Non-cell autonomous disruption of genomic interactions as a cause of dementia

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Summary/Abstract Olfactory dysfunction is considered a prodrome syndrome of Alzheimer’s Disease (AD) and Dementia. Yet, the molecular and cellular mechanisms that cause olfactory deficits in AD patients before the onset of cognitive decline remain unknown. Here, we built upon our recent observations on the mechanisms of SARS-CoV-2 mediated anosmia to decipher how protein misfolding and aggregation in a small fraction of sensory neurons can cause widespread deficits in odor detection by the olfactory system. Our studies on hamsters and humans, revealed that interchromosomal genomic interactions required for olfactory receptor (OR) expression are extremely fragile and dissipate rapidly in response to inflammatory signals elicited by SARS-CoV-2 infection. Strikingly, similar disruption of nuclear architecture is revealed by our preliminary data in mouse models for AD which also exhibit similar inflammatory signatures with the SARS-CoV-2 infected hamsters. Based on these striking similarities between the two conditions, we propose to investigate the provocative premise that anosmia in AD is caused by non-cell autonomous disruption of genomic OR compartments and, thus, OR downregulation. We will experimentally test whether sporadic expression of human APP mutants linked to AD can change the patterns of interchromosomal interactions of naive olfactory neurons, and we will explore if the serum of human APP-expressing mice can alter the nuclear architecture of wild type neurons, mimicking our observations for COVID-19. Finally, expanding on our recent skills in analyzing the nuclear architecture of olfactory neurons from human autopsies, we will investigate whether similar changes are observed in human olfactory neurons of AD patients. Our proposed experiments have the potential to uncover novel molecular and cellular mechanisms of propagation of AD pathology, and to enable the development of molecular diagnostics that can predict whether late onset olfactory dysfunction is a prodrome of AD.