Increased P2x2 receptors induced by amyloid-beta peptide participates in the neurotoxicity in alzheimer's disease

Godoy, Pamela A.; Mennickent, Daniela; Cuchillo-Ibanez, Inmaculada; Ramirez-Molina, Oscar; Silva-Grecchi, Tiare; Panes-Fernandez, Jessica; Castro, Patricio; Saez-Valero, Javier; Fuentealba, Jorge


Amyloid beta peptide (A beta) is tightly associated with the physiopathology of Alzheimer's Disease (AD) as one of the most important factors in the evolution of the pathology. In this context, we previously reported that A beta increases the expression of ionotropic purinergic receptor 2 (P2x2R). However, its role on the cellular and molecular A beta toxicity is unknown, especially in human brain of AD patients. Using cellular and molecular approaches in hippocampal neurons, PC12 cells, and human brain samples of patients with AD, we evaluated the participation of P2x2R in the physiopathology of AD. Here, we reported that A beta oligomers (A beta o) increased P2x2 levels in mice hippocampal neurons, and that this receptor increases at late Braak stages of AD patients. A beta o also increases the colocalization of APP with Rab5, an early endosomes marker, and decreased the nuclear/cytoplasmic ratio of Fe65 and PGC-1 alpha immunoreactivity. The overexpression in PC12 cells of P2x2a, but not P2x2b, replicated these changes in Fe65 and PGC-1 alpha; however, both overexpressed isoforms increased levels of A beta. Taken together, these data suggest that P2x2 is upregulated in AD and it could be a key potentiator of the physiopathology of A beta. Our results point to a possible participation in a toxic cycle that increases A beta production, Ca2+ overload, and a decrease of PGC-1 alpha. These novel findings put the P2x2R as a key novel pharmacological target to develop new therapeutic strategies to treat Alzheimer's Disease.

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Título según WOS: Increased P2×2 receptors induced by amyloid-β peptide participates in the neurotoxicity in alzheimer's disease
Volumen: 142
Fecha de publicación: 2021


Notas: ISI