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Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aß-evoked hippocampal pathology.
Monteiro-Fernandes, Daniela; Silva, Joana Margarida; Soares-Cunha, Carina; Dalla, Christina; Kokras, Nikolaos; Arnaud, François; Billiras, Rodolphe; Zhuravleva, Viktoriya; Waites, Clarissa; Bretin, Sylvie; Sousa, Nuno; Sotiropoulos, Ioannis.
Afiliação
  • Monteiro-Fernandes D; Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Campus Gualtar, Minho, Portugal.
  • Silva JM; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
  • Soares-Cunha C; Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Campus Gualtar, Minho, Portugal.
  • Dalla C; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
  • Kokras N; Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Campus Gualtar, Minho, Portugal.
  • Arnaud F; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
  • Billiras R; Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
  • Zhuravleva V; Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
  • Waites C; First Department of Psychiatry, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
  • Bretin S; Pôle Innovation Thérapeutique Neuropsychiatrie, Institut de Recherches Internationales Servier, Suresnes, France.
  • Sousa N; Pôle Innovation Thérapeutique Neuropsychiatrie, Institut de Recherches Internationales Servier, Suresnes, France.
  • Sotiropoulos I; Neurobiology and Behavior Graduate Program, Columbia University, New York, NY, USA.
Mol Psychiatry ; 26(10): 5899-5911, 2021 10.
Article em En | MEDLINE | ID: mdl-32467647
ABSTRACT
Despite considerable progress in the understanding of its neuropathology, Alzheimer's disease (AD) remains a complex disorder with no effective treatment that counteracts the memory deficits and the underlying synaptic malfunction triggered by the accumulation of amyloid beta (Aß) and Tau protein. Mounting evidence supports a precipitating role for chronic environmental stress and glutamatergic excitotoxicity in AD, suggesting that targeting of glutamate receptor signaling may be a promising approach against both stress and AD pathologies. In light of the limited cognitive benefit of the direct antagonism of NMDA receptors in AD, we here focus on an alternative way to modify glutamatergic signaling through positive allosteric modulation of AMPA receptors, by the use of a PAM-AMPA compound. Using non-transgenic animal model of Aß oligomer injection as well as the combined stress and Aß i.c.v. infusion, we demonstrate that positive allosteric modulation of AMPA receptors by PAM-AMPA treatment reverted memory, but not mood, deficits. Furthermore, PAM-AMPA treatment reverted stress/Aß-driven synaptic missorting of Tau and associated Fyn/GluN2B-driven excitotoxic synaptic signaling accompanied by recovery of neurotransmitter levels in the hippocampus. Our findings suggest that positive allosteric modulation of AMPA receptors restores synaptic integrity and cognitive performance in stress- and Aß-evoked hippocampal pathology. As the prevalence of AD is increasing at an alarming rate, novel therapeutic targeting of glutamatergic signaling should be further explored against the early stages of AD synaptic malfunction with the goal of attenuating further synaptic damage before it becomes irreversible.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Peptídeos beta-Amiloides / Doença de Alzheimer Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Peptídeos beta-Amiloides / Doença de Alzheimer Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2021 Tipo de documento: Article