Autophagy-Derived Alzheimer’s Pathogenesis

Ling, Daijun; Salvaterra, Paul M.

doi:10.5772/17681

Cited by 1 publication

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“…Our previously data (Ling et al, 2009 ; Ling and Salvaterra, 2011d ), as well as data presented here suggest a potential AEL-dependent mechanism for extracellular plaque-like formation in Aβ 1–42 -expressing Drosophila . First, APP amyloidogenic proteolysis is not necessary.…”

Section: Discussionsupporting

confidence: 80%

“…The underlying cellular pathogenic mechanisms resulting in these cardinal hallmarks of the disease are not completely understood and even less is known about other types of AD-related neuropathology such as the early intracellular accumulation of GVD (granulovacuolar degeneration) bodies, a feature not only of AD but also other neurodegenerative diseases (Okamoto et al, 1991 ). GVD bodies exhibit properties of autophagic, endocytic, and lysosomal vesicles (Funk et al, 2011 ; Ling and Salvaterra, 2011a ).…”

Section: Introductionmentioning

confidence: 99%

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Accumulation of Amyloid-Like Aβ_1–42 in AEL (Autophagy–Endosomal–Lysosomal) Vesicles: Potential Implications for Plaque Biogenesis

2014

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Abnormal accumulation of Aβ (amyloid β) within AEL (autophagy–endosomal–lysosomal) vesicles is a prominent neuropathological feature of AD (Alzheimer's disease), but the mechanism of accumulation within vesicles is not clear. We express secretory forms of human Aβ1–40 or Aβ1–42 in Drosophila neurons and observe preferential localization of Aβ1–42 within AEL vesicles. In young animals, Aβ1–42 appears to associate with plasma membrane, whereas Aβ1–40 does not, suggesting that recycling endocytosis may underlie its routing to AEL vesicles. Aβ1–40, in contrast, appears to partially localize in extracellular spaces in whole brain and is preferentially secreted by cultured neurons. As animals become older, AEL vesicles become dysfunctional, enlarge and their turnover appears delayed. Genetic inhibition of AEL function results in decreased Aβ1–42 accumulation. In samples from older animals, Aβ1–42 is broadly distributed within neurons, but only the Aβ1–42 within dysfunctional AEL vesicles appears to be in an amyloid-like state. Moreover, the Aβ1–42-containing AEL vesicles share properties with AD-like extracellular plaques. They appear to be able to relocate to extracellular spaces either as a consequence of age-dependent neurodegeneration or a non-neurodegenerative separation from host neurons by plasma membrane infolding. We propose that dysfunctional AEL vesicles may thus be the source of amyloid-like plaque accumulation in Aβ1–42-expressing Drosophila with potential relevance for AD.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Accumulation of Amyloid-Like Aβ_1–42 in AEL (Autophagy–Endosomal–Lysosomal) Vesicles: Potential Implications for Plaque Biogenesis

2014

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Autophagy-Derived Alzheimer’s Pathogenesis

Cited by 1 publication

References 123 publications

Accumulation of Amyloid-Like Aβ_1–42 in AEL (Autophagy–Endosomal–Lysosomal) Vesicles: Potential Implications for Plaque Biogenesis

Accumulation of Amyloid-Like Aβ_1–42 in AEL (Autophagy–Endosomal–Lysosomal) Vesicles: Potential Implications for Plaque Biogenesis

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Autophagy-Derived Alzheimer’s Pathogenesis

Cited by 1 publication

References 123 publications

Accumulation of Amyloid-Like Aβ1–42 in AEL (Autophagy–Endosomal–Lysosomal) Vesicles: Potential Implications for Plaque Biogenesis

Accumulation of Amyloid-Like Aβ1–42 in AEL (Autophagy–Endosomal–Lysosomal) Vesicles: Potential Implications for Plaque Biogenesis

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Accumulation of Amyloid-Like Aβ_1–42 in AEL (Autophagy–Endosomal–Lysosomal) Vesicles: Potential Implications for Plaque Biogenesis

Accumulation of Amyloid-Like Aβ_1–42 in AEL (Autophagy–Endosomal–Lysosomal) Vesicles: Potential Implications for Plaque Biogenesis