UNIVERSITY GRADUATE SCHOOL BULLETIN ANNOUNCEMENT

Florida International University
University Graduate School

Doctoral Dissertation Defense
Abstract

Defining the Microglia TSPO response to Amyloid and Tau Pathology in Alzheimer’s Disease
by Daniel Andres Martinez Perez

Alzheimer’s disease (AD) is the most common form of dementia and the most prevalent neurodegenerative disorder worldwide. AD is characterized by progressive cognitive decline and the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tau tangles (NFTs). These pathological features elicit a neuroinflammatory response in which the Translocator Protein 18 kDa (TSPO) is widely used as an imaging biomarker using Positron Emission Tomography (PET). However, its role in AD onset and progression remains unclear. Here, we investigated the temporal emergence, cellular sources, and pathological associations of TSPO using 5XFAD transgenic AD mice and postmortem human AD brain tissue.
In 5XFAD mice, TSPO levels increased in an age- and sex-dependent manner, with the earliest elevation detected in the subiculum at 1.5 months of age. Notably, TSPO upregulation preceded measurable cognitive deficits and increased serum levels of neurofilament light chain (NfL), a biomarker of neurodegeneration. The TSPO increase coincided with the early appearance of Aβ plaques in the subiculum and increased serum Aβ1-42/Aβ1-40 ratio. These findings indicate that TSPO upregulation represents an early neuroinflammatory event rather than a secondary response to neuronal degeneration. At the cellular level, increased TSPO levels originated from activated microglia, particularly those in direct contact with Aβ plaques, which expressed higher TSPO levels than non-plaque-associated microglia. Cell-type–specific analyses revealed that TSPO upregulation was primarily driven by microglia associated with A plaques, with no detectable contribution from astrocytes.
Analyses of human AD postmortem tissue corroborated these findings. That is, TSPO expression was increased in AD brains and localized to Aβ plaque-associated microglia but not astrocytes. Microglial number and TSPO volume per cell were elevated, predominantly in association with Aβ plaques and not with tau associated pathology in the form of neurofibrillary tau tangles and neuropil threads.
Collectively, these results identify microglial TSPO as an early plaque-associated marker of neuroinflammation in AD. These findings suggest that heightened TSPO expression reflects a microglial phenotype driven primarily by Amyloid-β pathology, potentially contributing to neuroinflammatory toxicity and AD progression. Furthermore, the results support the therapeutic potential of targeting TSPO-expressing microglia with ligand-based interventions.
Date: June 15, 2026
Time: 9.00 a.m.
Place: PG5, 134
Department: Environmental Health Sciences
Major Professor: Dr. Tomás R. Guilarte
https://fiu.zoom.us/j/84605288363?pwd=3FmR8lpnlPZZzDY0auNQHt8Lafl39G.1. Meeting ID: 846 0528 8363 Password: rquwu1