Alzheimer's disease (AD) produces a progressive degeneration of the brain that slowly destroys a victim's cognitive abilities and inflicts tremendous social and economic burden on families and society in general. As many as a 20% of the estimated five million Americans with AD are Veterans, and with no effective treatments available currently, the Alzheimer's Association expects the number of patients will triple in the next 20 years. The cause(s) of AD is unknown in most cases but growing evidence suggests that cellular clearance and protein degradation pathways may be impaired in the disease providing potential new targets for therapeutic intervention. Recently, several studies, including from our lab, have implicated the autophagy protein, beclin 1, in A? turnover and neurodegeneration. These studies show that full length beclin 1 together with its binding partner vps34 is strongly reduced in AD brains and that reducing beclin 1 in AD model mice results in more A? accumulation and neurodegeneration. Still the precise mechanisms of these effects remain unclear. Beclin 1 is classically attributed with initiating autophagy, which is the major pathway involved in the degradation of long- lived proteins and organelles. However, studies in yeast show that beclin 1 may also play a critical role in other cellular processes. Most notably, the beclin 1 ortholog Atg6 regulates vacuolar protein sorting in yeast, a rudimentary lysosomal sorting pathway that can promote the degradation or re-use of cellular components. Moreover, in mammalian cells autophagy proteins, including beclin 1, localize to phagocytic cups and autophagy can enhance phagocytosis. Our preliminary data demonstrate that reducing beclin 1 in microglia impairs their capacity to clear amyloid plaques from brain sections in situ as well as to phagocytose latex beads in culture. We find that knocking down beclin 1 leads to reduced levels of the retromer protein vps35, a mammalian protein involved in sorting cellular components to the lysosome or back to defined compartments (e.g., the cell surface) and impaired recycling of the phagocytic receptor CD36. Interestingly, beclin 1 can be cleaved by caspases and the resulting fragments may interfere with normal beclin 1 function. Taken together we propose the hypothesis that reduced beclin 1 or beclin 1 fragments impair microglial phagocytosis by disrupting vps35-mediated recycling of phagocytic receptors, resulting in the accumulation of A? and cellular debris during AD. To test this hypothesis and its relevance in contributing to the progression of AD we propose to determine whether impaired phagocytosis following beclin 1 reduction is mediated by diminished vps35 levels and impaired phagocytic receptor recycling, and whether full-length beclin 1 or its caspase-cleaved fragments modulate phagocytosis and receptor recycling. In addition, we propose to determine the consequences of reduced microglial beclin 1 on phagocytosis and Alzheimer's-like disease in mice. At the end of the proposed studies we expect to have a better understanding of the function of beclin 1 in microglia and how beclin 1 deficiency observed in AD patients may impair microglia clearance of A? and other proteins or particles in the brain. This knowledge will hopefully help us to identify novel targets for the treatment of this devastating disease.

Public Health Relevance

According to the National Center for Veterans Statistics, 43% of Veterans, or roughly 9.3 million men and women are older than 65. In 1992 only 26% were in that age group. With this dramatic increase in the aged population, there has been a profound increase in age-associated diseases with Alzheimer's disease taking the lead. According to statistics from the Alzheimer's Association an estimated one million or 20% of all AD cases in the US are Veterans. This clearly is a major challenge to the scientific community and health professionals alike and we believe our novel research approach using mouse models of AD can help in identifying possible therapeutic targets for this devastating disease.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001319-02
Application #
8422875
Study Section
Neurobiology D (NURD)
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
Indirect Cost
Name
Veterans Admin Palo Alto Health Care Sys
Department
Type
DUNS #
046017455
City
Palo Alto
State
CA
Country
United States
Zip Code
94304