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Review
. 2016;51(3):657-69.
doi: 10.3233/JAD-151075.

Do Microglia Default on Network Maintenance in Alzheimer's Disease?

Katherine A Southam, Adele J Vincent, David H Small
Free PMC article
Review

Do Microglia Default on Network Maintenance in Alzheimer's Disease?

Katherine A Southam et al. J Alzheimers Dis. 2016.
Free PMC article

Abstract

Although the cause of Alzheimer's disease (AD) remains unknown, a number of new findings suggest that the immune system may play a critical role in the early stages of the disease. Genome-wide association studies have identified a wide array of risk-associated genes for AD, many of which are associated with abnormal functioning of immune cells. Microglia are the brain's immune cells. They play an important role in maintaining the brain's extracellular environment, including clearance of aggregated proteins such as amyloid-β (Aβ). Recent studies suggest that microglia play a more active role in the brain than initially considered. Specifically, microglia provide trophic support to neurons and also regulate synapses. Microglial regulation of neuronal activity may have important consequences for AD. In this article we review the function of microglia in AD and examine the possible relationship between microglial dysfunction and network abnormalities, which occur very early in disease pathogenesis.

Keywords: Microglia; network abnormalities; neural networks; phagocytosis; synapse pruning.

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Figures

Fig.1
Fig.1
Increased microglial reactivity or increased protein clearance may reduce microglial synaptic maintenance. (1) Microglia monitor and prune CNS synapses throughout life in conjunction with peri-synaptic astrocytes. Microglia also phagocytose small amounts of extracellular protein such as Aβ, although it is not yet known whether microglia perform both phagocytic tasks simultaneously. Dysfunctional microglial activity at the synapse may produce one of the two following scenarios. (2) Increased pro-inflammatory activation of microglia results in increased production of inflammatory cytokines, co-activating peri-synaptic astrocytes, resulting in neuronal excitability and degeneration. (3) Alternatively, increased demands on microglial phagocytosis, such as elevated Aβ production, may reduce synaptic maintenance and result in increased Aβ at the synapse.
Fig.2
Fig.2
A model for microglial dysfunction that occurs downstream of Aβ, resulting in network dysfunction progressing to AD.
See this image and copyright information in PMC

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