Early loss of locus coeruleus innervation promotes cognitive and neuropathological changes before amyloid plaque deposition in a transgenic rat model of Alzheimer's disease

Lisi Flores‐Aguilar; Hélène Hall; Chiara Orciani; Morgan K. Foret; Olivia Kovecses; Adriana Ducatenzeiler; A. Claudio Cuello

doi:10.1111/nan.12835

journal article Jul 25, 2022

Early loss of locus coeruleus innervation promotes cognitive and neuropathological changes before amyloid plaque deposition in a transgenic rat model of Alzheimer's disease

Lisi Flores‐Aguilar Hélène Hall Chiara Orciani Morgan K. Foret Olivia Kovecses Adriana Ducatenzeiler A. Claudio Cuello

Neuropathology and Applied Neurobiology Vol. 48 No. 6 · Wiley

View at Publisher Save 10.1111/nan.12835

Abstract

AbstractAimsThe locus coeruleus (LC) is the main source of noradrenaline (NA) in the mammalian brain and has been found to degenerate during the initial stages of Alzheimer's disease (AD). Recent studies indicate that at late stages of the amyloid pathology, LC‐pathological alterations accelerate AD‐like pathology progression by interfering with the neuromodulatory and anti‐inflammatory properties of NA. However, the impact of LC degeneration at the earliest stages of amyloidosis on the AD‐like pathology is not well understood.MethodsThe LC was lesioned in wild‐type and McGill‐R‐Thy1‐APP transgenic (APP tg) rats by administeringN‐(2‐chloroethyl)‐N‐ethyl‐bromo‐benzylamine before amyloid plaque deposition. Cognitive deficits and AD‐like neuropathological changes were measured after the LC lesion.ResultsFour months post‐treatment, rats displayed a decrease in brain noradrenergic innervation. The LC lesion in APP tg‐treated rats enhanced cognitive deficits and decreased hippocampal cholinergic innervation and neurotrophin expression. In addition, the APP tg‐treated rats displayed an increased microglial and astroglial cell number in close vicinity to hippocampal amyloid‐beta burdened neurons. The recruited microglia showed cellular alterations indicative of an intermediate activation state.ConclusionsOur results indicate that early LC demise aggravates the early neuroinflammatory process, cognitive impairments, cholinergic deficits and neurotrophin deregulation at the earliest stages of the human‐like brain amyloidosis.

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Details

Published: Jul 25, 2022
Vol/Issue: 48(6)
License: View

Authors

L

Lisi Flores‐Aguilar

Department of Anatomy and Cell Biology McGill University Montreal Quebec Canada

H

Hélène Hall

Department of Pharmacology and Therapeutics McGill University Montreal Quebec Canada

C

Chiara Orciani

Department of Neurology and Neurosurgery McGill University Montreal Quebec Canada

M

Morgan K. Foret

Department of Pharmacology and Therapeutics McGill University Montreal Quebec Canada

O

Olivia Kovecses

Department of Pharmacology and Therapeutics McGill University Montreal Quebec Canada

A

Adriana Ducatenzeiler

Department of Pharmacology and Therapeutics McGill University Montreal Quebec Canada

A

A. Claudio Cuello

Department of Anatomy and Cell Biology McGill University Montreal Quebec Canada; Department of Pharmacology and Therapeutics McGill University Montreal Quebec Canada; Department of Neurology and Neurosurgery McGill University Montreal Quebec Canada; Visiting Professor, Department of Pharmacology University of Oxford Oxford UK

Funding

Canadian Institutes of Health Research

McGill University

Cite This Article

Lisi Flores‐Aguilar, Hélène Hall, Chiara Orciani, et al. (2022). Early loss of locus coeruleus innervation promotes cognitive and neuropathological changes before amyloid plaque deposition in a transgenic rat model of Alzheimer's disease. Neuropathology and Applied Neurobiology, 48(6). https://doi.org/10.1111/nan.12835

Early loss of locus coeruleus innervation promotes cognitive and neuropathological changes before amyloid plaque deposition in a transgenic rat model of Alzheimer's disease

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