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. 2022 Oct;48(6):e12835.
doi: 10.1111/nan.12835. Epub 2022 Jul 25.

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  1 , Hélène Hall  2 , Chiara Orciani  3 , Morgan K Foret  2 , Olivia Kovecses  2 , Adriana Ducatenzeiler  2 , A Claudio Cuello  1   2   3   4
Affiliations

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 et al. Neuropathol Appl Neurobiol. 2022 Oct.

Abstract

Aims: The 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.

Methods: The LC was lesioned in wild-type and McGill-R-Thy1-APP transgenic (APP tg) rats by administering N-(2-chloroethyl)-N-ethyl-bromo-benzylamine before amyloid plaque deposition. Cognitive deficits and AD-like neuropathological changes were measured after the LC lesion.

Results: Four 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.

Conclusions: Our 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.

Keywords: Alzheimer's disease; amyloid pathology; astroglia; cholinergic; locus coeruleus; microglia; neuroinflammation; neurotrophin.

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References

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