Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for β-amyloid peptide over-production and localization in Alzheimer’s disease

Yu, Wai Haung; Kumar, Asok; Peterhoff, Corrinne M.; Kulnane, Laura Shapiro; Uchiyama, Yasuo; Lamb, Bruce T.; Cuervo, Ana María; Nixon, Ralph A.

doi:10.1016/j.biocel.2004.05.010

Cited by 261 publications

(190 citation statements)

References 68 publications

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“…It has been reported that the expression of beclin-1, an essential regulator for initiating the autophagic process, is decreased in Alzheimer disease patients, and its depletion caused accumulation of amyloid ␤ (47). It has also been reported that amyloid ␤ and its precursor can co-localize to LC3-positive autophagosomes (48,49). These findings demonstrate the role of autophagy in clearance of amyloid ␤ protein and indicate how impaired autophagy in cholesterol-depleted cells could affect the clearance of amyloid ␤ and promote the pathological changes of Alzheimer disease in the diabetic brain.…”

Section: Discussionsupporting

confidence: 54%

Effect of Cholesterol Reduction on Receptor Signaling in Neurons

Fukui¹,

Ferris²,

Kahn

2015

Journal of Biological Chemistry

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Background: Cholesterol synthesis is decreased in the brain in diabetes. Results: Cholesterol depletion in neuron-derived cells results in impaired insulin/IGF-1 and neurotrophin signaling and altered apoptosis. Conclusion: Reduction of cellular cholesterol in diabetes causes defects in signal transduction and function in neuron-derived cells. Significance: Reduced brain cholesterol could contribute to the higher prevalence of cognitive dysfunction and Alzheimer disease in diabetes.

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Section: Discussionsupporting

confidence: 54%

Effect of Cholesterol Reduction on Receptor Signaling in Neurons

Fukui¹,

Ferris²,

Kahn

2015

Journal of Biological Chemistry

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“…This model wherein axonal accumulations of immature lysosomes at amyloid plaques act as pathologically meaningful sites of Aβ synthesis is consistent with lesion studies that support an axonal origin of Aβ (70,71), as well as with evidence for the endolysosomal localization and APP processing activities of γ-secretase (72)(73)(74)(75). The further elucidation of mechanisms whereby extracellular Aβ deposits negatively affect the axonal transport and maturation of lysosomes could lead to new therapeutic opportunities for limiting the amyloidogenic processing of APP.…”

Section: Discussionsupporting

confidence: 81%

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Gowrishankar

Yuan

et al. 2015

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

328

326

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Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.

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“…Alterations of the endosome/lysosome system have also been previously described in AD (37). Recently it has been shown that BACE and A␤ are enriched in lysosomes-related autophagic vesicles in APP transgenic mouse models (38). These authopagic vesicles also accumulate in dystrophic neuritis in AD brains (39).…”

Section: Discussionmentioning

confidence: 87%

BACE Is Degraded via the Lysosomal Pathway

Koh

Arnim

Hyman

et al. 2005

Journal of Biological Chemistry

155

127

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Amyloid plaques are formed by aggregates of amyloid-␤-peptide, a 37-43-amino acid fragment (primarily A␤ 40 and A␤ 42 ) generated by proteolytic processing of the amyloid precursor protein (APP) by ␤-and ␥-secretases. A type I transmembrane aspartyl protease, BACE (␤-site APP cleaving enzyme), has been identified to be the ␤-secretase. BACE is targeted through the secretory pathway to the plasma membrane where it can be internalized to endosomes. The carboxyl terminus of BACE contains a di-leucine-based signal for sorting of transmembrane proteins to endosomes and lysosomes. In this study, we set out to determine whether BACE is degraded by the lysosomal pathway and whether the di-leucine motif is necessary for targeting BACE to the lysosomes. Here we show that lysosomal inhibitors, chloroquine and NH 4 Cl, lead to accumulation of endogenous and ectopically expressed BACE in a variety of cell types, including primary neurons. Furthermore, the inhibition of lysosomal hydrolases results in the redistribution and accumulation of BACE in the late endosomal/lysosomal compartments (lysosomeassociated membrane protein 2 (LAMP2)-positive). In contrast, the BACE-LL/AA mutant, in which Leu 499 and Leu 500 in the COOHterminal sequence (DDISLLK) were replaced by alanines, only partially co-localized with LAMP2-positive compartments following inhibition of lysosomal hydrolases. Collectively, our data indicate that BACE is transported to the late endosomal/lysosomal compartments where it is degraded via the lysosomal pathway and that the di-leucine motif plays a role in sorting BACE to lysosomes.

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Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for β-amyloid peptide over-production and localization in Alzheimer’s disease

Cited by 261 publications

References 68 publications

Effect of Cholesterol Reduction on Receptor Signaling in Neurons

Effect of Cholesterol Reduction on Receptor Signaling in Neurons

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

BACE Is Degraded via the Lysosomal Pathway

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