title: Brain aging and Aβ₁₋₄₂ neurotoxicity converge via deterioration in autophagy-lysosomal system: a conditional Drosophila model linking Alzheimer's neurodegeneration with aging.
abstract: 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 (Aβ₁₋₄₂), but not Aβ₁₋₄₀ 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 Aβ₁₋₄₂ expression limited to young animals exacerbates the aging process to a greater extent than Aβ₁₋₄₂ 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 Aβ₁₋₄₂ 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.
authors.affiliation: Department of Neuroscience, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Daijun
authors.initials: D
authors.lastname: Ling
authors.forename: Paul M
authors.initials: PM
authors.lastname: Salvaterra
mesh_terms: D000367:Age Factors; D000375:Aging; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000633:toxicity*; D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006727:Hormone Antagonists / Q000008:administration & dosage; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D018613:Microscopy, Confocal / Q000379:methods; D046529:Microscopy, Electron, Transmission / Q000379:methods; D015735:Mifepristone / Q000008:administration & dosage; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010446:Peptide Fragments / Q000235:genetics / Q000633:toxicity*
chemical_list: D016229:Amyloid beta-Peptides; D029721:Drosophila Proteins; D006727:Hormone Antagonists; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D049452:Green Fluorescent Proteins; D015735:Mifepristone