Amyloid-β plaque-associated microglia drive TSPO upregulation in Alzheimer’s disease

Jul 17, 2025Acta neuropathologica

Immune Cells Around Amyloid Plaques May Increase TSPO Levels in Alzheimer's Disease

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Abstract

Brain levels increase in the 5XFAD mouse model of Alzheimer's disease as early as 1.5 months of age.

Increased TSPO levels are first observed in the subiculum of 5XFAD mice at 1.5 months, coinciding with Aβ aggregation.
This early rise in TSPO occurs before significant increases in neurofilament light chain levels and cognitive function deficits.
The increase in TSPO is linked to activated microglia in direct contact with Aβ plaques, which exhibit higher TSPO levels compared to other microglia.
Astrocytes are activated overall, but do not show an increase in TSPO levels in the context of the 5XFAD model.
Findings in postmortem human brain tissue from early-onset AD cases confirm the relevance of increased TSPO levels and microglial TSPO content associated with Aβ plaques.

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18 kDA (TSPO) imaging using positron emission tomography (PET) is widely used to assess neuroinflammation in Alzheimer's disease (AD). However, the significance of the increase in brain TSPO levels in AD pathophysiology is not known. Here, we show that in the 5XFAD transgenic mouse model, brain TSPO levels increase in an age-, brain region-, and sex-dependent fashion. TSPO levels were first increased in the subiculum at 1.5 months of age in male and female 5XFAD mice compared to wildtype mice. The TSPO increase in the subiculum of 1.5-month 5XFAD mice coincided with the appearance of Aβ aggregation and increased serum Aβ/Aβratio which occurred prior to increased serum neurofilament light chain (Nfl) levels and well before cognitive function deficits. We also discovered that the brain TSPO increase was driven by an expansion of activated microglia in contact with Aβ-plaques, that also expressed higher TSPO levels per microglia than microglia not in contact with plaques. While overall, astrocytes were highly activated, the increased TSPO signal in the 5XFAD mouse brain did not increase in astrocytes. We also compared the 5XFAD mouse findings to postmortem human brain tissue from early-onset autosomal-dominant Presenilin 1 (PSEN1)-E280A mutation AD cases. The results in PSEN1-E280A cases confirmed the 5XFAD mouse findings relevant to increased TSPO levels and an increase in TSPO per microglia contacting Aβ-plaques. In summary, TSPO is an early biomarker of neuroinflammation in the AD brain that first increases in the subiculum simultaneously with increased Aβ aggregation and serum Aβ/Aβratio. The increased TSPO response in the 5XFAD mouse brain and in the brain from PSEN1-E280A mutation AD cases reflects Aβ-plaque-associated microglia with a high TSPO content. This microglia subtype is likely to promote the progression of AD pathology, neurodegeneration, and cognitive decline and their high TSPO content may serve as a target for TSPO ligand-based therapy. 1-42 1-40 1-42 1-40

Key numbers

1.5 months

Increase in levels

levels first increase in the subiculum of 5XFAD mice

Higher levels per microglia

Microglial activation

Plaque-associated microglia express more than non-contacting microglia

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Amyloid-β plaque-associated microglia drive TSPO upregulation in Alzheimer’s disease

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