Dataset Information

Pyk2 overexpression in postsynaptic neurons blocks amyloid ?_1-42-induced synaptotoxicity in microfluidic co-cultures.

ABSTRACT: Recent meta-analyses of genome-wide association studies identified a number of genetic risk factors of Alzheimer's disease; however, little is known about the mechanisms by which they contribute to the pathological process. As synapse loss is observed at the earliest stage of Alzheimer's disease, deciphering the impact of Alzheimer's risk genes on synapse formation and maintenance is of great interest. In this article, we report a microfluidic co-culture device that physically isolates synapses from pre- and postsynaptic neurons and chronically exposes them to toxic amyloid ? peptides secreted by model cell lines overexpressing wild-type or mutated (V717I) amyloid precursor protein. Co-culture with cells overexpressing mutated amyloid precursor protein exposed the synapses of primary hippocampal neurons to amyloid ?_1-42 molecules at nanomolar concentrations and induced a significant decrease in synaptic connectivity, as evidenced by distance-based assignment of postsynaptic puncta to presynaptic puncta. Treating the cells with antibodies that target different forms of amyloid ? suggested that low molecular weight oligomers are the likely culprit. As proof of concept, we demonstrate that overexpression of protein tyrosine kinase 2 beta-an Alzheimer's disease genetic risk factor involved in synaptic plasticity and shown to decrease in Alzheimer's disease brains at gene expression and protein levels-selectively in postsynaptic neurons is protective against amyloid ?_1-42-induced synaptotoxicity. In summary, our lab-on-a-chip device provides a physiologically relevant model of Alzheimer's disease-related synaptotoxicity, optimal for assessing the impact of risk genes in pre- and postsynaptic compartments.

SUBMITTER: Kilinc D

PROVIDER: S-EPMC7941669 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Pyk2 overexpression in postsynaptic neurons blocks amyloid β<sub>1-42</sub>-induced synaptotoxicity in microfluidic co-cultures.

Kilinc Devrim D Vreulx Anaïs-Camille AC Mendes Tiago T Flaig Amandine A Marques-Coelho Diego D Verschoore Maxime M Demiautte Florie F Amouyel Philippe P Eysert Fanny F Dourlen Pierre P Chapuis Julien J Costa Marcos R MR Malmanche Nicolas N Checler Frédéric F Lambert Jean-Charles JC

Brain communications 20200828 2

Recent meta-analyses of genome-wide association studies identified a number of genetic risk factors of Alzheimer's disease; however, little is known about the mechanisms by which they contribute to the pathological process. As synapse loss is observed at the earliest stage of Alzheimer's disease, deciphering the impact of Alzheimer's risk genes on synapse formation and maintenance is of great interest. In this article, we report a microfluidic co-culture device that physically isolates synapses ...[more]

PMID: 33718872

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Project description:Amyloid beta (Abeta) 1-42 oligomers accumulate in brains of patients with Mild Cognitive Impairment (MCI) and disrupt synaptic plasticity processes that underlie memory formation. Synaptic binding of Abeta oligomers to several putative receptor proteins is reported to inhibit long-term potentiation, affect membrane trafficking and induce reversible spine loss in neurons, leading to impaired cognitive performance and ultimately to anterograde amnesia in the early stages of Alzheimer's disease (AD). We have identified a receptor not previously associated with AD that mediates the binding of Abeta oligomers to neurons, and describe novel therapeutic antagonists of this receptor capable of blocking Abeta toxic effects on synapses in vitro and cognitive deficits in vivo. Knockdown of sigma-2/PGRMC1 (progesterone receptor membrane component 1) protein expression in vitro using siRNA results in a highly correlated reduction in binding of exogenous Abeta oligomers to neurons of more than 90%. Expression of sigma-2/PGRMC1 is upregulated in vitro by treatment with Abeta oligomers, and is dysregulated in Alzheimer's disease patients' brain compared to age-matched, normal individuals. Specific, high affinity small molecule receptor antagonists and antibodies raised against specific regions on this receptor can displace synthetic Abeta oligomer binding to synaptic puncta in vitro and displace endogenous human AD patient oligomers from brain tissue sections in a dose-dependent manner. These receptor antagonists prevent and reverse the effects of Abeta oligomers on membrane trafficking and synapse loss in vitro and cognitive deficits in AD mouse models. These findings suggest sigma-2/PGRMC1 receptors mediate saturable oligomer binding to synaptic puncta on neurons and that brain penetrant, small molecules can displace endogenous and synthetic oligomers and improve cognitive deficits in AD models. We propose that sigma-2/PGRMC1 is a key mediator of the pathological effects of Abeta oligomers in AD and is a tractable target for small molecule disease-modifying therapeutics.

Dataset Information

Pyk2 overexpression in postsynaptic neurons blocks amyloid ?_1-42-induced synaptotoxicity in microfluidic co-cultures.

Publications

Pyk2 overexpression in postsynaptic neurons blocks amyloid β<sub>1-42</sub>-induced synaptotoxicity in microfluidic co-cultures.

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Dataset Information

Pyk2 overexpression in postsynaptic neurons blocks amyloid ?1-42-induced synaptotoxicity in microfluidic co-cultures.

Publications

Pyk2 overexpression in postsynaptic neurons blocks amyloid β<sub>1-42</sub>-induced synaptotoxicity in microfluidic co-cultures.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Pyk2 overexpression in postsynaptic neurons blocks amyloid ?_1-42-induced synaptotoxicity in microfluidic co-cultures.