Neural Regeneration Research ›› 2020, Vol. 15 ›› Issue (7): 1208-1219.doi: 10.4103/1673-5374.272571

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Shifting equilibriums in Alzheimer’s disease: the complex roles of microglia in neuroinflammation, neuronal survival and neurogenesis

Sophie C. Gray, Kerri J. Kinghorn* , Nathaniel S. Woodling*   

  1. Institute of Healthy Ageing and Department of Genetics, Evolution and Environment, University College London, London, UK
  • Online:2020-07-15 Published:2020-09-12
  • Contact: Kerri J. Kinghorn, MD, PhD, k.kinghorn@ucl.ac.uk; Nathaniel S. Woodling, PhD, n.woodling@ucl.ac.uk.

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Abstract:

Alzheimer’s disease is the leading cause of dementia. Its increased prevalence in developed countries, due
to the sharp rise in ageing populations, presents one of the costliest challenges to modern medicine. In
order to find disease-modifying therapies to confront this challenge, a more complete understanding of
the pathogenesis of Alzheimer’s disease is necessary. Recent studies have revealed increasing evidence for
the roles played by microglia, the resident innate immune system cells of the brain. Reflecting the well-es
tablished roles of microglia in reacting to pathogens and inflammatory stimuli, there is now a growing
literature describing both protective and detrimental effects for individual cytokines and chemokines pro
duced by microglia in Alzheimer’s disease. A smaller but increasing number of studies have also addressed
the divergent roles played by microglial neurotrophic and neurogenic factors, and how their perturbation
may play a key role in the pathogenesis of Alzheimer’s disease. Here we review recent findings on the roles
played by microglia in neuroinflammation, neuronal survival and neurogenesis in Alzheimer’s disease. In
each case, landmark studies have provided evidence for the divergent ways in which microglia can either
promote neuronal function and survival, or perturb neuronal function, leading to cell death. In many cases,
the secreted molecules of microglia can lead to divergent effects depending on the magnitude and context
of microglial activation. This suggests that microglial functions must be maintained in a fine equilibrium,
in order to support healthy neuronal function, and that the cellular microenvironment in the Alzheimer’s
disease brain disrupts this fine balance, leading to neurodegeneration. Thus, an understanding of microglial
homeostasis, both in health and across the trajectory of the disease state, will improve our understanding of
the pathogenic mechanisms underlying Alzheimer’s disease, and will hopefully lead to the development of
microglial-based therapeutic strategies to restore equilibrium in the Alzheimer’s disease brain.

Key words: adult neurogenesis, Alzheimer’s disease, IGF-1, microglia, neuroinflammation, Trem2