Synaptic dysfunction, tau spreading, and cognitive resilience through the lens of tau oligomers in Alzheimer’s disease and related dementias

The central aim of this dissertation is to elucidate the molecular mechanisms underlying human tauopathies, with an emphasis on Alzheimer’s disease (AD)—the most prevalent and well-characterized tauopathy. Pathological tau species are among the earliest inclusions observed in post-mortem brains of individuals with dementia and strongly correlate with cognitive decline. This work focuses on the role of the microtubule-associated protein tau, particularly in its oligomeric conformation (tauO), in mediating synaptic dysfunction, trans-synaptic spread, and selective vulnerability. Given that synapses form the neural basis of memory encoding, investigating whether and how tauO modulate synaptic pathophysiology may offer critical insights into the pathogenesis of human tauopathies. This dissertation is structured around four stand-alone experimental chapters, framed by an Introduction and Conclusion, and draws upon analyses of post-mortem human brain specimens from healthy Controls, AD, and primary age-related tauopathy (PART) cases. Chapter 1 provides a conceptual framework, reviewing literature on tau biology, synaptic mechanisms, and selective vulnerability. In Chapter 2, we show that amyloid-β oligomers (AβO) promote the binding and internalization of tauO into human synaptosomes via specific membrane protein pathways, suggesting a mechanism for Aβ-facilitated trans-synaptic spread of tau pathology. Chapter 3 reveals that distinct tau species exert region-specific effects on the synaptic excitation/inhibition (sE/I) ratio, with oligomeric and fibrillar tau associated with a pro-inhibitory shift in the PART hippocampus. Chapter 4 builds on this observation by showing that tauO preferentially target presynaptic and GABAergic terminals, functionally enhancing ligand-gated GABAergic currents without affecting excitatory (kainate-sensitive) responses. Proteomic analysis of brain-derived tau oligomers (BDTO) from PART autopsy brain specimens reveals enrichment in presynaptic vesicle release machinery, reinforcing the concept of targeted synaptic vulnerability. In Chapter 5, we look beyond the synapse to identify vulnerability- and resilience-associated pathways through unbiased proteomic profiling and comparative analysis of BDTO from AD, NDAN, and PART, revealing candidate modifiers of tauO-mediated neurodegeneration. Collectively, this work advances our understanding of synaptic pathophysiology, tau spreading, and cognitive resilience, unified by the central role of tau oligomers. These findings offer novel mechanistic insights that may inform the rational design of future biomarkers and therapeutic strategies to combat human tauopathies.

Name thesis:degree_name

Neuroscience (Doctoral)

Grantor

The University of Texas Medical Branch at Galveston

Year dc:date.issued

2026

Author dc:creator

• Kadamangudi, Shrinath 1993-

Advisor dc:contributor.advisor

• Taglialatela, Giulio (gtaglial@utmb.edu)

Committee members dc:contributor.committeemember

• Kayed, Rakez (rakayed@utmb.edu)
• Krishnan, Balaji (bakrishn@utmb.edu)
• Diamond, Marc (Marc.Diamond@UTSouthwestern.edu)
• Limon, Agenor (aglimonr@utmb.edu)

Language dc:language.iso

English

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/12885

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/12885