Overexpression of TGFBR3 Aggravates Cognitive Impairment and Neuroinflammation by Promoting Microglia M1 Polarization in the APP/PS1 Mouse Model of Alzheimer's Disease.

Transforming growth factor beta receptor 3 (TGFBR3), also known as betaglycan, is a member of the TGF-β receptor family. In our previous study, bioinformatics analysis revealed that TGFBR3 levels are elevated in patients with Alzheimer's disease (AD) and identified TGFBR3 as a potential risk factor for the disease. However, the precise role of TGFBR3 in the pathogenesis of AD remains largely unclear. In this study, we first validated the elevated levels of TGFBR3 in postmortem brain tissues from AD patients using immunohistochemical staining. Subsequently, gain-of-function experiments and behavioral tests were conducted to explore the functional role of TGFBR3 in the APP/PS1 mouse model. Our findings confirmed that TGFBR3 levels were significantly increased in AD patients compared to normal controls. Overexpression of TGFBR3 in APP/PS1 mice impaired spatial learning and memory abilities and promoted amyloid-β (Aβ) accumulation. Additionally, TGFBR3 overexpression exacerbated neuronal apoptosis and synaptic loss. We also observed that overexpression of TGFBR3 triggered an inflammatory response by promoting microglial polarization to the M1 phenotype, although it had no effect on astrocyte activation. In conclusion, our study demonstrates that increased TGFBR3 levels worsen cognitive impairment and accelerate pathological progression in APP/PS1 mice, suggesting that TGFBR3 could serve as a potential therapeutic target for AD treatment.