‘S1-03-04: The autophagy protein Beclin 1 is reduced in early Alzheimer's disease and regulates Abeta accumulation in vivo

Abstract

Background: Autophagy is the principal cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. It has recently been implicated in neurodegeneration but it is unclear whether it is detrimental or protective. Methods: We used postmortem human brain tissue, mouse models of Alzheimer’s disease (AD) and autophagy, lentiviral vectors, and cell culture models to study expression and function of Beclin 1, a protein with a key role in autophagy, in AD pathogenesis. Results: We discovered that Beclin 1 is decreased early in affected brain regions of patients with AD. Heterozygous deletion of Beclin 1 (Bcn1) in mice decreased neuronal autophagy and resulted in neurodegeneration and disruption of lysosomes. In transgenic mice that express human amyloid precursor protein (APP), a model for AD, genetic reduction of Bcn1 expression increased intraneuronal beta amyloid (A ) accumulation, extracellular A deposition, neurodegeneration, and caused microglial changes and profound neuronal ultrastructural abnormalities. Increasing Beclin 1 expression by lentiviral delivery reduced both intracellular and extracellular amyloid pathology in APP transgenic mice. Conclusions: We conclude that Beclin 1 deficiency disrupts neuronal autophagy, modulates APP metabolism and promotes neurodegeneration in mice and that increasing Beclin 1 may have therapeutic potential in AD.