Brain aging and Ab1–42 neurotoxicity converge via deterioration in autophagy–lysosomal system: a conditional Drosophila model linking Alzheimer’s neurodegeneration with aging
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Daijun Ling Paul M. Salvaterra
- چاپ و سال / کشور: 2010
Description
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 (Ab1–42), but not Ab1–40 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 lateonset 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 Ab1–42 expression limited to young animals exacerbates the aging process to a greater extent than Ab1–42 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 Ab1–42 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
Acta Neuropathol (2011) 121:183–191Received: 2 August 2010 / Revised: 24 September 2010 / Accepted: 28 October 2010 / Published online: 14 November 2010 DOI 10.1007/s00401-010-0772-0
