Cholesterol as a causative factor in Alzheimer's disease: a debatable hypothesis

Wood, W. Gibson; L, Li; Müller, Wernér E.G.; Eckert, Gunter P.

doi:10.1111/jnc.12637

Cited by 178 publications

(151 citation statements)

References 166 publications

(294 reference statements)

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“…Yet, the Km is significantly more favorable for the reaction in bicelles, which contains CHAPSO, a cholesterol mimic. Cholesterol is a modulator of both membranes (51,52) and C100 catalysis (53)(54)(55)(56)(57). Indeed, relevant regions of C100 are partitioned well inside the lipid bilayer and specifically bind cholesterol (53).…”

Section: Discussionmentioning

confidence: 99%

Both positional and chemical variables control in vitro proteolytic cleavage of a presenilin ortholog

Naing

Kalyoncu

Smalley³

et al. 2018

Journal of Biological Chemistry

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Mechanistic details of intramembrane aspartyl protease (IAP) chemistry, which is central to many biological and pathogenic processes, remain largely obscure. Here, we investigated the in vitro kinetics of a microbial intramembrane aspartyl protease (mIAP) fortuitously acting on the renin substrate angiotensinogen and the C-terminal transmembrane segment of amyloid precursor protein (C100), which is cleaved by the presenilin subunit of γ-secretase, an Alzheimer disease (AD)-associated IAP. mIAP variants with substitutions in active-site and putative substrate gating residues generally exhibit impaired, but not abolished, activity toward angiotensinogen, and retain the predominant cleavage site (His-Thr). The aromatic ring, but not its hydroxyl substituent, in Tyr of the catalytic Tyr-Asp (YD) motif plays a catalytic role, and the hydrolysis reaction incorporates bulk water as in soluble aspartyl proteases. mIAP hydrolyzes the transmembrane region of C100 at two major presenilin cleavage sites, one corresponding to the AD-associated Aβ42 peptide (Ala-Thr) and the other the nonpathogenic Aβ48 (Thr-Leu). For the former site, we observed more favorable kinetics in lipid bilayer-mimicking bicelles than in detergent solution, indicating that substrate-lipid and substrate-enzyme interactions both contribute to catalytic rates. High-resolution MS analyses across four substrates support a preference for threonine at the scissile bond. However, results from threonine-scanning mutagenesis of angiotensinogen indicate a competing positional preference for cleavage. Our results indicate that IAP cleavage is controlled by both positional and chemical factors, opening up new avenues for selective IAP inhibition for therapeutic interventions. INTRODUCTIONIntramembrane proteases (IPs) cleave within a transmembrane (TM) helix of membranebound substrates to release cytoplasmic or extracellular proteins/peptides, which in turn translocate to different regions of the cell where they elicit their corresponding biological response related to, for example, cell differentiation, development, and metabolism (1). Despite their broad biomedical reach, basic questions surrounding the structure of the active enzyme, how substrates are presented, and how hydrolysis chemistry occurs in an active site sequestered within the hydrophobic lipid membrane, remain active areas of research.The least biochemically understood IP is the intramembrane aspartyl protease (IAP) enzyme class, one of just three bona fide IP types that hydrolyze substrates within the hydrophobic lipid environment by using different catalytic nucleophiles (2). IAPs employ membrane-

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Section: Discussionmentioning

confidence: 99%

Both positional and chemical variables control in vitro proteolytic cleavage of a presenilin ortholog

Naing

Kalyoncu

Smalley³

et al. 2018

Journal of Biological Chemistry

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“…3) [61,62]. APP and the secretases are integral membrane proteins, and numerous studies have demonstrated a role of cholesterol in the proteolytic processing of APP and the generation of Aβ [63,64,65,66]. However, the exact molecular mechanisms and the relevance of cholesterol in AD pathogenesis is still under debate [63,64,65,66].…”

Section: S1p - a Potential Mediator In The Pathogenesis Of Alzheimer'mentioning

confidence: 99%

“…APP and the secretases are integral membrane proteins, and numerous studies have demonstrated a role of cholesterol in the proteolytic processing of APP and the generation of Aβ [63,64,65,66]. However, the exact molecular mechanisms and the relevance of cholesterol in AD pathogenesis is still under debate [63,64,65,66]. The role of lipid homeostasis in the brain, particularly that of membrane lipids, in AD pathogenesis has been recognized and considered in multitudinous studies [67,68].…”

