PP1 inhibition by Abeta peptide as a potential pathological mechanism in Alzheimer's disease.
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.
Vintém
Ana Paula B
AP
Laboratório de Transdução de Sinais, Centro de Biologia Celular, Universidade de Aveiro, Aveiro, Portugal.
Henriques
Ana Gabriela
AG
da Cruz E Silva
Odete A B
OA
da Cruz E Silva
Edgar F
EF
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
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