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O3‐05‐02: The amyloid‐GSK3‐tau connection to neurodegeneration revealed by combining transgenic and viral models
Author(s) -
Van Leuven Fred,
Jaworski Tomasz,
Dewachter Ilse,
Kügler Sebastian
Publication year - 2009
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2009.05.458
Subject(s) - tauopathy , neurodegeneration , neuroscience , tau protein , genetically modified mouse , biology , hippocampus , amyloid (mycology) , transgene , hippocampal formation , microbiology and biotechnology , alzheimer's disease , pathology , medicine , genetics , disease , botany , gene
Background: Alzheimer disease (AD) is the most common cause of dementia in adults, resulting in impairment of cognition and memory. The molecular pathogenesis of AD is not well understood. Dysregulation of intracellular calcium signaling has been implicated in the pathogenesis of AD. Many putative etiologic factors of AD, including excitotoxicity, b-amyloid neurotoxicity, and free-radical injury, have in common the potential for disrupting intracellular calcium homeostasis. As the major Ca2þ-regulated protease in the central nervous system, calpain I is activated by seven-fold in AD brain as compared with control brain and that the activation of calpain I is positively correlated to tau phosphorylation, suggesting that calpain I activation may be involved in tau hyperphosphorylation in AD brain. Methods: By using Western blots, dot blots, in vitro proteolysis and enzyme activity assay, we determined the expression of Dyrk1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) in AD and control brain tissues, investigated the effect of proteolysis by calpain I on Dyrk1A activity, and analyzed the relationship of truncation of Dyrk1A with calpain I activation and tau phosphorylation. Results: We found that Dyrk1A in AD brain was truncated and the truncation was correlated to the activation of calpain I. Proteolysis of Dyrk1A by calpain I in vitro increased Dyrk1A activity toward the longest isoform of human tau (tau441) significantly. Truncation of Dyrk1A in AD brain was positively correlated to tau phosphorylation at several sites. Dyrk1A is a Ser/Thr kinase. Its gene is located at the Down syndrome critical region (DSCR) of chromosome 21 and may contribute to neurofibrillary degeneration in Down syndrome patients. Dyrk1A phosphorylated tau at Thr212 most effectively and the pre-phosphorylation of tau by Dyrk1A made tau become more favorable substrate for GSK-3b. Conclusions: These findings suggest that activation of calpain I due to dysregulation of intracellular calcium homeostasis may proteolyze and activate Dyrk1A to phosphorylate tau, which primes tau for further phosphorylation by GSK-3b. Taken together, our findings provide a mechanistic linkage between dysregulation of calcium homeostasis and abnormal hyperphosphorylation of tau in AD.