Section: S1p - a Potential Mediator In The Pathogenesis Of Alzheimer'mentioning

confidence: 99%

Sphingosine-1-Phosphate: Boon and Bane for the Brain

Echten‐Deckert

Hagen-Euteneuer

Karaca

et al. 2014

Cell Physiol Biochem

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Sphingosine-1-phosphate (S1P), an evolutionary conserved bioactive lipid, is essential for brain development, but might also exert detrimental effects in terminally differentiated post-mitotic neurons. Its concentration in the brain is tightly regulated by specific kinases and phosphatases, and mainly by the S1P degrading enzyme, S1P-lyase (S1PL). The role of S1P in neurons was initially studied in primary cultures by using structural analogues. During the last 3 years generation of a S1PL deficient mouse model substantially promoted our knowledge on the functional role of S1P metabolism in the brain, and its potential relation to neurodegenerative diseases. However, our understanding of the molecular mechanisms that underlie the physiological and pathophysiological actions of S1P in neurons remains rather scarce.

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“…This increase in plasma cholesterol level in HFD-induced amnesia corroborated with other study results that elevated serum cholesterol level could be an important risk factor for AD. [4][5][6] Atorvastatin and simvastatin in 5 mg/kg b.w. dose significantly decreased the plasma cholesterol level whereas piracetam did not show any significant change in plasma cholesterol level.…”

Section: Discussionmentioning

confidence: 99%

“…[1,2] It appears that cholesterol turnover plays an important role in the deposition and clearance of amyloid peptide in brain. [3][4][5][6] Oxygen free radicals produced within the neurons National Journal of Physiology, Pharmacy and Pharmacology 1294 2017 | Vol 7 | Issue 12 can cause tissue damage and are also implicated in aging and neurodegenerative process. [7,8] The most widely used treatments for AD at present are the reversible acetylcholinesterase inhibitors, which aim at prolonging cognitive functions through decreased degradation of acetylcholine at synaptic cleft.…”

Section: Introductionmentioning

confidence: 99%

Statins: Are they also memory enhancers? A study in relation to their hypocholesterolemic and antioxidant effects in Swiss albino mice

Mishra¹,

Nayak²,

Sarangi³

2017

Natl J Physiol Pharm Pharmacol

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Background:The most common cause of dementia with progressive loss of memory is Alzheimer's disease (AD), a neurodegenerative disorder that occurs due to increased oxidative stress, deposition of amyloid protein, and loss of cholinergic neurons. Statins, by their hypocholesterolemic, antioxidant, and other activities may be helpful in this regard. Aims and Objectives: The aim of this study is to examine the relation between memory restoring effect, lipid lowering effect as well as the antioxidant properties of statins in experimental dementia models using Swiss albino mice. Materials and Methods: Cognitive ability was tested in randomly selected young Swiss albino mice with two exteroceptive behavioral models, passive avoidance paradigm, and Morris Water Maze (MWM) by assigning 30 animals divided equally into 5 groups for each model. Amnesia was induced by feeding high-fat-diet for 90 days in 4 groups of mice. The 5 th group served as control with young mice. Piracetam, atorvastatin, and simvastatin were given, respectively, to 3 of the amnesic groups of each model whereas the 4 th group treated with vehicle served as positive control. Results:Step-down latency was significantly higher in young mice as well as amnesic mice treated with piracetam, simvastatin, or atorvastatin in comparison to vehicle-treated amnesic mice. Similar result was also seen during retrieval test in MWM, although all the groups performed comparably during acquisition trial. Brain malondialdehyde (MDA) levels were significantly low in all the groups who performed well in either of the exteroceptive behavioral models. Cholesetrol levels in young control and statin-treated groups were significantly low in comparison to piracetam-or vehicle-treated mice. Conclusions: Atorvastatin and simvastatin improved the cognitive ability in terms of learning as well as retrieval of learned experience which may be attributed to their hypocholesterolemic and antioxidant properties.

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Cholesterol as a causative factor in Alzheimer's disease: a debatable hypothesis

Cited by 178 publications

References 166 publications

Both positional and chemical variables control in vitro proteolytic cleavage of a presenilin ortholog

Both positional and chemical variables control in vitro proteolytic cleavage of a presenilin ortholog

Sphingosine-1-Phosphate: Boon and Bane for the Brain

Statins: Are they also memory enhancers? A study in relation to their hypocholesterolemic and antioxidant effects in Swiss albino mice

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