O4-05-02: Deficiency of the Beclin 1 autophagy protein promotes Alzheimer’s disease pathology

Abstract

Background: Autophagy is involved in the intracellular turnover of proteins and cell organelles and has a key role in regulating cell fate in response to stress. However, it is controversial whether autophagy exerts a pathological or protective role in neurodegenerative diseases, and it is unknown whether defects in the autophagy pathway contribute to neurodegeneration. Objectives: To determine the role of the autophagy protein Beclin 1 in Alzheimer’s Disease. Methods: Beclin 1 downregulation in affected regions of AD brains was identified by microarray analysis, and confirmed by immunoblotting. Beclin 1 deficient transgenic mice (Beclin 1 ) were crossed with mice expressing human amyloid precursor protein (APP) and analyzed for neurodegeneration and amyloid deposition. Beclin 1 expression was knocked down by siRNA in B103/APP neuroblastoma cells and APP metabolism studied. The affect of pharmacological induction of autophagy on APP metabolism in the same cell line was also studied. Results: In a search for genes associated with Alzheimer’s disease (AD) we discovered that expression of Beclin 1, a protein essential for autophagy, is reduced by 50-70% in affected entorhinal and frontal cortex of AD human brains. Heterozygous deletion of the beclin 1 gene decreased neuronal autophagy and promoted neuronal degeneration in normal mice. In transgenic mice that express human APP, a model for AD, genetic reduction of beclin 1 expression resulted in increased accumulation of APP fragments and -amyloid (A ), increased neurodegeneration and increased microgliosis. In addition, reducing Beclin 1 expression in B103/APP neuroblastoma cells by siRNA increased cellular APP, APP-CTF and secreted A levels. In contrast, inducing autophagy in B103/APP cells decreased cellular APP and APP-CTF levels. Conclusions: Beclin 1 deficiency disrupts neuronal autophagy and promotes neurodegeneration and AD-like disease. This work was funded by the John Douglas French Alzheimer’s Foundation and the National Institute of Aging.