Activation of TREM2 via single-domain antibodies improves synaptic and cognitive function in 5×FAD mice.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, and dysfunction of triggering receptor expressed on myeloid cells 2 (TREM2) in microglia increases AD risk. TREM2 activation promotes protective microglial functions and mitigates AD pathology. Although TREM2-activating antibodies show therapeutic potential, the mechanisms underlying TREM2-mediated rescue effects remain unclear. Here, we show that two TREM2-activating single-domain antibodies (sdAbs), 10C11 and 10E12, activate microglia and rescue cognitive deficits in early-stage transgenic mice with five familial Alzheimer's disease mutations (5×FAD) following ventral hippocampal injection. 10E12 reduces Aβ plaques and preserves synaptic function, whereas 10C11 protects synapses without affecting plaque burden. Both antibodies reduce C1q levels in AD model mice, suggesting that TREM2 activation exerts multifaceted functions in AD. Together, this study presents two TREM2-targeting sdAbs with AD therapeutic potential and provides insights into the cellular mechanisms underlying TREM2 activation and microglial modulation.