Regulation of Tau Gene Expression by AP and the Amyloid Precursor Protein in Cultured Cortical Neurons

The two characteristic lesions of Alzheimer's disease are intracellular neurofibrillary tangles and extracellular accumulation of amyloid plaques. Tangles are composed of abnormally hyper-phosphorylated forms of the microtubule-associated protein tau, whereas amyloid (AP) is derived from proteolytic processing of the amyloid precursor protein (APP). These lesions are thought to be etiologically distinct, and are spatially dissociated in postmortem brains. We show that AP, wild-type APP751, or familial APP751 mutations can stimulate aberrant increases in tau protein and mRNA in primary cultured cortical neurons. Neurons infected with recombinant herpes simplex virus (HSV) vectors expressing wild-type or mutated APP751 or APP695 cDNA significantly increased APP expression. Both HSVAPP751 and HSV-APP695 increased levels of 6 kb tau mRNA; however, tau protein was increased by HSV-APP751, but not HSV-APP695, suggesting that the Kunitz protease inhibitor (KPI) domain in APP751 may increase the post-translational stability of tau. There were no differences in total tau protein levels between infections with wild-type and mutated APP751. However, infections with mutated APP751 resulted in hyper-phosphorylation of tau in comparison to infection with wild-type APP751. HSV expressing A•I_ 4 2 cDNA increased both APP and tau expression (mRNA and protein). In addition to 6 kb tau mRNA, HSV-APIl 42 also increased a 2 kb tau transcript which codes for a nuclear tau isoform that appears to be up-regulated in Alzheimer's disease. Hence, this study indicates that APP751 and AP142 can stimulate abnormal increases in tau expression and hyper-phosphorylation, and suggests a potential link between amyloid plaques and neurofibrillary tangles. Thesis Supervisor: Richard J. Wurtman, M.D. Title: Professor of Neuroscience and Cecil H. Green Distinguished Professor