CADM3 deficiency exacerbates amyloid and synaptic pathology in Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by progressive cognitive decline, synaptic dysfunction, and amyloid beta (Aβ) accumulation. However, molecular regulators linking synaptic instability with amyloidogenic processing remain poorly understood. We investigated cell adhesion molecule 3 (CADM3) as a potential integrative regulator. CADM3 expression was analyzed in postmortem human AD brains and transgenic mouse models. Cadm3-deficient mice were crossed with 5xFAD mice, and amyloid pathology, neuroinflammation, synaptic gene expression, and amyloid precursor protein (APP) processing were assessed. CADM3 expression was reduced in human AD brains and mouse models. Genetic loss of CADM3 exacerbated amyloid deposition, microglial activation, and synaptic gene dysregulation and significantly increased β-site APP cleaving enzyme 1, C99, and Aβ42 levels. CADM3 was enriched at the plasma membrane of synaptic compartments in cultured neurons. Our findings suggest that CADM3 modulates the intersection between synaptic adhesion and amyloid pathology.