A specific pilose antler peptide LVLVEAELRE ameliorates cognitive deficits in SAMP8 mice via Celsr2

Pilose antler peptide (PAP), an extract derived from the traditional Chinese medicinal material Pilose antler, has shown promise in the treatment of neurodegenerative diseases. However, the precise molecular mechanisms underlying its anti-Alzheimer's disease (AD) effects remain to be fully elucidated.

This study focuses on a specific PAP monomer with a defined sequence (LVLVEAELRE), herein referred to as PAP, to explore its potential role and molecular mechanisms in AD treatment.

Senescence-accelerated mouse prone 8 (SAMP8) mice were employed to evaluate the effects of PAP on cognitive function, classical AD pathologies (Aβ and p-Tau), and synaptic plasticity. To further elucidate the causal role of Cadherin EGF LAG seven-pass G-type receptor 2 (Celsr2), bidirectional viral manipulations (AAV-shCelsr2 for knockdown and AAV-OECelsr2 for overexpression) were performed in vivo. Furthermore, cellular thermal shift assays (CETSA), molecular docking, and microscale thermophoresis (MST) were utilized to validate the direct interaction between PAP and Celsr2.

PAP administration significantly improved cognitive impairment, mitigated Aβ deposition and Tau hyperphosphorylation, and enhanced synaptic plasticity in SAMP8 mice. Mechanistically, PAP upregulated Celsr2 expression, restored AMPA receptor subunits, and inhibited neuronal senescence. Crucially, Celsr2 knockdown abolished these neuroprotective benefits, whereas Celsr2 overexpression synergistically amplified the therapeutic efficacy of PAP. Finally, MST and docking analyses confirmed that PAP possesses a high and specific binding affinity for WT Celsr2.

This study demonstrates that PAP ameliorates AD-like pathology by regulating Celsr2, highlighting its potential as a promising preclinical drug candidate. The research findings provide a theoretical basis for the development of PAP-based therapeutic strategies for Alzheimer's disease.