Contribution of GABAergic interneurons to amyloid-β plaque pathology in an APP knock-in mouse model

Author:

Rice Heather C.,Marcassa Gabriele,Chrysidou Iordana,Horré Katrien,Young-Pearse Tracy L.,Müller Ulrike C.,Saito Takashi,Saido Takaomi C.,Vassar Robert,de Wit Joris,De Strooper BartORCID

Abstract

AbstractThe 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.

Funder

Alzheimer's Association

Stichting Alzheimer Onderzoek

European Research Council

FWO

KU Leuven

The Flemish Government and Vlaams Initiatief voor Netwerken voor Dementie Onderzoek

Arthur Bax and Anna Vanluffelen chair for Alzheimer’s disease

Publisher

Springer Science and Business Media LLC

Subject

Cellular and Molecular Neuroscience,Neurology (clinical),Molecular Biology

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