Aging is a crucial cause of cognitive decline and a major risk factor for Alzheimer's disease (AD); however, AD's underlying molecular mechanisms remain unclear. Recently, tetraspanins have emerged as important modulators of synaptic function and memory. We demonstrate that the level of tetraspanin CD82 is upregulated in the brains of AD patients and middle-aged mice. In young adult mice, injection of AAV-CD82 to the hippocampus induced AD-like cognitive deficits and impairments in neuronal spine density. CD82 overexpression increased TRPM7 alpha-kinase cleavage via caspase-3 activation and induced Numb phosphorylation at Thr346 and Ser348 residues. CD82 overexpression promoted beta-amyloid peptide (A beta) secretion which could be reversed by Numb T346S348 mutants. Importantly, hippocampus-related memory functions were improved in Cd82(-/-) mice. Taken together, our findings provide the evidence that links the elevated CD82-TRPM7-Numb signaling to age-related cognitive impairment.