Dataset Information

Neuroligin-1 is altered in the hippocampus of Alzheimer's disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers.

ABSTRACT: Synapse loss occurs early and correlates with cognitive decline in Alzheimer's disease (AD). Synaptotoxicity is driven, at least in part, by amyloid-beta oligomers (A?o), but the exact synaptic components targeted by A?o remain to be identified. We here tested the hypotheses that the post-synaptic protein Neuroligin-1 (NLGN1) is affected early in the process of neurodegeneration in the hippocampus, and specifically by A?o, and that it can modulate A?o toxicity. We found that hippocampal NLGN1 was decreased in patients with AD in comparison to patients with mild cognitive impairment and control subjects. Female 3xTg-AD mice also showed a decreased NLGN1 level in the hippocampus at an early age (i.e., 4 months). We observed that chronic hippocampal A?o injections initially increased the expression of one specific Nlgn1 transcript, which was followed by a clear decrease. Lastly, the absence of NLGN1 decreased neuronal counts in the dentate gyrus, which was not the case in wild-type animals, and worsens impairment in spatial learning following chronic hippocampal A?o injections. Our findings support that NLGN1 is impacted early during neurodegenerative processes, and that A?o contributes to this effect. Moreover, our results suggest that the presence of NLGN1 favors the cognitive prognosis during A?o-driven neurodegeneration.

SUBMITTER: Dufort-Gervais J

PROVIDER: S-EPMC7181681 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Neuroligin-1 is altered in the hippocampus of Alzheimer's disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers.

Dufort-Gervais Julien J Provost Chloé C Charbonneau Laurence L Norris Christopher M CM Calon Frédéric F Mongrain Valérie V Brouillette Jonathan J

Scientific reports 20200424 1

Synapse loss occurs early and correlates with cognitive decline in Alzheimer's disease (AD). Synaptotoxicity is driven, at least in part, by amyloid-beta oligomers (Aβo), but the exact synaptic components targeted by Aβo remain to be identified. We here tested the hypotheses that the post-synaptic protein Neuroligin-1 (NLGN1) is affected early in the process of neurodegeneration in the hippocampus, and specifically by Aβo, and that it can modulate Aβo toxicity. We found that hippocampal NLGN1 wa ...[more]

PMID: 32332783

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Project description:MiRNA molecules are important post-transcriptional regulators of gene expression in the brain function. Altered miRNA profiles could represent a defensive response against the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease (AD). Endogenous miRNAs have lower toxic effects than other gene silencing methods, thus enhancing the expression of defensive miRNA could be an effective therapy. However, little is known about the potential of targeting miRNAs for the treatment of AD. Here, we examined the function of the miR-200 family (miR-200a, -141, -429, -200b, -200c), identified using miRNA microarray analysis of cortical tissue from Tg2576 transgenic mice. In murine primary neurons, we found that upregulation of miR-200b or -200c was induced by the addition of amyloid beta (Aβ). Neurons transfected with miR-200b or -200c reduced secretion of Aβ in conditioned medium. Moreover, mice infused with miR-200b/c into the brain were relieved of memory impairments induced by intracerebroventricular injection of oligomeric Aβ, and demonstrated proper spatial learning in the Barnes maze. To gain further understanding of the relationship between miR-200b/c and Aβ, we identified target mRNAs via an RNA-binding protein immunoprecipitation-microarray assay. Western blot analysis showed that expression of ribosomal protein S6 kinase B1 (S6K1), a candidate target, was inhibited by miR-200c. S6K1, a downstream effector of mammalian target of rapamycin (mTOR), serves as a negative feedback mediator that phosphorylates insulin receptor substrate 1 at serine residues (IRS-1pSer). S6K1-dependent IRS-1pSer suppresses insulin signaling leading to insulin resistance, which is frequently observed in AD brains. Notably, miR-200b/c transfection of SH-SY5Y cells reduced the levels of IRS-1pSer. This finding indicates that miR-200b/c has the potential to alleviate insulin resistance via modulation of S6K1. Taken together, miR-200b/c may contribute to reduce Aβ secretion and Aβ-induced cognitive impairment by promoting insulin signaling.

Dataset Information

Neuroligin-1 is altered in the hippocampus of Alzheimer's disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers.

Publications

Neuroligin-1 is altered in the hippocampus of Alzheimer's disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers.

Similar Datasets

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