DESTABILIZATION OF BETA-CATENIN BY MUTATIONS IN PRESENILIN-1 POTENTIATES NEURONAL APOPTOSIS

Mutations of the presenilin-1 gene are a major cause of familial early -onset Alzheimer's disease(1-4). Presenilin-1 can associate with membe rs of the catenin family of signalling proteins, but the significance of this association is unknown(5,6). Here we show that presenilin-1 fo rms a complex with beta-catenin in vivo that increases beta-catenin st ability, Pathogenic mutations in the presenilin-1 gene reduce the abil ity of presenilin-1 to stabilize beta-catenin, and lead to increased d egradation of beta-catenin in the brains of transgenic mice, Moreover, beta-catenin levels are markedly reduced in the brains of Alzheimer's disease patients with presenilin-1 mutations. Loss of beta-catenin si gnalling increases neuronal vulnerability to apoptosis induced by amyl oid-beta protein, Thus, mutations in presenilin-1 may increase neurona l apoptosis by altering the stability of beta-catenin, predisposing in dividuals to early-onset Alzheimer's disease.