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Induced neuronal activity does not attenuate amyloid beta-induced synaptic loss in vitro.

ABSTRACT: Aim: The accumulation of amyloid beta (A?) is one of the characteristics of Alzheimer's disease. The excessive accumulation of A? has been suggested to result in a decrease in the number of synapses. Although the number of synapses is generally modulated by neuronal activity, whether neuronal activity affects A?-induced synapse loss remains unknown. Therefore, we addressed this question using a primary culture of hippocampal neurons.

Method: The neuronal activity of cultured hippocampal neurons from mouse pups was increased using the chemogenetic technique designer receptors exclusively activated by designer drugs (DREADD). The cultured neurons were treated with A?, and synapse density was assessed by immunocytochemistry.

Results: A? decreased the synapse density probably by decreasing postsynapse. On the other hand, enhanced neuronal activity did not affect the synapse density significantly. However, there was a trend that enhanced neuronal activity increased especially presynapse density.

Conclusion: We found that enhanced neuronal activity did not affect A?-induced synapse loss in vitro.

SUBMITTER: Kono R

PROVIDER: S-EPMC7292309 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Induced neuronal activity does not attenuate amyloid beta-induced synaptic loss in vitro.

Kono Rena R Kim Gyu Li GL Nagata Hidetaka H Ikegaya Yuji Y Koyama Ryuta R

Neuropsychopharmacology reports 20190803 4

<h4>Aim</h4>The accumulation of amyloid beta (Aβ) is one of the characteristics of Alzheimer's disease. The excessive accumulation of Aβ has been suggested to result in a decrease in the number of synapses. Although the number of synapses is generally modulated by neuronal activity, whether neuronal activity affects Aβ-induced synapse loss remains unknown. Therefore, we addressed this question using a primary culture of hippocampal neurons.<h4>Method</h4>The neuronal activity of cultured hippoca ...[more]

PMID: 31376224

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Project description:Introduction: ?-Amyloid protein (A?) putatively plays a seminal role in synaptic loss in Alzheimer's disease (AD). While there is no consensus regarding the synaptic-relevant species of A?, it is known that A? oligomers (A?Os) are noticeably increased in the early stages of AD, localizing at or within the synapse. In cell and animal models, A?Os have been shown to attach to synapses and instigate synapse dysfunction and deterioration. To establish the pathological mechanism of synaptic loss in AD, it will be important to identify the synaptic targets to which A?Os attach. Methods: An unbiased approach using far western ligand blots has identified three synaptic proteins to which A?Os specifically attach. These proteins (p100, p140, and p260) were subsequently enriched by detergent extraction, ultracentrifugation, and CHT-HPLC column separation, and sequenced by LC-MS/MS. P100, p140, and p260 were identified. These levels of A?Os targets in human AD and aging frontal cortexes were analyzed by quantitative proteomics and western-blot. The polyclonal antibody to A?Os was developed and used to block the toxicity of A?Os. The data were analyzed with one-way analysis of variance. Results: A?Os binding proteins p100, p140, and p260 were identified as Na/K-ATPase, synGap, and Shank3, respectively. ?3-Na/K-ATPase, synGap, and Shank3 proteins showed loss in the postsynaptic density (PSD) of human AD frontal cortex. In short term experiments, oligomers of A? inhibited Na/K-ATPase at the synapse. Na/K-ATPase activity was restored by an antibody specific for soluble forms of A?. ?3-Na/K-ATPase protein and synaptic ?-amyloid peptides were pulled down from human AD synapses by co-immunoprecipitation. Results suggest synaptic dysfunction in early stages of AD may stem from inhibition of Na/K-ATPase activity by A? oligomers, while later stages could hypothetically result from disrupted synapse structure involving the PSD proteins synGap and Shank3. Conclusion: We identified three A?O binding proteins as ?3-Na/K-ATPase, synGap, and Shank3. Soluble A? oligomers appear capable of attacking neurons via specific extracellular as well as intracellular synaptic proteins. Impact on these proteins hypothetically could lead to synaptic dysfunction and loss, and could serve as novel therapeutic targets for AD treatment by antibodies or other agents.

Project description:Backgroundβ Amyloid (Aβ)-mediated neuronal hyperactivity, a key feature of the early stage of Alzheimer's disease (AD), is recently proposed to be initiated by the suppression of glutamate reuptake. Nevertheless, the underlying mechanism by which the impaired glutamate reuptake causes neuronal hyperactivity remains unclear. Chronic suppression of the glutamate reuptake causes accumulation of ambient glutamate that could diffuse from synaptic sites at the dendrites to the soma to elevate the tonic activation of somatic N-methyl-D-aspartate receptors (NMDARs). However, less attention has been paid to the potential role of tonic activity change in extrasynaptic glutamate receptors (GluRs) located at the neuronal soma on generation of neuronal hyperactivity.MethodsWhole-cell patch-clamp recordings were performed on CA1 pyramidal neurons in acute hippocampal slices exposed to TFB-threo-β-benzyloxyaspartic acid (TBOA) or human Aβ1-42 peptide oligomer. A series of dendritic patch-clamp recordings were made at different distances from the soma to identify the location of the changes in synaptic inputs. Moreover, single-channel recording in the cell-attached mode was performed to investigate the activity changes of single NMDARs at the soma.ResultsBlocking glutamate uptake with either TBOA or the human Aβ1-42 peptide oligomer elicited potentiation of synaptic inputs in CA1 hippocampal neurons. Strikingly, this potentiation specifically occurred at the soma, depending on the activation of somatic GluN2B-containing NMDARs (GluN2B-NMDARs) and accompanied by a substantial and persistent increment in the open probability of somatic NMDARs. Blocking the activity of GluN2B-NMDARs at the soma completely reversed both the TBOA-induced or the Aβ1-42-induced somatic potentiation and neuronal hyperactivity.ConclusionsThe somatic potentiation of synaptic inputs may represent a novel amplification mechanism that elevates cell excitability and thus contributes to neuronal hyperactivity initiated by impaired glutamate reuptake in AD.

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Induced neuronal activity does not attenuate amyloid beta-induced synaptic loss in vitro.

Publications

Induced neuronal activity does not attenuate amyloid beta-induced synaptic loss in vitro.

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