications

References 8 publications

Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo

Simvastatin strongly reduces levels of Alzheimer's disease β-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo

Independent Inhibition of Alzheimer Disease β- and γ-Secretase Cleavage by Lowered Cholesterol Levels

Brain Cholesterol: Long Secret Life Behind a Barrier

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