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Publication
A Becn1 mutation mediates hyperactive autophagic sequestration of amyloid
oligomers and improved cognition in Alzheimer's disease.
Authors Rocchi A, Yamamoto S, Ting T, Fan Y, Sadleir K, Wang Y, Zhang W, Huang S, Levine
B, Vassar R, He C
Submitted By Submitted Externally on 7/24/2018
Status Published
Journal PLoS genetics
Year 2017
Date Published 8/1/2017
Volume : Pages 13 : e1006962
PubMed Reference 28806762
Abstract Impairment of the autophagy pathway has been observed during the pathogenesis of
Alzheimer's disease (AD), a neurodegenerative disorder characterized by abnormal
deposition of extracellular and intracellular amyloid ß (Aß) peptides. Yet the
role of autophagy in Aß production and AD progression is complex. To study
whether increased basal autophagy plays a beneficial role in Aß clearance and
cognitive improvement, we developed a novel genetic model to hyperactivate
autophagy in vivo. We found that knock-in of a point mutation F121A in the
essential autophagy gene Beclin 1/Becn1 in mice significantly reduces the
interaction of BECN1 with its inhibitor BCL2, and thus leads to constitutively
active autophagy even under non-autophagy-inducing conditions in multiple
tissues, including brain. Becn1F121A-mediated autophagy hyperactivation
significantly decreases amyloid accumulation, prevents cognitive decline, and
restores survival in AD mouse models. Using an immunoisolation method, we found
biochemically that Aß oligomers are autophagic substrates and sequestered inside
autophagosomes in the brain of autophagy-hyperactive AD mice. In addition to
genetic activation of autophagy by Becn1 gain-of-function, we also found that
ML246, a small-molecule autophagy inducer, as well as voluntary exercise, a
physiological autophagy inducer, exert similar Becn1-dependent protective
effects on Aß removal and memory in AD mice. Taken together, these results
demonstrate that genetically disrupting BECN1-BCL2 binding hyperactivates
autophagy in vivo, which sequestrates amyloid oligomers and prevents AD
progression. The study establishes new approaches to activate autophagy in the
brain, and reveals the important function of Becn1-mediated autophagy
hyperactivation in the prevention of AD.




Strains




Genes
SymbolDescription
Becn1beclin 1 (coiled-coil, myosin-like BCL2-interacting protein)

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