SARS-CoV-2 potentiation of Tau pathology in a Rhesus macaque model of tauopathy

Project Summary SARS-CoV-2 infection has emerged as a potential risk factor for long-term cognitive decline and Alzheimer's disease and related dementias (ADRD). Clinical data increasingly suggest that even mild COVID-19 cases can lead to measurable reductions in executive function, memory, and brain volume. These changes are accompanied by elevations in biomarkers of neuronal injury, glial activation, and abnormal tau phosphorylation, suggesting a mechanistic link between viral infection and neurodegeneration. However, the biological relationship between SARS-CoV-2 and tau pathology remains poorly defined. Key questions include whether SARS-CoV-2 enhances tau seeding and spread, and whether early tau pathology sensitizes the brain to immune challenge, worsening outcomes. Rodent models are limited by species-specific barriers to infection and limited modeling of human tauopathies. To overcome these challenges, we will use two complementary and translationally validated models in adult rhesus macaques developed by our group. The first employs intranasal and intratracheal inoculation to induce SARS-CoV-2 neuroinvasion, with viral proteins spreading through the olfactory connectome. The second approach utilizes intracortical AAV-2xTau delivery to the entorhinal cortex, triggering tau pathology that spreads through the medial temporal lobe. These models have independently demonstrated reproducible neuroinflammatory and structural effects. Their integration offers a unique opportunity to evaluate the synergy between infection and neurodegeneration. Specific Aim 1 will test whether prior SARS-CoV-2 infection potentiates tau pathology and associated neuroinflammation. Specific Aim 2 will assess whether pre-existing tau pathology is aggravated by a subsequent viral infection. Both arms include longitudinal biomarker sampling, high-resolution neuroimaging (MRI, OCT), and postmortem analyses of tau aggregation, glial activation, synaptic integrity, and vascular pathology. Analyses will leverage advanced 3D morphometrics, ultrastructural techniques, and NULISA proteomics to reveal multi-level interactions across biological systems. This proposal directly addresses a pressing public health concern: how viral infections may modify the trajectory of neurodegenerative disease. By clarifying whether and how SARS-CoV-2 alters tau vulnerability or progression, our findings will inform long-term monitoring and therapeutic strategies for aging individuals with or at risk for ADRD. Results will also help define broader principles of how systemic immune challenges intersect with preclinical neurodegeneration, a body of knowledge critical to the care of our growing aged population.