We searched PubMed for journal articles published in English between Jan 1, 2009, and Oct 31, 2014, for the terms “neuroinflammation” or “inflammation” and “Alzheimer”, and included those papers judged to be most relevant to the focus of this Review. Additionally, we identified and included older papers with ground-breaking findings that led to recent research, using PubMed and by searches of the authors' own files and the reference lists of selected papers.
ReviewNeuroinflammation in Alzheimer's disease
Introduction
At first glance, the specialties of immunology and neurobiology could not be more different. From a cellular perspective, the brain represents stasis, whereas the immune system represents motion. But these two perspectives have come together as efforts to understand the pathogenesis of neurodegenerative disease have borne fruit. Emerging evidence suggests that inflammation has a causal role in disease pathogenesis, and understanding and control of interactions between the immune system and the nervous system might be key to the prevention or delay of most late-onset CNS diseases. In Alzheimer's disease, neuroinflammation is not a passive system activated by emerging senile plaques and neurofibrillar tangles, but instead contributes as much (or more) to pathogenesis as do plaques and tangles themselves.1 The important role of neuroinflammation is supported by findings that genes for immune receptors, including TREM22 and CD33,3, 4 are associated with Alzheimer's disease. Analysis of clinical manifestations that precede the dementia stage of Alzheimer's disease, such as mild cognitive impairment, further support an early and substantial involvement of inflammation in disease pathogenesis. In this Review we provide an overview of the neuroinflammatory landscape during Alzheimer's disease, including associated cell types and mediators, methods used to visualise neuroinflammation, and its clinical presentation and potential treatments.
Section snippets
Microglia
Microglia, the resident phagocytes of the CNS, are ubiquitously distributed in the brain. Microglia constantly use highly motile processes to survey their assigned brain regions for the presence of pathogens and cellular debris, and simultaneously provide factors that support tissue maintenance (figure 1).5 At the same time, microglia are important players in the maintenance and plasticity of neuronal circuits, contributing to the protection and remodelling of synapses.6 To some extent, this
Cytokines
Microglia and astrocytes are arguably the major source of cytokines in Alzheimer's disease. Cytokines contribute to nearly every aspect of neuroinflammation, including proinflammatory and anti-inflammatory processes, bystander neuronal injury, chemoattraction, and response of microglia to Aβ deposits. Microglia activation is both characterised by and modulated by cytokines. Increases in Aβ concentration in ageing TgAPPsw and PSAPP transgenic mice are associated with increased concentrations of
Factors that drive neuroinflammation
Aβ deposition alone might be sufficient to induce an inflammatory reaction that subsequently contributes to cognitive decline and development of Alzheimer's disease. In view of the possibility that Aβ deposition precedes cognitive deficits or clinical manifestation by decades, one might speculate that exogenous or endogenous factors can modify the innate immune response mounted by Aβ-exposed microglia. Thus, environmentally modifiable Alzheimer's disease risk factors, including systemic
In-vivo laser-scanning microscopy
During the past few decades, analysis of innate immunity of the brain was restricted to cell culture experiments and immunohistochemical detection of microglia. Little was known about the functional state of these cells in vivo. Methodological advances such as generation of transgenic mice with enhanced-GFP-labelled microglia, cranial window implantation, and Aβ plaque labelling with the fluorescent dye methoxy-XO4 have enabled longitudinal and live monitoring of the functional state of
Characterisation and monitoring of neuroinflammation in Alzheimer's disease
Although emerging evidence suggests that inflammation has a causal role in Alzheimer's disease pathogenesis, detection of inflammatory markers has not yet been established as a valuable method for diagnosis or monitoring of Alzheimer's disease. Nevertheless, novel data from a gene-expression analysis of post-mortem brains from patients with late-onset Alzheimer's disease highlighted an immune and microglia network dominated by genes implicated in phagocytosis.188 These data, together with
Anti-inflammatory drugs
Non-steroidal anti-inflammatory drug (NSAID) epidemiology and clinical trial results (table)204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219 have produced some healthy scepticism about apparent stage-dependent outcomes, but the disappointing results of these studies are perhaps not surprising when one considers that normal physiological cytokine regulation of glia activation and microglial phenotypes is highly context-dependent and stage-dependent.5 Contextual
Conclusions and future directions
Evidence exists that neuroinflammation might drive the pathogenic process in Alzheimer's disease. The brain can no longer be viewed as an immune-privileged organ, and advances in immunology need to be integrated into the known pathogenic pathways of diverse neurodegenerative disorders. The ligand–receptor interactions in the CNS microenvironment that keep microglia under tight control in the healthy brain are perturbed in chronic neurodegenerative disease, but when and how this occurs in
Search strategy and selection criteria
References (232)
- et al.
Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease
Cell
(2013) - et al.
Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta
Neuron
(2013) - et al.
Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor
Cell
(2013) - et al.
Microglial cells internalize aggregates of the Alzheimer's disease amyloid beta-protein via a scavenger receptor
Neuron
(1996) - et al.
Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers
Blood
(2011) - et al.
The chemokine system in diverse forms of macrophage activation and polarization
Trends Immunol
(2004) - et al.
Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes
Trends Immunol
(2002) - et al.
Other functions, other genes: alternative activation of antigen-presenting cells
Immunity
(1999) - et al.
Transcriptome-based network analysis reveals a spectrum model of human macrophage activation
Immunity
(2014) - et al.
Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease
Neuron
(2006)