Alzheimer's Disease (AD) is an age-related disorder that causes a dramatic loss of cognitive function and affects millions of elderly individuals worldwide. It is characterized pathologically by the presence of protein aggregates of beta amyloid (AB) and tau and a progressive neurodegeneration. There is exceedingly strong evidence that abnormal assemblies of AB are neurotoxic and have a key role in AD. Why AB accumulates or induces neurodegeneration is unclear. Following up on a report that linked Beclin 1, an essential protein involved in the early steps of autophagy, to neurodegeneration and cell death in the lurcher mouse we decided to explore the possibility that Beclin 1 and autophagy may have a role in AD. Autophagy is the major pathway involved in the degradation of long-lived proteins and organelles, cellular remodeling, and survival during nutrient starvation. It is unclear whether autophagy exerts a pathological or protective role in neurodegeneration and Alzheimer's Disease. We discovered that expression of Beclin 1 is reduced more than 50% in gray matter of the frontal cortex in postmortem brains from AD cases compared with age-matched cases of Lewy body variant of AD, Huntington's disease, Parkinson's disease, or nondemented controls. This decrease was not simply due to a loss of neurons since levels of the neuronal protein neuron specific enolase were not altered. We found that genetic reduction of Beclin 1 expression in beclin 1-/+ haploinsufficient mice results in less autophagy in primary neurons and is associated with neurodegeneration in 9-month-old mice. Beclin 1 deficiency in APP transgenic mice, a model for AD, results in increased accumulation of fragments of APP and AB in cells and in the extracellular space and was associated with increased inflammation. In addition, increased autophagy in cultured neuroblastoma cells reduces APP fragments while siRNA mediated reduction in Beclin 1 expression increases APP fragments and AB. Together, these studies provide strong evidence for a role of Beclin 1 and autophagy in AD pathogenesis and they open a new pathway to potentially target this disease. The goal of this application is to determine how Beclin 1 is regulated in neurons and in mouse brains, how it affects the production and turnover of AB and its precursors, and whether increased production of Beclin 1 may be protective and ameliorate neurodegeneration and AD-like disease in mice. We also expect to establish that Beclin 1 is a major modifier of AD pathogenesis and that increasing Beclin 1 levels reduces disease. If successful, our findings may provide new targets for the treatment of AD and neurodegeneration.

Public Health Relevance

Alzheimer's Disease (AD) affects millions of people worldwide. It is characterized by the accumulation of proteins in the brain inside and outside of neurons. We discovered a novel mechanism that neurons use to normally rid themselves of old or damaged proteins to be defective in AD. If we inhibit this protein degradation process in AD mice they develop more disease. We propose to study this process to try to reduce disease in mice and possibly in AD.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Refolo, Lorenzo
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Palo Alto Institute for Research & Edu, Inc.
Palo Alto
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O'Brien, Caitlin E; Bonanno, Liana; Zhang, Hui et al. (2015) Beclin 1 regulates neuronal transforming growth factor-? signaling by mediating recycling of the type I receptor ALK5. Mol Neurodegener 10:69
Mosher, Kira Irving; Wyss-Coray, Tony (2014) Microglial dysfunction in brain aging and Alzheimer's disease. Biochem Pharmacol 88:594-604
O'Brien, Caitlin E; Wyss-Coray, Tony (2014) Sorting through the roles of beclin 1 in microglia and neurodegeneration. J Neuroimmune Pharmacol 9:285-92
Miller, Zachary A; Rankin, Katherine P; Graff-Radford, Neill R et al. (2013) TDP-43 frontotemporal lobar degeneration and autoimmune disease. J Neurol Neurosurg Psychiatry 84:956-62
Lucin, Kurt M; O'Brien, Caitlin E; Bieri, Gregor et al. (2013) Microglial beclin 1 regulates retromer trafficking and phagocytosis and is impaired in Alzheimer's disease. Neuron 79:873-86
Czirr, Eva; Wyss-Coray, Tony (2012) The immunology of neurodegeneration. J Clin Invest 122:1156-63
Jaeger, Philipp A; Pickford, Fiona; Sun, Chung-Huan et al. (2010) Regulation of amyloid precursor protein processing by the Beclin 1 complex. PLoS One 5:e11102
Jaeger, Philipp A; Wyss-Coray, Tony (2010) Beclin 1 complex in autophagy and Alzheimer disease. Arch Neurol 67:1181-4
Lucin, Kurt M; Wyss-Coray, Tony (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64:110-22
Spencer, Brian; Potkar, Rewati; Trejo, Margarita et al. (2009) Beclin 1 gene transfer activates autophagy and ameliorates the neurodegenerative pathology in alpha-synuclein models of Parkinson's and Lewy body diseases. J Neurosci 29:13578-88

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