DOI: 10.1002/alz.078088 ISSN: 1552-5260

Age‐ and Sex‐ dependent changes in Translocator Protein 18 kDa (TSPO) expression, cellular sources, and association with amyloid‐β plaques in the 5XFAD murine model of Alzheimer’s Disease

Daniel Andres Martinez Perez, Jennifer L. McGlothan, Tomás R Guilarte
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



Alzheimer’s disease (AD) is a neurodegenerative disorder that affects cognition, memory, and social abilities with devastating effects on individuals and families. The hallmark AD pathology is the formation of amyloid‐β‐(Aβ)‐plaques and Tau neurofibrillary tangles leading to neurodegeneration. Neuroinflammation, and microglia activation, also play an important role in the initiation and progression of AD, a process that begins earlier than cognitive decline. TSPO is a well‐validated and widely used biomarker of neuroinflammation that is expressed in glial cells, and it is markedly increased in the brain of AD subjects and in AD animal models. Previous studies have not assessed a detailed trajectory of TSPO in the progression of AD. In the present study, we determined the age‐and sex‐dependent increase in brain TSPO levels, cellular sources, and association with Aβ‐plaques in parallel with behavior.


Behavioral performance was measured using the Barnes Maze (cognition) in male and female wild‐type (WT) and 5XFAD mice at 3 months (3M), and 7 months (7M). To evaluate pathological endpoints, we measured Aβ‐load (number, size, and % area covered), TSPO quantitative autoradiography using the TSPO‐specific radioligand [3H]‐DPA‐713, and quadruple‐label immunofluorescent confocal imaging to determine the cellular sources of the TSPO response and its association with Aβ‐plaques.


At 3M, we observed no significant differences in behavioral performance between WT and 5XFAD in either sex. At 7M, 5XFAD males showed no cognitive dysfunction, however, there was a significant cognitive impairment in 5XFAD females. We found an increase of Aβ‐plaques in an age‐and sex‐dependent manner. TSPO autoradiography showed a significant increase in TSPO levels in 5XFAD mice in both sexes and ages with a higher increase in females. Furthermore, we show that TSPO expression is colocalized with plaque‐associated microglia and not astrocytes.


These results indicate that brain TSPO is an early biomarker of neuroinflammation and TSPO levels increase at the same time that Aβ‐aggregation and much earlier than cognitive decline. Furthermore, the increase in TSPO levels was associated with microglia surrounding or embedded with Aβ‐plaques suggesting a role in plaque formation.

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