title: Tau Protein Mediates APP Intracellular Domain (AICD)-Induced Alzheimer's-Like Pathological Features in Mice.
abstract: Amyloid precursor protein (APP) is cleaved by gamma-secretase to simultaneously generate amyloid beta (Aβ) and APP Intracellular Domain (AICD) peptides. Aβ plays a pivotal role in Alzheimer's disease (AD) pathogenesis but recent studies suggest that amyloid-independent mechanisms also contribute to the disease. We previously showed that AICD transgenic mice (AICD-Tg) exhibit AD-like features such as tau pathology, aberrant neuronal activity, memory deficits and neurodegeneration in an age-dependent manner. Since AD is a tauopathy and tau has been shown to mediate Aβ-induced toxicity, we examined the role of tau in AICD-induced pathological features. We report that ablating endogenous tau protects AICD-Tg mice from deficits in adult neurogenesis, seizure severity, short-term memory deficits and neurodegeneration. Deletion of tau restored abnormal phosphorylation of NMDA receptors, which is likely to underlie hyperexcitability and associated excitotoxicity in AICD-Tg mice. Conversely, overexpression of wild-type human tau aggravated receptor phosphorylation, impaired adult neurogenesis, memory deficits and neurodegeneration. Our findings show that tau is essential for mediating the deleterious effects of AICD. Since tau also mediates Aβ-induced toxic effects, our findings suggest that tau is a common downstream factor in both amyloid-dependent and-independent pathogenic mechanisms and therefore could be a more effective drug target for therapeutic intervention in AD.
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, United States of America.
authors.forename: Kaushik
authors.identifier: http://orcid.org/0000-0001-5681-7042
authors.initials: K
authors.lastname: Ghosal
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, United States of America.
authors.forename: Qingyuan
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Department of Neurology, Duke University, Durham, North Carolina, 27710, United States of America.
authors.forename: Hana N
authors.initials: HN
authors.lastname: Dawson
authors.affiliation: Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, 44195, United States of America.
authors.forename: Sanjay W
authors.initials: SW
authors.lastname: Pimplikar
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D055786:Gene Knockout Techniques; D006801:Humans; D007608:Kainic Acid / Q000009:adverse effects; D008094:Lithium / Q000494:pharmacology; D008297:Male; D018782:Maze Learning; D008570:Memory, Short-Term; D051379:Mice; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D016875:tau Proteins; D008094:Lithium; D007608:Kainic Acid