Astrocytes in Health and Neurodegenerative Disease 1321 Astrocytes and neuroinflammation in Alzheimer’s disease Emma C. Phillips*, Cara L. Croft*, Ksenia Kurbatskaya*, Michael J. O’Neill†, Michael L. Hutton†, Diane P. Hanger*, Claire J. Garwood‡ 1 and Wendy Noble* 1,2 *Department of Neuroscience, Institute of Psychiatry, King’s College London, De Crespigny Park, London SE5 8AF, U.K. †Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey GU20 6PH, U.K. ‡Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, U.K. Abstract Increased production of amyloid β -peptide (Aβ ) and altered processing of tau in Alzheimer’s disease (AD) are associated with synaptic dysfunction, neuronal death and cognitive and behavioural deficits. Neuroinflammation is also a prominent feature of AD brain and considerable evidence indicates that inflammatory events play a significant role in modulating the progression of AD. The role of microglia in AD inflammation has long been acknowledged. Substantial evidence now demonstrates that astrocyte-mediated inflammatory responses also influence pathology development, synapse health and neurodegeneration in AD. Several anti-inflammatory therapies targeting astrocytes show significant benefit in models of disease, particularly with respect to tau-associated neurodegeneration. However, the effectiveness of these approaches is complex, since modulating inflammatory pathways often has opposing effects on the development of tau and amyloid pathology, and is dependent on the precise phenotype and activities of astrocytes in different cellular environments. An increased understanding of interactions between astrocytes and neurons under different conditions is required for the development of safe and effective astrocyte-based therapies for AD and related neurodegenerative diseases. Introduction Alzheimer’s disease (AD) is a progressive neurodegenerative disease and the most common form of dementia. Clinical symptoms of AD include memory loss, confusion and behavioural changes. AD is characterized neuropatholo- gically by the development of amyloid β -peptide (Aβ ) containing extracellular plaques, intracellular neurofibrillary tangles, comprising mainly abnormally phosphorylated and aggregated tau protein, and widespread synaptic degeneration and neuronal loss [1]. It seems likely that several interconnected events lead to synaptic dysfunction and neuronal death in AD. A complex relationship between Aβ and tau is believed to play a key role in these processes [1], with tau deficiency protecting from Aβ -induced neurodegeneration and cognitive decline [2]. Neuroinflammation is another prominent feature of AD brain that plays a significant role in modulating disease progression [3]. Key words: Alzheimer’s disease, astrocyte, glia, inflammation, tauopathy. Abbreviations: Aβ, amyloid β-peptide; AD, Alzheimer’s disease; APP, amyloid precursor protein; BDNF, brain-derived neurotrophic factor; CR1, complement receptor 1; IFN, interferon; IL, interleukin; LTP, long-term potentiation; MAPK, mitogen-activated protein kinase; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; NFAT, nuclear factor of activated T-cells; NLRP3, nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain-containing 3; NMDA, N-methyl-d-aspartate; N-SMase, neutral sphingomyelinase; PS, presenilin; TGF-β, transforming growth factor β; TNF, tumour necrosis factor. 1 These authors contributed equally to this work. 2 To whom correspondence should be addressed (email wendy.noble@kcl.ac.uk). Neuroinflammation in AD Rather than being simply a ‘bystander’ pathology, experi- mental evidence demonstrates that neuroinflammation plays an active role in the development and progression of AD [3,4]. In support of this view, genome-wide association studies have shown that variants of several immune genes, including complement receptor 1 (CR1) and triggering receptor expressed on myeloid cells 2 (TREM2), increase the risk of developing AD [5]. Aβ -containing plaques in AD brain are surrounded by a halo of activated glial cells [6], and Aβ is known to lead to the activation of astrocytes and microglia, along with induction of inflammatory signalling cascades [7,8]. Both microglia and astrocytes release a myriad of pro- and anti-inflammatory cytokines under different conditions. Changes in the cellular environment elicit a range of responses that are not well defined or predictable, and that probably account for reports of both protective and neurotoxic effects of glial stimulation in models of disease [8–10]. Cytokines can be classified into several subfamilies, including the interferons (IFNs), interleukin (IL)-1, IL- 2, IL-10 and IL-17, tumour necrosis factors (TNFs) and chemokines, including monocyte chemoattractant proteins (MCPs) and macrophage inflammatory proteins (MIPs). There is usually some redundancy in these secreted factors, with several different cytokines having similar actions. Cytokines signal via a number of pathways that have been implicated in AD. For example, binding of MCP-1, IL-1, IL-6, TNFα and IFNs to their neuronal receptors leads to Biochem. Soc. Trans. (2014) 42, 1321–1325; doi:10.1042/BST20140155 C  The Authors Journal compilation C  2014 Biochemical Society Biochemical Society Transactions www.biochemsoctrans.org