Cholesterol-Dependent γ-Secretase Activity in Buoyant Cholesterol-Rich Membrane Microdomains

Wahrle, Suzanne E.; Das, Pritam; Nyborg, Andrew C.; McLendon, Chris; Shoji, Mikio; Kawarabayashi, Tatsuhiko; Younkin, Linda H.; Younkin, Steven G.; Golde, Todd E.

doi:10.1006/nbdi.2001.0470

Cited by 407 publications

(357 citation statements)

References 42 publications

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“…Cholesterol levels are thought to modulate the processing of amyloid precursor protein by controlling secretase activity. Current evidence suggests that α-secretase resides in phospholipid-rich domains, while γ and β-secretases are found in lipid rafts (Riddell et al 2001;Wahrle et al 2002;Cordy et al 2003). Experimentally reducing cholesterol in tissue culture has been shown to enhance α-secretase activity and to inhibit γ-secretase activity and reduce the production of pathogenic forms of Aβ (Bodovitz and Klein 1996;Kojro et al 2001;Ehehalt et al 2003).…”

Section: Discussionmentioning

confidence: 99%

ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brain

Bandaru

Troncoso

Wheeler

et al. 2009

Neurobiology of Aging

129

106

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The ε4 allele of ApoE is associated with an earlier onset and faster progression of Alzheimer's disease in patients with the familial form of this neurodegenerative condition. Although ApoE4 has been repeatedly associated with altered sphingomyelin and cholesterol levels in tissue culture and rodent models, there has not been a direct quantification of sphingomyelin or sterol levels in the brains of patients with different forms of ApoE. We measured the sphingolipid and sterol content of human brain tissues and found no evidence of perturbed sterol or sphingolipid biochemistry in the brains of individuals expressing ApoE4 who did not have a preexisting neurodegenerative condition. Nevertheless, ApoE4 was associated with gross abnormalities in the sterol and sphingolipid content of numerous brain regions in patients with Alzheimer's diseease. The findings suggest that ApoE4 may not by itself alter sterol or sphingolipid metabolism in the brain under normal conditions, but that other neuropathologic changes of Alzheimer's are required to unmask the effect of ApoE4, and to perturb sterol and sphingolipid biochemistry.

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Section: Discussionmentioning

confidence: 99%

ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brain

Bandaru

Troncoso

Wheeler

et al. 2009

Neurobiology of Aging

129

106

View full text Add to dashboard Cite

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“…By reducing cellular cholesterol level through lovastatin and methyl‐β‐cyclodextrin, the formation of Aβ is inhibited (Hartmann, Kuchenbecker, & Grimm, 2007; Simons et al, 1998; Vetrivel & Thinakaran, 2010). Cholesterol levels can also directly regulate β‐secretase‐mediated production of Aβ (Fassbender et al, 2001; Simons et al, 1998; Wahrle et al, 2002). Inclusion of cholesterol or sphingolipids in phosphatidylcholine‐containing vesicles leads to increased γ‐secretase activity (Osawa et al, 2008; Osenkowski, Ye, Wang, Wolfe, & Selkoe, 2008).…”

Section: Lifestyle Associations and Interventions For Aging And Admentioning

confidence: 99%

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

et al. 2018

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Alzheimer's disease is the most prevalent cause of dementia, which is defined by the combined presence of amyloid and tau, but researchers are gradually moving away from the simple assumption of linear causality proposed by the original amyloid hypothesis. Aging is the main risk factor for Alzheimer's disease that cannot be explained by amyloid hypothesis. To evaluate how aging and Alzheimer's disease are intrinsically interwoven with each other, we review and summarize evidence from molecular, cellular, and system level. In particular, we focus on study designs, treatments, or interventions in Alzheimer's disease that could also be insightful in aging and vice versa.

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“…Previous studies have reported the presence of PS1 derivatives in membrane domains resistant to extraction with certain detergents, indicative of raft localization (30,33,37,38). The choice of detergent is a critical step in isolation of lipid rafts as it is becoming clear that raft domains that differ in their protein composition and properties can be subclassified based on their differential solubility in select detergents (48,49,52,53).…”

Section: Ps1 and Mature Nicastrin Are Present In Lubrol Wx-insolublementioning

confidence: 99%

“…Third, BACE1 is localized and cleaves APP in lipid rafts (33,36). Fourth, buoyant cholesterolrich DIMs contain high levels of ␥-secretase activity (33,37), and a subset of PS1 and nicastrin partition into these membrane domains (30,31,33,37). Interestingly, a recent study reported that ␥-secretase cleavage occurs in lipid rafts, but ␥-secretase catalytic activity is independent of the presence of cholesterol (38).…”

mentioning

confidence: 99%

Association of γ-Secretase with Lipid Rafts in Post-Golgi and Endosome Membranes

Vetrivel¹,

Cheng²,

Lin

et al. 2004

Journal of Biological Chemistry

392

369

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Alzheimer's disease-associated ␤-amyloid peptides (A␤) are generated by the sequential proteolytic processing of amyloid precursor protein (APP) by ␤-and ␥-secretases. There is growing evidence that cholesterol-and sphingolipid-rich membrane microdomains are involved in regulating trafficking and processing of APP. BACE1, the major ␤-secretase in neurons is a palmitoylated transmembrane protein that resides in lipid rafts. A subset of APP is subject to amyloidogenic processing by BACE1 in lipid rafts, and this process depends on the integrity of lipid rafts. Here we describe the association of all four components of the ␥-secretase complex, namely presenilin 1 (PS1)-derived fragments, mature nicastrin, APH-1, and PEN-2, with cholesterol-rich detergent insoluble membrane (DIM) domains of non-neuronal cells and neurons that fulfill the criteria of lipid rafts. In PS1 ؊/؊ /PS2 ؊/؊ and NCT ؊/؊ fibroblasts, ␥-secretase components that still remain fail to become detergent-resistant, suggesting that raft association requires ␥-secretase complex assembly. Biochemical evidence shows that subunits of the ␥-secretase complex and three TGN/endosomeresident SNAREs cofractionate in sucrose density gradients, and show similar solubility or insolubility characteristics in distinct non-ionic and zwitterionic detergents, indicative of their co-residence in membrane microdomains with similar protein-lipid composition. This notion is confirmed using magnetic immunoisolation of PS1-or syntaxin 6-positive membrane patches from a mixture of membranes with similar buoyant densities following Lubrol WX extraction or sonication, and gradient centrifugation. These findings are consistent with the localization of ␥-secretase in lipid raft microdomains of postGolgi and endosomes, organelles previously implicated in amyloidogenic processing of APP.Alzheimer's disease, a neurodegenerative dementing disorder, is pathologically characterized by the cerebral deposition of 39 -42 amino acid peptides termed ␤-amyloid (A␤) 1 peptides.

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Cholesterol-Dependent γ-Secretase Activity in Buoyant Cholesterol-Rich Membrane Microdomains

Cited by 407 publications

References 42 publications

ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brain

ApoE4 disrupts sterol and sphingolipid metabolism in Alzheimer's but not normal brain

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

Association of γ-Secretase with Lipid Rafts in Post-Golgi and Endosome Membranes

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