Deletion of Mint proteins decreases amyloid production in transgenic mouse models of Alzheimer's disease.
Mints/X11s are neuronal adaptor proteins that bind to amyloid-beta precursor protein (APP). Previous studies suggested that Mint/X11 proteins influence APP cleavage and affect production of pathogenic amyloid-beta (Abeta) peptides in Alzheimer's disease; however, the biological significance of Mint/X11 binding to APP and their possible role in Abeta 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 Abeta peptides. We show that deletion of all three individual Mint proteins delays the age-dependent production of amyloid plaque numbers and Abeta40 and Abeta42 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 beta-cleavage but does not impair subsequent gamma-cleavage. These results suggest that the three Mint/X11 proteins regulate Abeta production by a novel mechanism that may have implications for therapeutic approaches to altering APP cleavage in Alzheimer's disease.
Ho
Angela
A
Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, USA. aho1@bu.edu
Liu
Xinran
X
Südhof
Thomas C
TC
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency*; D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009474:Neurons; D019913:Nuclear Localization Signals / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C513072:Apba1 protein, mouse; D009419:Nerve Tissue Proteins; D019913:Nuclear Localization Signals; D010446:Peptide Fragments; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D053829:Amyloid Precursor Protein Secretases