Brain aging and Aβ_1–42 neurotoxicity converge via deterioration in autophagy–lysosomal system: a conditional Drosophila model linking Alzheimer’s neurodegeneration with aging

Aging is known to be the most prominent risk factor for Alzheimer’s disease (AD); however, the underlying mechanism linking brain aging with AD pathogenesis remains unknown. The expression of human amyloid beta 42 peptide (Aβ_1–42), but not Aβ_1–40 in Drosophila brain induces an early onset and progressive autophagy–lysosomal neuropathology. Here we show that the natural process of brain aging also accompanies a chronic and late-onset deterioration of neuronal autophagy–lysosomal system. This process is characterized by accumulation of dysfunctional autophagy–lysosomal vesicles, a compromise of these vesicles leading to damage of intracellular membranes and organelles, necrotic-like intraneuronal destruction and neurodegeneration. In addition, conditional activation of neuronal autophagy in young animals is protective while late activation is deleterious for survival. Intriguingly, conditional Aβ_1–42 expression limited to young animals exacerbates the aging process to a greater extent than Aβ_1–42 expression in old animals. These data suggest that the neuronal autophagy–lysosomal system may shift from a functional and protective state to a pathological and deleterious state either during brain aging or via Aβ_1–42 neurotoxicity. A chronic deterioration of the neuronal autophagy–lysosomal system is likely to be a key event in transitioning from normal brain aging to pathological aging leading to Alzheimer’s neurodegeneration.