Neurobiology of Disease Deletion of Mint Proteins Decreases Amyloid Production in Transgenic Mouse Models of Alzheimer’s Disease

Mints/X11s are neuronal adaptor proteins that bind to amyloidprecursor protein (APP). Previous studies suggested that Mint/X11 proteins influence APP cleavage and affect production of pathogenic amyloid(A ) peptides in Alzheimer’s disease; however, the biological significance of Mint/X11 binding to APP and their possible role in A production remain unclear. Here, we crossed conditional and constitutive Mint1, Mint2, and Mint3 knock-out mice with transgenic mouse models of Alzheimer’s disease overproducing human A peptides. We show that deletion of all three individual Mint proteins delays the age-dependent production of amyloid plaque numbers and A 40 and A 42 levels with loss of Mint2 having the largest effect. Acute conditional deletion of all three Mints in cultured neurons suppresses the accumulation of APP C-terminal fragments and the secretion of ectodomain APP by decreasing -cleavage but does not impair subsequent -cleavage. These results suggest that the three Mint/X11 proteins regulate A production by a novel mechanism that may have implications for therapeutic approaches to altering APP cleavage in Alzheimer’s disease.