Τίτλος:
Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aβ-evoked hippocampal pathology
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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 (Aβ) 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 Aβ oligomer injection as well as the combined stress and Aβ 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/Aβ-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 Aβ-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. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.
Συγγραφείς:
Monteiro-Fernandes, D.
Silva, J.M.
Soares-Cunha, C.
Dalla, C.
Kokras, N.
Arnaud, F.
Billiras, R.
Zhuravleva, V.
Waites, C.
Bretin, S.
Sousa, N.
Sotiropoulos, I.
Περιοδικό:
Journal of Molecular Psychiatry
Εκδότης:
Springer Nature BV
Λέξεις-κλειδιά:
AMPA receptor; AMPA receptor agonist; amyloid beta protein; n methyl dextro aspartic acid receptor; neurotransmitter; protein kinase Fyn; s 47445; tau protein; unclassified drug; AMPA receptor; amyloid beta protein; tau protein, allosterism; Alzheimer disease; amnesia; animal cell; Article; cell fractionation; cognition; controlled study; excitotoxicity; experimental behavioral test; glutamatergic signaling; high performance liquid chromatography; hippocampus; male; mass spectrometry; memory; nonhuman; physiological stress; prevalence; rat; signal transduction; synapse; Western blotting; Alzheimer disease; animal; hippocampus; memory disorder; metabolism, Alzheimer Disease; Amyloid beta-Peptides; Animals; Hippocampus; Memory Disorders; Receptors, AMPA; tau Proteins
DOI:
10.1038/s41380-020-0794-5
