title: Kidins220 accumulates with tau in human Alzheimer's disease and related models: modulation of its calpain-processing by GSK3β/PP1 imbalance.
abstract: Failures in neurotrophic support and signalling play key roles in Alzheimer's disease (AD) pathogenesis. We previously demonstrated that downregulation of the neurotrophin effector Kinase D interacting substrate (Kidins220) by excitotoxicity and cerebral ischaemia contributed to neuronal death. This downregulation, triggered through overactivation of N-methyl-D-aspartate receptors (NMDARs), involved proteolysis of Kidins220 by calpain and transcriptional inhibition. As excitotoxicity is at the basis of AD aetiology, we hypothesized that Kidins220 might also be downregulated in this disease. Unexpectedly, Kidins220 is augmented in necropsies from AD patients where it accumulates with hyperphosphorylated tau. This increase correlates with enhanced Kidins220 resistance to calpain processing but no higher gene transcription. Using AD brain necropsies, glycogen synthase kinase 3-β (GSK3β)-transgenic mice and cell models of AD-related neurodegeneration, we show that GSK3β phosphorylation decreases Kidins220 susceptibility to calpain proteolysis, while protein phosphatase 1 (PP1) action has the opposite effect. As altered activities of GSK3β and phosphatases are involved in tau aggregation and constitute hallmarks in AD, a GSK3β/PP1 imbalance may also contribute to Kidins220 decreased clearance, accumulation and hampered neurotrophin signalling from early stages of the disease pathogenesis. These results encourage searches for mutations in Kidins220 gene and their possible associations to dementias. Finally, our data support a model where the effects of excitotoxicity drastically differ when occurring in cerebral ischaemia versus progressively sustained toxicity along AD progression. The striking differences in Kidins220 stability resulting from chronic versus acute brain damage may also have important implications for the therapeutic intervention of neurodegenerative disorders.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Madrid 28029, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: López-Menéndez
authors.forename: Andrea
authors.initials: A
authors.lastname: Gamir-Morralla
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Jurado-Arjona
authors.forename: Alonso M
authors.initials: AM
authors.lastname: Higuero
authors.forename: Miguel R
authors.initials: MR
authors.lastname: Campanero
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.forename: Félix
authors.initials: F
authors.lastname: Hernández
authors.forename: Jesús
authors.initials: J
authors.lastname: Ávila
authors.forename: Margarita
authors.initials: M
authors.lastname: Díaz-Guerra
authors.forename: Teresa
authors.initials: T
authors.lastname: Iglesias
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000473:pathology; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000473:pathology; D019319:Okadaic Acid / Q000009:adverse effects; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C482591:KIDINS220 protein, human; C054369:MAPT protein, human; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D016875:tau Proteins; D019319:Okadaic Acid; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D054645:Protein Phosphatase 1; D002154:Calpain