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  • Review Article
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The role of astrocytic α7 nicotinic acetylcholine receptors in Alzheimer disease

Nature Reviews Neurology volume 19, pages 278–288 (2023)Cite this article

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Abstract

The ongoing search for therapeutic interventions in Alzheimer disease (AD) has highlighted the complexity of this condition and the need for additional biomarkers, beyond amyloid-β (Aβ) and tau, to improve clinical assessment. Astrocytes are brain cells that control metabolic and redox homeostasis, among other functions, and are emerging as an important focus of AD research owing to their swift response to brain pathology in the initial stages of the disease. Reactive astrogliosis — the morphological, molecular and functional transformation of astrocytes during disease — has been implicated in AD progression, and the definition of new astrocytic biomarkers could help to deepen our understanding of reactive astrogliosis along the AD continuum. As we highlight in this Review, one promising biomarker candidate is the astrocytic α7 nicotinic acetylcholine receptor (α7nAChR), upregulation of which correlates with Aβ pathology in the brain of individuals with AD. We revisit the past two decades of research into astrocytic α7nAChRs to shed light on their roles in the context of AD pathology and biomarkers. We discuss the involvement of astrocytic α7nAChRs in the instigation and potentiation of early Aβ pathology and explore their potential as a target for future reactive astrocyte-based therapeutics and imaging biomarkers in AD.

Key points

  • Overexpression of α7 nicotinic acetylcholine receptors (α7nAChRs) in astrocytes correlates with amyloid-β (Aβ) pathology in the brain of individuals with Alzheimer disease (AD).

  • Experiments in animal models of AD indicate that α7nAChRs contribute to Aβ spreading and deposition.

  • Reactive astrocytes characterized by α7nAChR overexpression hold promise as an early biomarker for AD.

  • Experimental work using α7nAChRs agonists suggests that through the modulation of reactive astrogliosis, Aβ spreading might be prevented at an early stage of AD.

  • A multitracer imaging approach with astrocyte and α7nAChR PET radiotracers is essential to further explore the role of α7nAChRs and their interplay with reactive astrogliosis across the AD continuum.

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Fig. 1: Timeline of research into α7nAChRs.
Fig. 2: A hypothetical model of α7nAChR–Aβ interactions in AD.

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Acknowledgements

The authors’ work is financially supported by the Swedish Foundation for Strategic Research (SSF; RB13-0192), the Swedish Research Council (projects 2017-02965, 2017-06086, 2020-01990), the Swedish Brain Foundation, the Swedish Alzheimer Foundation, the Swedish Dementia Foundation, the Center for Innovative Medicine (CIMED) Region Stockholm, Åhlens Foundation, the Michael J Fox Foundation (MJFF-019728), the Alzheimer Association USA (AARF-21-848395), Loo and Hans Osterman Foundation for Medical Research, and the Recherche sur Alzheimer Foundation (Paris, France).

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Authors and Affiliations

  1. Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden

    Igor C. Fontana, Amit Kumar & Agneta Nordberg

  2. Theme Inflammation and Aging, Karolinska University Hospital, Stockholm, Sweden

    Agneta Nordberg

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All authors researched data for the article and contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Agneta Nordberg.

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Competing interests

A.N. holds a patent on PET radiotracer analogues of the compound ASEM (PCT/SE 20221050413). I.C.F. and A.K. declare no competing interests.

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Glossary

11C-l-deprenyl-D2

The most commonly used PET radiotracer in the clinical setting for imaging of monoamine oxidase B in reactive astrocytes.

Aβ isoforms

The range of different amyloid-β (Aβ) peptides, including Aβ1–38, Aβ1–40 and Aβ1–42, that are generated by the sequential cleavage of amyloid precursor protein by β-secretase and γ-secretase.

APP NL-F

APP knock-in mice that express human amyloid-β and have two pathogenic mutations — the Swedish (NL) and the Iberian (F) — in the APP gene.

APP/PS1

Transgenic mouse that mimics amyloid-β pathology in Alzheimer disease. The animals bear the amyloid precursor protein Swedish mutation and the presenilin 1 gene containing an L166P mutation.

Glial fibrillary acidic protein

(GFAP). An intermediate filament protein mostly found in astrocytes. Traditionally considered to be a universal marker of pathological reactive astrogliosis, although advanced transcriptomic and biomarker research indicates that not all reactive astrocytes express GFAP.

Mild cognitive impairment

(MCI). The initial stage of cognitive impairment that is often a precursor to Alzheimer disease.

Soluble Aβ oligomers

A pre-plaque amyloid-β (Aβ) conformational state that comprises around 2–45 Aβ monomers and is suggested to be the main toxic culprit in Alzheimer disease.

Tg2576

A mouse model of amyloid-β pathology that overexpresses a mutant form of amyloid precursor protein (APP; isoform 695) combined with the APP Swedish mutation.

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Fontana, I.C., Kumar, A. & Nordberg, A. The role of astrocytic α7 nicotinic acetylcholine receptors in Alzheimer disease. Nat Rev Neurol 19, 278–288 (2023). https://doi.org/10.1038/s41582-023-00792-4

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