Knockdown of TREML2 Alleviates Neuropathological Hallmarks and Cognitive Deficiency in a Model of Sporadic Alzheimer's Disease

Objective: Recently, we revealed that triggering receptor expressed on myeloid cells-like 2 (TREML2) modulated inflammation by regulating microglial polarization and NLRP3 inflammasome activation. However, the role of TREML2 in Alzheimer's disease (AD) pathogenesis remains poorly understood. In this study, we tried to observe the impact of TREML2 on neuropathological hallmarks (including amyloid-β (Aβ) pathology, hyperphosphorylated tau and neuroinflammation) and cognitive deficiency in senescence-accelerated mouse prone substrain 8 (SAMP8) mice, an animal model of sporadic AD.

Methods: A lentiviral-based strategy was employed to manipulate TREML2 levels in the brain of SAMP8 mice. Enzyme-linked immunosorbent assay was used to detect the protein levels of inflammatory cytokines, Aβ₄₂ and hyperphosphorylated tau. The mRNA levels of microglial polarization markers were assessed by qRT-PCR. Morris water maze test was performed to evaluate the spatial cognitive functions.

Results: TREML2 overexpression elevated inflammatory cytokines levels, induced microglial M1-type polarization, and exacerbated Aβ and tau pathology in SAMP8 mice. Contrastingly, knocking down TREML2 mitigated inflammatory cytokines release, promoted microglial M2-type polarization, ameliorated Aβ and tau pathology, and rescued cognitive deficiency in SAMP8 mice.

Conclusion: This study offers the first in vivo evidence that TREML2 contributes to the pathogenesis of AD. Furthermore, this study also proves that inhibition of TREML2 signaling may represent a potential treatment strategy for this disease.