Rice, HC;
Marcassa, G;
Chrysidou, I;
Horré, K;
Young-Pearse, TL;
Müller, UC;
Saito, T;
... De Strooper, B; + view all
(2020)
Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model.
Molecular Neurodegeneration
, 15
, Article 3. 10.1186/s13024-019-0356-y.
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Abstract
The amyloid-β (Aβ) peptide, the primary constituent of amyloid plaques found in Alzheimer’s disease (AD) brains, is derived from sequential proteolytic processing of the Amyloid Precursor Protein (APP). However, the contribution of different cell types to Aβ deposition has not yet been examined in an in vivo, non-overexpression system. Here, we show that endogenous APP is highly expressed in a heterogeneous subset of GABAergic interneurons throughout various laminae of the hippocampus, suggesting that these cells may have a profound contribution to AD plaque pathology. We then characterized the laminar distribution of amyloid burden in the hippocampus of an APP knock-in mouse model of AD. To examine the contribution of GABAergic interneurons to plaque pathology, we blocked Aβ production specifically in these cells using a cell type-specific knock-out of BACE1. We found that during early stages of plaque deposition, interneurons contribute to approximately 30% of the total plaque load in the hippocampus. The greatest contribution to plaque load (75%) occurs in the stratum pyramidale of CA1, where plaques in human AD cases are most prevalent and where pyramidal cell bodies and synaptic boutons from perisomatic-targeting interneurons are located. These findings reveal a crucial role of GABAergic interneurons in the pathology of AD. Our study also highlights the necessity of using APP knock-in models to correctly evaluate the cellular contribution to amyloid burden since APP overexpressing transgenic models drive expression in cell types according to the promoter and integration site and not according to physiologically relevant expression mechanisms.
Type: | Article |
---|---|
Title: | Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model |
Location: | England |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1186/s13024-019-0356-y |
Publisher version: | https://doi.org/10.1186/s13024-019-0356-y |
Language: | English |
Additional information: | This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
Keywords: | APP knock-in, Alzheimer’s disease, Amyloid plaques, Amyloid precursor protein, BACE1, GABA receptor, GABAergic neurons, Hippocampus, Interneurons |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UK Dementia Research Institute HQ |
URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10089545 |
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