Microglial dysfunction in brain aging and Alzheimer's disease - PubMed (original) (raw)

Review

Microglial dysfunction in brain aging and Alzheimer's disease

Kira Irving Mosher et al. Biochem Pharmacol. 2014.

Abstract

Microglia, the immune cells of the central nervous system, have long been a subject of study in the Alzheimer's disease (AD) field due to their dramatic responses to the pathophysiology of the disease. With several large-scale genetic studies in the past year implicating microglial molecules in AD, the potential significance of these cells has become more prominent than ever before. As a disease that is tightly linked to aging, it is perhaps not entirely surprising that microglia of the AD brain share some phenotypes with aging microglia. Yet the relative impacts of both conditions on microglia are less frequently considered in concert. Furthermore, microglial "activation" and "neuroinflammation" are commonly analyzed in studies of neurodegeneration but are somewhat ill-defined concepts that in fact encompass multiple cellular processes. In this review, we have enumerated six distinct functions of microglia and discuss the specific effects of both aging and AD. By calling attention to the commonalities of these two states, we hope to inspire new approaches for dissecting microglial mechanisms.

Keywords: Aging; Alzheimer's disease; Microglia; Neurodegeneration; Neuroinflammation.

Published by Elsevier Inc.

PubMed Disclaimer

Figures

Figure 1

Figure 1

The hallmarks of microglial aging. The six major effector functions/phenotypes of microglia that are the focus of this review are highlighted at the outer ring of this schematic: proliferation, morphology, motility and migration, intercellular communication, proteostasis, and phagocytosis. Within the inner ring of the circle we describe the effects of aging on each of these functions.

Figure 2

Figure 2

Microglia molecules genetically implicated in Alzheimer’s disease. Recent studies have identified novel risk factors for AD such as TREM2, which together with previous work, strongly point to a role for microglia and immune mechanisms in the disease. NLRP3 inflammasome activation in microglia mediates a harmful inflammatory response that contributes to AD pathology. On the other hand, microglia express several receptors that bind Aβ (such as scavenger receptor A, RAGE, CD36, CR1, CR3, and toll-like receptors) as well as enzymes that degrade soluble Aβ (i.e., insulin-degrading enzyme, neprilysin, MMP), which may contribute to the clearance of amyloid thus offer protective functions. Likewise, beclin 1, which is decreased in the brains of AD patients, regulates the recycling of receptors such as CD36 and TREM2 and phagocytosis.

Figure 3

Figure 3

Understanding the intersection of microglial aging and Alzheimer’s disease. The hallmarks of microglial aging may be further exacerbated in AD as a result of disease-associated genetic variants and environmental influences. Potential connections between these phenotypes are shown in the figure. Such impairments in microglial functions may contribute to both aging and disease phenotypes and neuronal degeneration and dysfunction.

Similar articles

Cited by

References

    1. Stelzmann R, Norman Schnitzlein H, Reed Murtagh F. An English translation of Alzheimer’s 1907 paper, “Über eine eigenartige Erkankung der Hirnrinde”. Clinical anatomy. 1995;8(6):429–431. - PubMed
    1. Samorajski T. How the human brain responds to aging. J Am Geriatr Soc. 1976;24(1):4–11. - PubMed
    1. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Cell. 2013;153(6):1194–1217. - PMC - PubMed
    1. Hanisch U-K, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10(11):1387–94. - PubMed
    1. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci. 2005;8(6):752–758. - PubMed

Publication types

MeSH terms

Grants and funding

LinkOut - more resources