Martin Darvas - US grants

Alzheimer 's disease (AD) affects millions of Americans and causes significant morbidity and mortality. Although genetic determinants of AD have been a major focus of research over the last three decades, there is limited insight into co-factors that contribute to AD pathology and progression. Recent genetic associations implicating alterations in innate immunity to risk for AD, suggest that environmental factors, such as infection, may modulate brain immune function and could also play a role in AD. Previous studies have suggested that chronic infection of neurotropic herpesviruses could be one factor that contributes to the development of AD pathology. In particular, herpes simplex virus type 1 (HSV-1) DNA has been found in AD brains and in ?-amyloid plaques. Through careful multiscale network analysis of the large RNA-seq. datasets within the Accelerating Medicines Partnership-AD (AMP-AD) consortium, we have observed an increased abundance of transcripts derived from several herpesvirus family members across multiple brain regions from subjects with AD, and we have found that HSV-1 expression was associated with the clinical dementia score of AD patients. Notably, this observation has been replicated across three independent AMP- AD RNA-seq studies. We found evidence of viral mimicry upon viewing our viral/AD-associated genes through the lens of transcriptional regulatory networks. We have identified candidate transcription factors and their downstream targets associated with viral expression, as well as kinases that regulate activity of those transcription factors. Additionally, HSV-1 transcripts were associated with increased expression of several key regulators of APP processing. We propose to explore this provocative transcriptomic data using a set of experiments that will determine if expression of herpesviruses encoded proteins and HSV-1 infection contributes to the development and progression of AD. We hypothesize that neurotropic herpesvirus infection alters transcriptional regulatory networks of known AD genes to drive pathology. Two parallel lines of investigation will be conducted. The first will combine the experience of the multidisciplinary team with neuropathology, HSV-1 biology, HSV infection in mice and RNA-seq analysis to directly ask (1) whether active viral infection with HSV-1 can alter AD pathology or enhance preexisting pathology in mouse models of AD pathology, and (2) perform longitudinal assessments of changes in AD-relevant RNA expression in HSV-1 infected AD mice. Through our comparative approach and computational modeling, we will characterize how HSV-1 infection impacts known AD pathways and neuropathological features. The second will leverage the use of adeno-associated viral vectors to express candidate transcription factors identified in AMP-AD RNA-seq. studies in: brain slice cultures and mouse models of AD pathology. As a result, we will establish new models and a testing procedure including ex vivo and in vivo models that allow us to explore our provocative RNA-seq. AMP-AD data in way that could rapidly inform a novel anti-viral based therapeutic approach to AD.

Abstract The parent grant for this supplement application is R01 AG067193, ?A geroscience approach for treating Alzheimer's disease?. The supplement proposal is an extension of the parent grant and is titled ?A geroscience approach for investigating resilience to SARS-CoV-2 pathology in mice with Alzheimers disease?. The extension is designed to look at the complications of COVID-19 in the presence of cognitive impairment and neuropathological lesions of Alzheimer's disease in an aging mouse model. This is translationally relevant because patients with cognitive impairment related to Alzheimer's disease (AD) are at increased risk for complications of SARS-CoV-2 infection. Several factors are involved including cognitive impairment resulting in failure to follow exposure guidelines, such as crowd mingling, hand washing and other decontamination procedures. In addition, many individuals that require various levels of intensive care may come in close contact with others with similar poor health conditions that may be carrying the virus. Lastly, the debilitating effects of AD may inherently increase susceptibility to the severe complications of SARS-CoV-2 infection known to occur in older frail people. For these reasons, it is critical to investigate the mitigating factors associated with increasing resilience to pathological consequences of infection to prevent increased morbidity and mortality in an already susceptible elderly population. Given that a major risk factor for developing severe and fatal SARS-CoV-2 pathology is aging, it is thus a centerpiece for the geroscience concept that examines the relationship between biological aging and age-related diseases through multiple processes, and that aging intervention requires targeting multiple aging processes. Our parent grant is set up to address this concept for AD. The development of a multidrug cocktail that targets multiple aging processes and increases resilience to AD pathology should, by definition, also increase resilience to SARS-CoV-2 pathology in AD patients. The hypothesis of this supplement proposal is that a drug cocktail of rapamycin, acarbose, and phenylbutyrate, targeting multiple aging processes, will increase resilience to the pathological consequences of SARS-CoV-2 infection in an aging mouse model of AD. Aim 1 will investigate effects of treatment with an anti-aging drug cocktail in AD mice infected with SARS-CoV-2. Aim 2 will develop pathology profiles to show that treatment of AD mice with an anti-aging drug cocktail will enhance resilience and improve health by targeting processes of aging and prevent the devastating pathology caused by SARS-CoV-2 infection. This approach has tremendous clinical health implications for AD patients but perhaps just as important for individuals in the early stage of disease such as mild cognitive impairment. The concept of a drug cocktail that could successfully increase resilience to COVID-19 pathology in Alzheimers disease patients would be expected to have a significant impact on the health of people at increased risk for infection.