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 β (Aβ) peptides. Yet the role of autophagy in Aβ production and AD progression is complex. To study whether increased basal autophagy plays a beneficial role in Aβ 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 Aβ 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 Aβ 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.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by protein aggregation and deposition, leading to progressive neuronal loss and cognitive decline among elderly populations [1]
We engineered a single mutation into a key autophagy gene Becn1, which disrupts an inhibitory binding and leads to constitutively active autophagy in brain
We obtained direct evidence for the first time that oligomerized amyloids are substrates of autophagy. These findings are important, as we demonstrated the reversal of AD progression by modulating the activity of a single autophagy gene
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by protein aggregation and deposition, leading to progressive neuronal loss and cognitive decline among elderly populations [1]. Amyloid plaques are formed by amyloid-β (Aβ) peptides, generated by sequential enzymatic cleavages of amyloid precursor protein (APP) at the plasma membrane [4, 5]. Besides the well-recognized extracellular deposition of Aβ, recent studies revealed the accumulation of intracellular pools of Aβ in AD brain. Intracellular Aβ can be generated at the trans-Golgi network and endoplasmic reticulum as part of the secretory pathway, or be reuptaken by neurons and glial cells from the secreted extracellular pools [6, 7]. Many therapeutic efforts have been made to eliminate Aβ aggregation and deposition at either the synthesis or the degradation stage, no effective therapies are available so far to cure AD, and the mechanism driving the neurodegenerative progression remains unclear [8]
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