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Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?
Nature Reviews Neurologyvolume 17, pages157–172 (2021)Cite this article
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Abstract
Alzheimer disease (AD) is the most common form of neurodegenerative disease, estimated to contribute 60–70% of all cases of dementia worldwide. According to the prevailing amyloid cascade hypothesis, amyloid-β (Aβ) deposition in the brain is the initiating event in AD, although evidence is accumulating that this hypothesis is insufficient to explain many aspects of AD pathogenesis. The discovery of increased levels of inflammatory markers in patients with AD and the identification of AD risk genes associated with innate immune functions suggest that neuroinflammation has a prominent role in the pathogenesis of AD. In this Review, we discuss the interrelationships between neuroinflammation and amyloid and tau pathologies as well as the effect of neuroinflammation on the disease trajectory in AD. We specifically focus on microglia as major players in neuroinflammation and discuss the spatial and temporal variations in microglial phenotypes that are observed under different conditions. We also consider how these cells could be modulated as a therapeutic strategy for AD.
Key points
Neuroinflammation has demonstrated a key role in the pathogenesis of Alzheimer disease (AD), the most prevalent form of dementia.
Neuroinflammation encompasses a variety of inflammatory events in the CNS under pathological conditions.
Among the innate immune cells, microglia are the primary players in neuroinflammation.
Activated microglia exhibit diverse phenotypes and have multifaceted interactions with amyloid-β and tau species as well as with neuronal circuits.
Activated microglia might have diverse influences on the progression of AD, depending on the stage of disease, individual susceptibility and state of microglial priming.
Microglia could potentially be modulated at various points in the AD trajectory to either prevent or modify disease progression.
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F.L. is sponsored by the China Scholarship Council to undertake postgraduate research.
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Department of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, London, UK
Fangda Leng & Paul Edison
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F.L. contributed to writing of the manuscript. P.E. made substantial contributions to discussions of the content and revision of the manuscript. Both authors researched data for the manuscript.
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P.E. declares that he was formerly funded by the Medical Research Council and now by the Higher Education Funding Council for England (HEFCE), that he has received grants from Alzheimer’s Drug Discovery Foundation, Alzheimer’s Research UK, Alzheimer’s Society UK, GE Healthcare, Novo Nordisk and Piramal Life Sciences, and that he has acted as a consultant to Novo Nordisk and Pfizer. The other authors declare no competing interests.
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Leng, F., Edison, P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?.Nat Rev Neurol17, 157–172 (2021). https://doi.org/10.1038/s41582-020-00435-y
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