Differential Effects of Brain-Derived Tau Oligomers on Neurogenesis in Alzheimer's Disease and Cognitively Resilient Individuals - PROJECT SUMMARY Impairment of adult hippocampal neurogenesis (AHN), a critical process for maintaining cognitive function, accelerates cognitive decline in Alzheimer’s disease (AD). A subset of individuals, termed non- demented with AD neuropathology (NDAN), however, exhibit resilience; they retain cognitive function and neurogenic capacity despite the presence of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) of tau, the hallmark pathological features of AD. This cognitive preservation has been linked to the maintenance of hippocampal neural stem cells (NSCs) and enhanced neurogenesis in NDAN individuals. Our preliminary findings uncover a novel difference between these patient groups within the very proteins associated with cognitive decline. We show that brain-derived tau oligomers (BDTOs) isolated from AD patients may accelerate NSC differentiation in vitro and in vivo, disrupting normal developmental trajectories, whereas NDAN BDTOs do not affect proper differentiation timelines. These results suggest that AD and NDAN BDTOs exert fundamentally different biological effects on neurogenesis, potentially acting through divergent signaling pathways governing NSC quiescence and lineage determination. Aim 1 will define how AD- versus NDAN-BDTOs alter NSC quiescence, proliferation, and differentiation using immunofluorescence, western blotting, and single-cell transcriptomics focused on REST-regulated pathways. Aim 2 will determine how these tau polymorphs influence hippocampal neurogenesis in vivo using retroviral labeling of NSCs and fluorescence-activated cell sorting (FACS)-isolated neurogenic populations subjected to single-nuclei sequencing. Together, these studies will clarify whether NDAN-BDTOs actively preserve neurogenic capacity or simply lack disruptive cues present in AD-BDTOs, advancing our understanding of cognitive resilience and revealing restorative therapeutic targets for AD. The integrated in vitro and in vivo design supports comprehensive training in molecular neurobiology, transcriptomics, and retroviral lineage tracing, while providing direct experience with high-dimensional datasets and cross-platform integration. Coursework, next-generation sequencing (NGS) and biostatistical workshops, targeted instruction through UTMB’s sequencing, proteomics, and biostatistics cores will all strengthen my technical and analytical skillset deepening my capacity for rigorous, reproducible science. The training environment, centered in the Micci and Taglialatela laboratories, enriched by the Mitchell Center for Neurodegenerative Diseases, the Moody Brain Health Institute, and UTMB’s interdisciplinary seminar series, provides a rigorous and collaborative setting for scientific development. Mentorships from Drs. Micci, Taglialatela, Montalbano, Hommel, Abisambra, and Marino will reinforce growth in experimental design, computational reasoning, and scientific communication, ensuring sustained progress toward research independence. These combined research and training activities will prepare me to pursue my long-term goal of becoming an independent researcher focused on regenerative and resilience-based strategies in neurodegeneration.
