Calcium-mediated transient phosphorylation of tau and amyloid precursor protein followed by intraneuronal amyloid-beta accumulation.
Intraneuronal accumulation of hyperphosphorylated protein tau in paired helical filaments together with amyloid-beta peptide (Abeta) deposits confirm the clinical diagnosis of Alzheimer disease. A common cellular mechanism leading to the production of these potent toxins remains elusive. Here we show that, in cultured neurons, membrane depolarization induced a calcium-mediated transient phosphorylation of both microtubule-associated protein tau and amyloid precursor protein (APP), followed by a dephosphorylation of these proteins. Phosphorylation was mediated by glycogen synthase kinase 3 and cyclin-dependent kinase 5 protein kinases, while calcineurin was responsible for dephosphorylation. Following the transient phosphorylation of APP, intraneuronal Abeta accumulated and induced neurotoxicity. Phosphorylation of APP on Thr-668 was indispensable for intraneuronal accumulation of Abeta. Our data demonstrate that an increase in cytosolic calcium concentration induces modifications of neuronal metabolism of APP and tau, similar to those found in Alzheimer disease.
Pierrot
Nathalie
N
Laboratory of Experimental Pharmacology, Université Catholique de Louvain, 1200 Brussels, Belgium.
Santos
Susana Ferrao
SF
Feyt
Christine
C
Morel
Marina
M
Brion
Jean-Pierre
JP
Octave
Jean-Noël
JN
D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D011189:Potassium Chloride / Q000737:chemistry; D051381:Rats; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; D011189:Potassium Chloride; D002118:Calcium