Dataset Information

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: β-Amyloid protein (Aβ) putatively plays a seminal role in synaptic loss in Alzheimer's disease (AD). While there is no consensus regarding the synaptic-relevant species of Aβ, it is known that Aβ oligomers (AβOs) are noticeably increased in the early stages of AD, localizing at or within the synapse. In cell and animal models, AβOs 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 AβOs attach. Methods: An unbiased approach using far western ligand blots has identified three synaptic proteins to which AβOs 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 AβOs targets in human AD and aging frontal cortexes were analyzed by quantitative proteomics and western-blot. The polyclonal antibody to AβOs was developed and used to block the toxicity of AβOs. The data were analyzed with one-way analysis of variance. Results: AβOs binding proteins p100, p140, and p260 were identified as Na/K-ATPase, synGap, and Shank3, respectively. α3-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 Aβ inhibited Na/K-ATPase at the synapse. Na/K-ATPase activity was restored by an antibody specific for soluble forms of Aβ. α3-Na/K-ATPase protein and synaptic β-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 Aβ oligomers, while later stages could hypothetically result from disrupted synapse structure involving the PSD proteins synGap and Shank3. Conclusion: We identified three AβO binding proteins as α3-Na/K-ATPase, synGap, and Shank3. Soluble Aβ 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.

Dataset Information

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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