Molecular Targets Modulating Neuro COVID Sequelae Linked to Tauopathy

The COVID-19 pandemic caused by SARS-CoV-2 (CoV2) virus has left a large cohort of individuals suffering from ongoing neurological sequelae known as neuro-COVID. The condition involves CoV2 neurotropism and long-term inflammatory responses, including increases in neurodegenerative and neurotoxic proteins such as

tau. Despite progress made, the molecular mechanisms underlying CoV2-induced tauopathy are unknown. Aging activates innate immune mechanisms and inflammation, and the latter has been linked to tau pathology. Together these observations have provided a strong scientific premise for this proposal, which aims to investigate

CoV2-induced molecular changes in the context of aging and tauopathy to identify critical mechanisms underlying the development of neuro-COVID symptoms using mouse models. To this end, data in a mouse- adapted CoV2-MA10 virus infection in C57BL/6 mice show increased expression of genes involved in neuroinflammation and tauopathy risk that increase with age, which models neuro-COVID seen in the patient’s

brains. Our preliminary studies led to the identification of two groups of proteins: one involved in protein misfolding/tauopathy (FKBP51) and the other related to innate immune activation including genes involved in IFN regulation (IFI204). Our studies also showed that CoV2-MA10 accelerates tau pathology in PS19 tau

transgenic mice, establishing a model to further study tauopathy mechanisms that are accelerated by CoV2. Most notably, intranasal instillation of dendriplexes (DPX) comprising dendrimers and plasmid encoding short hairpin RNA (pshRNA) for the lead target FKBP51 in MA10-infected C57BL6 mice significantly reduced

neuroinflammation, and expression of FKBP51 and Tau phosphorylation. These findings lead to the central hypothesis that age-dependent CoV2 neuro-invasion-induced tau pathology is caused by innate immune activation and elevated FKBP51 expression. We further hypothesize that CoV2 infection induces similar

inflammation and protein misfolding in PS19 tauopathic mice, accelerating neuropathology and cognitive deficits. These hypotheses will be tested in the following two specific aims. SA #1 will assess age as a primary variable that exacerbates inflammation leading to tauopathy and long-term cognitive decline in C57BL/6 mice following

CoV2-MA10 infection. SA #2 will examine the progression of tauopathy in PS19 transgenic mice following CoV2- MA10 Infection. Each of these aims will: i) characterize neuropathology and behavior; ii) identify target mechanisms underlying the pathology and neuro-COVID sequelae using spatial transcriptomic profiling; and iii)

validate the role of FKBP51, IFI204 and other novel leads in neuropathological and cognitive consequences, using DPX formulations carrying pshRNA for these leads. This multi-PI and multi-disciplinary approach to understanding the mechanisms leading to neuro-COVID is expected to expand our basic knowledge and identify

new mechanistic targets increasing our understanding of the impact of CoV2 on pre-existing age-related or genetically pre-disposed neurodegeneration.