# Selective vulnerability and resilience to trans-synaptic pathological tau spreading in Alzheimers disease

> **NIH NIH R21** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2024 · $240,000

## Abstract

PROJECT SUMMARY
 The incidence of Alzheimer’s disease (AD) is on the rise, and we are in dire need of effective
treatments. In AD, the spatiotemporal progression of tau pathology within the CNS remains the strongest
neuropathological correlate of cognitive impairment, thus constituting a likely effective treatment target ( long-
term goal). Compelling evidence supports a trans-synaptic framework for pathological tau spreading, driven
primarily by the propagation of toxic soluble tau oligomer (tauO) conformers between functionally connected
brain regions. Numerous investigations further postulate the influence of amyloid-beta (Aβ) on trans-
neuronal pathological tau spreading, while emerging evaluations of primary tauopathies (e.g. Primary Age
Related Tauopathy—PART), which lack Aβ, observe limited regional tau spreading alongside little-to-no
amnestic changes. Within the trans-synaptic spreading framework, however, the precise mechanisms by
which tauO selectively engage key synaptic subtypes (e.g. excitatory vs. inhibitory), and the role of Aβ in
this process, remain unknown. We thus hypothesize that Aβ modulates pathological tau spreading by
increasing oligomeric tau binding and internalization to vulnerable synapses. To support this hypothesis, we
provide novel preliminary evidence for increased binding and internalization of toxic tauO binding in the
presence of soluble Aβ oligomers in human synapses. In Aim 1, we will determine the role of AβO in
modulating synaptic tauO binding within a framework of cellular, regional and clinical resilience to
pathological tau burden. In Aim 2, we will determine key synaptic proteins that modulate the binding and/or
internalization of tauO in the presence and absence of AβO. To execute these aims, we have developed an
innovative and translationally relevant approach to interrogate mechanisms of tau binding directly in human
synapses isolated from post-mortem autopsy specimen using an array of biochemical techniques. At the
completion of this project, we expect to document previously unappreciated mechanisms that modulate
synaptic tauO binding and internalization—a key component of pathological tau spreading.

## Key facts

- **NIH application ID:** 10984333
- **Project number:** 1R21AG089708-01
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Giulio Taglialatela
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $240,000
- **Award type:** 1
- **Project period:** 2024-07-15 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984333

## Citation

> US National Institutes of Health, RePORTER application 10984333, Selective vulnerability and resilience to trans-synaptic pathological tau spreading in Alzheimers disease (1R21AG089708-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10984333. Licensed CC0.

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