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 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. Indeed, the production of A?, which accumulates into amyloid plaques in AD brains, is not increased in sporadic AD but it is now largely accepted that, instead, its clearance is impaired. One way in which A? can be cleared from brains is through microglial phagocytosis. We, and others, discovered that microglia become inflamed and defective in phagocytosis with ?normal? aging, and our unpublished results show that a young systemic environment can reverse some of these dysfunctions. Aged, dysfunctional microglia may thus be a predisposing factor for age-related neurodegeneration including AD. However, the mechanisms of age-related microglial dysfunction are poorly understood. We propose here to investigate the mechanisms of impaired microglial phagocytosis in the aging brain and to evaluate therapeutic strategies to reverse this impairment in models of AD. Preliminary data from an unbiased CRISPR-Cas9 knockout screen suggest that cell-surface sialic acid, an immunomodulatory glycan modification, inhibits phagocytosis in aged microglia, and that CD22, a sialic acid receptor upregulated on aged microglia in mice and in humans with AD, mediates this inhibition. Based on the available published background and our preliminary data we hypothesize that CD22 on microglia inhibits phagocytosis and that targeting CD22 can improve phagocytosis and ameliorate AD-like disease and neurodegeneration. We propose to use genomic and genetic tools to find potential modulators of CD22 function to establish CD22 as an age-related inhibitor of microglial phagocytosis and generate a framework for understanding the mechanistic basis of this function. We propose, furthermore, to inhibit CD22 genetically or using a monoclonal antibody in transgenic mice expressing mutant human amyloid precursor protein APP751Lon,Swe and developing disease around 10 months of age as well as overexpress CD22 transgenically in microglia in newly developed APP knock-in (APPki) mice, which express non-mutated human A? in the endogenous mouse APP gene and develop disease around 18 months of age. At completion of the proposed studies we will have a solid foundation of understanding how CD22 regulates phagocytosis in microglia, and aging microglia in particular, and whether targeting CD22 may have therapeutic potential for treating AD-like disease in Veterans and their loved ones.

Public Health Relevance

According to the National Center for Veterans Statistics, 53% of Veterans, or roughly 9.86 million men and women were older than 65 in 2016. 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 #
5I01BX004544-02
Application #
9911972
Study Section
Special Emphasis Panel (ZRD1)
Project Start
2019-04-01
Project End
2023-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
2
Fiscal Year
2020
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