Brain membrane cholesterol domains, aging and amyloid beta-peptides

Wood, W. Gibson; Schroeder, Friedhelm; Igbavboa, Urule; Avdulov, N. A.; Chochina, Svetlana V.

doi:10.1016/s0197-4580(02)00018-0

Cited by 145 publications

(119 citation statements)

References 105 publications

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“…Even though elevated Ca 2+ levels may contribute to asymmetric collapse, it is doubtful elevated Ca 2+ is the chief contributor (Castegna et al, 2004;Mohmmad Abdul and Butterfield, 2005). Furthermore, changes in membrane cholesterol also are observed in response to oxidative stress, elevated levels of amyloid-beta protein (Aβ), and aging (Lopez-Revuelta et al, 2007;Wood et al, 2002;Wood et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Lange

Cenini

Piroddi

et al. 2008

Neurobiology of Disease

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Oxidative stress, a hallmark of Alzheimer disease (AD), has been shown to induce lipid peroxidation and apoptosis disrupting cellular homeostasis. Normally, the aminophospholipid phosphatidylserine (PtdSer) is asymmetrically distributed on the cytosolic leaflet of the lipid bilayer. Under oxidative stress conditions, asymmetry is altered, characterized by the appearance of PtdSer on the outer leaflet, to initiate the first stages of an apoptotic process. PtdSer asymmetry is actively maintained by the ATP-dependent translocase flippase, whose function is inhibited if covalently bound by lipid peroxidation products, 4-hydroxynonenal (HNE) and acrolein, within the membrane bilayer in which they are produced. Additionally, pro-apoptotic proteins Bax and caspase-3 have been implemented in the oxidative modification of PtdSer resulting in subsequent asymmetric collapse, while antiapoptotic protein Bcl-2 has been found to prevent this process.The current investigation focused on detection of PtdSer on the outer leaflet of the bilayer in synaptosomes from brain of subjects with AD and amnestic mild cognitive impairment (MCI), as well as expression levels of apoptosis-related proteins Bcl-2, Bax, and caspase-3. Fluorescence and Western blot analysis suggest PtdSer exposure on the outer leaflet is significantly increased in brain from subjects with MCI and AD contributing to early apoptotic elevation of pro-and anti-apoptotic proteins and finally neuronal loss. MCI is considered a possible transition point between normal cognitive aging and probable AD. Brain from subjects with MCI is reported to have increased levels of tissue oxidation; therefore, the results of this study could mark the progression of patients with MCI into AD. This study contributes to a model of apoptosis-specific oxidation of phospholipids consistent with the notion that PtdSer exposure is required for apoptotic-cell death.

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Section: Discussionmentioning

confidence: 99%

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Lange

Cenini

Piroddi

et al. 2008

Neurobiology of Disease

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“…In contrast, hypercholesterolemia may be entirely different from HBP or DM in the manner of associating with responsiveness to ChEI. Cholesterol has been found to modulate amyloid ß peptide synthesis [44] and to control interactions between amyloid ß peptide and neuronal membranes that are regarded as the initiation of a neurotoxic cascade [45]. Hypercholesterolemia was significantly associated with amyloid deposition independent of the apolipoprotein E genotype and considered as a risk factor of AD pathology in the younger subjects [46].…”

Section: Discussionmentioning

confidence: 99%

Do Vascular Lesions and Related Risk Factors Influence Responsiveness to Donepezil Chloride in Patients with Alzheimer’s Disease?

Fukui

Taguchi²

2005

Dement Geriatr Cogn Disord

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The purpose was to identify vascular influences on the responsiveness to donepezil chloride. The study included 50 untreated probable Alzheimer’s disease patients with the Modified Hachinski Ischemic Score <4. We assessed baseline cognitive status using the Revised Hasegawa Dementia Scale (HDS-R), Clinical Dementia Rating (CDR) and the clock drawing test (CDT). The response to 5 mg of donepezil was monitored by the CDT for 12 months. Patients were classified as true responders (TR), unchanged (UC) and non-responders according to changes on the CDT in response to treatment. High HDS-R scores, low CDT scores, low CDR and presence of hypertension (HBP) and periventricular hyperintensities (PVH) predicted a TR- or UC-type outcome. Aggravation of executive function by HBP and/or PVH and its improvement by donepezil may have been detected by the CDT.

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“…Changes in distribution of cholesterol and lipids within cell membranes are known to occur during aging (36). It is possible, therefore, that the local membrane environment may be altered such that more BACE, and͞or other enzymes or cofactors involved in amyloidogenic processing become raft-localized, and therefore aging provides a more cooperative environment for production of A␤.…”

Section: Disruption Of Raft Domains By Decreasing Cellular Cholesteromentioning

confidence: 99%

Exclusively targeting β-secretase to lipid rafts by GPI-anchor addition up-regulates β-site processing of the amyloid precursor protein

Cordy

Hussain

Dingwall

et al. 2003

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

346

279

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␤-Secretase (BACE, Asp-2) is a transmembrane aspartic proteinase responsible for cleaving the amyloid precursor protein (APP) to generate the soluble ectodomain sAPP␤ and its C-terminal fragment CTF␤. CTF␤ is subsequently cleaved by ␥-secretase to produce the neurotoxic͞synaptotoxic amyloid-␤ peptide (A␤) that accumulates in Alzheimer's disease. Indirect evidence has suggested that amyloidogenic APP processing may preferentially occur in lipid rafts. Here, we show that relatively little wild-type BACE is found in rafts prepared from a human neuroblastoma cell line (SH-SY5Y) by using Triton X-100 as detergent. To investigate further the significance of lipid rafts in APP processing, a glycosylphosphatidylinositol (GPI) anchor has been added to BACE, replacing the transmembrane and C-terminal domains. The GPI anchor targets the enzyme exclusively to lipid raft domains. Expression of GPI-BACE substantially up-regulates the secretion of both sAPP␤ and amyloid-␤ peptide over levels observed from cells overexpressing wild-type BACE. This effect was reversed when the lipid rafts were disrupted by depleting cellular cholesterol levels. These results suggest that processing of APP to the amyloid-␤ peptide occurs predominantly in lipid rafts and that BACE is the rate-limiting enzyme in this process. The processing of the APP695 isoform by GPI-BACE was up-regulated 20-fold compared with wild-type BACE, whereas only a 2-fold increase in the processing of APP751/770 was seen, implying a differential compartmentation of the APP isoforms. Changes in the local membrane environment during aging may facilitate the cosegregation of APP and BACE leading to increased ␤-amyloid production.

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Brain membrane cholesterol domains, aging and amyloid beta-peptides

Cited by 145 publications

References 105 publications

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Loss of phospholipid asymmetry and elevated brain apoptotic protein levels in subjects with amnestic mild cognitive impairment and Alzheimer disease

Do Vascular Lesions and Related Risk Factors Influence Responsiveness to Donepezil Chloride in Patients with Alzheimer’s Disease?

Exclusively targeting β-secretase to lipid rafts by GPI-anchor addition up-regulates β-site processing of the amyloid precursor protein

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