title: PP1 inhibition by Abeta peptide as a potential pathological mechanism in Alzheimer's disease.
abstract: Abnormal protein phosphorylation has been associated with several neurodegenerative disorders, including Alzheimer's disease (AD). Abeta is the toxic peptide that results from proteolytic cleavage of the Alzheimer's amyloid precursor protein, a process where protein phosphatases are known to impact. The data presented here demonstrates that protein phosphatase 1 (PP1), an abundant neuronal serine/threonine-specific phosphatase highly enriched in dendritic spines, is specifically inhibited by Abeta peptides both in vitro and ex vivo. Indeed, the pathologically relevant Abeta(1-40) and Abeta(1-42) peptides, as well as Abeta(25-35), specifically inhibit PP1 with low micromolar potency, as compared to inactive controls and other disease related peptides (e.g. the prion related Pr(118-135) and Pr(106-126)). Interestingly, PP1 inhibition is increased by Abeta aggregation, indicating a possible direct neurotoxic effect of the aggregated peptide. PP1 involvement in processes like long-term depression, memory and learning, and synaptic plasticity, prompt us to suggest that PP1 may constitute an important physiological target for Abeta and, therefore, increased Abeta production and/or aggregation may lead to abnormal PP1 activity and likely contribute to the progressive neuropsychiatric AD condition. Thus, PP1 activity and levels constitute potential biomolecular candidates for diagnostics and therapeutics.
authors.affiliation: Laboratório de Transdução de Sinais, Centro de Biologia Celular, Universidade de Aveiro, Aveiro, Portugal.
authors.forename: Ana Paula B
authors.initials: AP
authors.lastname: Vintém
authors.forename: Ana Gabriela
authors.initials: AG
authors.lastname: Henriques
authors.forename: Odete A B
authors.initials: OA
authors.lastname: da Cruz E Silva
authors.forename: Edgar F
authors.initials: EF
authors.lastname: da Cruz E Silva
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D004032:Diet; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology* / Q000502:physiology*; D010455:Peptides / Q000378:metabolism; D011328:Prions / Q000494:pharmacology; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors*; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D007527:Isoenzymes; D010446:Peptide Fragments; D010455:Peptides; D011328:Prions; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C082632:prion protein (106-126); C417023:prion protein (118-135); D054645:Protein Phosphatase 1