APP induces neuronal apoptosis through APP-BP1-mediated downregulation of beta-catenin.
Alzheimer's disease (AD) is a neurodegenerative disease associated with progressive dementia. This mini-review focuses on how the amyloid precursor protein (APP) plays a central role in AD and Down syndrome as the regulator of the APP-BP1/hUba3 activated neddylation pathway. It is argued that the physiological function of APP is to downregulate the level of beta-catenin. However, this APP function is abnormally amplified in patients with familial AD (FAD) mutations in APP and presenilins, resulting in the hyperactivation of neddylation and the decrease of beta-catenin below a threshold level. Evidence in the literature is summarized to show that dysfunction of APP in downregulating beta-catenin may underlie the mechanism of neuronal death in AD and Down syndrome.
Chen
Y Z
YZ
Department of Geriatrics, College of Medicine, University of Arkansas for Medical Sciences, AR 72205, USA. ChenYuzhi@uams.edu
D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004314:Down Syndrome / Q000378:metabolism / Q000503:physiopathology; D015536:Down-Regulation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008954:Models, Biological; D009154:Mutation; D000075687:NEDD8 Protein; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D053764:Presenilin-1; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes; D014452:Ubiquitins / Q000378:metabolism / Q000502:physiology; D051176:beta Catenin
D016564:Amyloid beta-Protein Precursor; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; C508853:PSEN1 protein, human; D053764:Presenilin-1; D015534:Trans-Activators; D025801:Ubiquitin; D014452:Ubiquitins; D051176:beta Catenin; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human