Neuronal membrane cholesterol loss enhances amyloid peptide generation

Abad‐Rodríguez, José; Ledesma, María Dolores; Craessaerts, Katleen; Perga, Simona; Medina, Miguel; Delacourte, André; Dingwall, Colin; Strooper, Bart De; Dotti, Carlos G.

doi:10.1083/jcb.200404149

Cited by 306 publications

(294 citation statements)

References 28 publications

(48 reference statements)

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“…Use of a glycosylphosphatidylinositol (GPI) anchor to target β-secretase to lipid rafts increased Aβ formation, and this amyloidogenic effect was inhibited when lipid rafts were disrupted by depleting cholesterol from the membrane (Cordy et al 2003). Nonetheless, there have been reports that lowering cholesterol increases Aβ production (Abad-Rodriguez et al 2004), suggesting that maintaining homeostatic levels of cholesterol in brain may be important for normal neuronal function. In addition, Aβ may enhance neutral sphingomyelinase activity, increase ceramide levels, and further the production of pathogenic forms of Aβ (Lee et al 2004).…”

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

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“…Cite this article as Cold Spring Harb Perspect Med 2012;2:a006270 Rodriguez et al 2004). This would be consistent with the finding that BACE1 undergoes palmitoylation.…”

Section: Trafficking and Proteolytic Processing Of Appmentioning

confidence: 99%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

871

892

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Accumulations of insoluble deposits of amyloid b-peptide are major pathological hallmarks of Alzheimer disease. Amyloid b-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the b-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. b-and g-secretase liberate by sequential cleavage the neurotoxic amyloid b-peptide, whereas a-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid b-peptide generation and therefore disease onset and progression.

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“…Experimental evidence has revealed the disorganization of DRMs in AD brains, possibly because of low cholesterol content (Ledesma et al, 2003a). In a recent study, it has been described that DRMs participate in the segregation of APP from BACE, therefore reducing APP b-cleavage and Ab production in cultured primary neurons and CHO cells, respectively (Abad-Rodriguez et al, 2004). Furthermore, disruption of DRMs results in diminished activity of the Abdegrading enzyme plasmin, because of decreased membrane plasminogen binding to the plasma membrane (Ledesma et al, 2000(Ledesma et al, , 2003a.…”

Section: Introductionmentioning

confidence: 99%

The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Aβ generation in vivo

Crameri

Biondi

Kuehnle

et al. 2006

EMBO J

Self Cite

160

179

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The cholesterol-synthesizing enzyme seladin-1, encoded by the Dhcr24 gene, is a flavin adenine dinucleotidedependent oxidoreductase and regulates responses to oncogenic and oxidative stimuli. It has a role in neuroprotection and is downregulated in affected neurons in Alzheimer's disease (AD). Here we show that seladin-1-deficient mouse brains had reduced levels of cholesterol and disorganized cholesterol-rich detergent-resistant membrane domains (DRMs). This was associated with inefficient plasminogen binding and plasmin activation, the displacement of b-secretase (BACE) from DRMs to APP-containing membrane fractions, increased b-cleavage of APP and high levels of Ab peptides. In contrast, overexpression of seladin-1 increased both cholesterol and the recruitment of DRM components into DRM fractions, induced plasmin activation and reduced both BACE processing of APP and Ab formation. These results establish a role of seladin-1 in the formation of DRMs and suggest that seladin-1-dependent cholesterol synthesis is involved in lowering Ab levels. Pharmacological enhancement of seladin-1 activity may be a novel Ab-lowering approach for the treatment of AD.

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Neuronal membrane cholesterol loss enhances amyloid peptide generation

Cited by 306 publications

References 28 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

Trafficking and Proteolytic Processing of APP

The role of seladin-1/DHCR24 in cholesterol biosynthesis, APP processing and Aβ generation in vivo

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