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Identification of an acute functional cross-talk between amyloid-β and glucocorticoid receptors at hippocampal excitatory synapses.

Abstract：

:Amyloid-β is a peptide released by synapses in physiological conditions and its pathological accumulation in brain structures necessary for memory processing represents a key toxic hallmark underlying Alzheimer's disease. The oligomeric form of Amyloid-β (Aβο) is now believed to represent the main Amyloid-β species affecting synapse function. Yet, the exact molecular mechanism by which Aβο modifies synapse function remains to be fully elucidated. There is accumulating evidence that glucocorticoid receptors (GRs) might participate in Aβο generation and activity in the brain. Here, we provide evidence for an acute functional cross-talk between Aβ and GRs at hippocampal excitatory synapses. Using live imaging and biochemical analysis of post-synaptic densities (PSD) in cultured hippocampal neurons, we show that synthetic Aβo (100 nM) increases GR levels in spines and PSD. Also, in these cultured neurons, blocking GRs with two different GR antagonists prevents Aβo-mediated PSD95 increase within the PSD. By analyzing long-term potentiation (LTP) and long-term depression (LTD) in ex vivo hippocampal slices after pharmacologically blocking GR, we also show that GR signaling is necessary for Aβo-mediated LTP impairment, but not Aβo-mediated LTD induction. The necessity of neuronal GRs for Aβo-mediated LTP was confirmed by genetically removing GRs in vivo from CA1 neurons using conditional GR mutant mice. These results indicate a tight functional interplay between GR and Aβ activities at excitatory synapses.

journal_name

Neurobiol Dis

journal_title

Neurobiology of disease

authors

Kootar S,Frandemiche ML,Dhib G,Mouska X,Lorivel T,Poupon-Silvestre G,Hunt H,Tronche F,Bethus I,Barik J,Marie H

doi

10.1016/j.nbd.2018.07.001

subject

Has Abstract

pub_date

2018-10-01 00:00:00

pages

117-128

eissn

0969-9961

issn

1095-953X

pii

S0969-9961(18)30210-9

journal_volume

118

pub_type

杂志文章

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