R01AG083963

Investigating the role of long-term latent herpes simplex virus infection on APOE4-associated Alzheimer's disease pathogenesis - project summary.

47 million people worldwide are living with Alzheimer's disease (AD) or a related form of dementia. In the US alone, the annual health care costs for people with AD will exceed 1 trillion dollars by 2050. However, current treatments do not robustly prevent disease progression.

The major risk factors for the late-onset form of AD are advanced age and possession of the E4 allele of apolipoprotein E (APOE). Importantly, increasing data support the hypothesis that latent herpes simplex virus 1 (HSV-1) infection is also a risk factor, especially in combination with the APOE4 allele. This suggests that current antivirals may halt or delay neurodegenerative disease progression in APOE4 carriers who are infected with HSV-1.

A major gap in the study of this association, however, is the absence of an HSV infection model reflecting the complexity of long-term latent infection, particularly in the context of APOE4 and AD.

In our preliminary studies, we observed that HSV-1-infected APOE4 mice, compared to mock-infected APOE4 mice and HSV-1-infected WT mice, displayed robust spatial memory deficits, as well as oxidative stress, iron dysregulation, and gliosis in the CNS when assessed 15 months post infection (MPI), but not at 3 MPI.

The objective of this proposal is to use this model, as well as complementary in vitro models, to fully elucidate the effects of long-term latent HSV-1 infection, in the context of differential APOE isoform expression, on brain function and AD pathogenesis. We will also assess whether treatment with a novel, brain-penetrant antiviral medication can block these effects.

We anticipate that the full study proposed herein will uncover unique and important interactions between HSV-1 infection and APOE genotype in driving AD pathogenesis, potentially leading to safe and effective new therapeutic strategies for preventing or slowing AD in at-risk individuals.

The Trustees Of Columbia University In The City Of New York

NOT APPLICABLE

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

New York, New York 100323725 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-22-093)

Amendment Since initial award the total obligations have increased 295% from $831,493 to $3,281,330.