Cell adhesion molecule 3

Cell adhesion molecule 3 (CADM3) is a 398-amino acid transmembrane protein that mediates both homophilic and heterophilic cell–cell adhesion in a calcium-independent manner. It interacts with IGSF4, NECTIN1, and NECTIN3, and associates with EPB41L1 to regulate cell junction structure and function (UniProt: Q8N126). CADM3 is primarily implicated in peripheral nervous system integrity; mutations cause Charcot-Marie-Tooth disease, axonal type 2FF (CMT2FF; MIM 619519), a progressive neuropathy with early-childhood onset affecting motor function in lower and upper limbs (UniProt: Q8N126).

In Alzheimer's disease, CADM3 is significantly downregulated in post-mortem brain tissue. Quantitative proteomics analysis from human AD brain versus age-matched controls detected reduced CADM3 protein levels with a mean log2 fold-change of −0.59 (Chaparral AD proteomics). This downregulation suggests compromised cell–cell adhesion and junctional integrity may contribute to neuronal dysfunction in AD pathology, though the functional consequences remain to be determined.