Inflammation in Alzheimer's disease: insights from immunotherapy.

More than 20 years after its initial formulation, the amyloid cascade hypothesis—which postulates that build-up of toxic amyloid-β species initiates a series of events that culminates in neurodegeneration and symptoms (Hardy and Higgins, 1992)—continues to dominate thinking on the pathogenesis of Alzheimer’s disease. Although the exact sequence of events linking amyloid-β accumulation to aggregation of hyperphosphorylated tau in different neuronal compartments, neuronal loss, synaptic dysfunction and symptoms remains unknown, there is now a substantial body of evidence implicating neuroinflammation in the pathogenesis of Alzheimer’s disease. Thus activated microglia accumulate around amyloid plaques both in the brains of individuals with Alzheimer’s disease and in transgenic mice, and have been implicated in promoting neurodegeneration (Akiyama et al. , 2000). Imaging studies using the 11C- R -PK11195 PET ligand provide evidence that activated microglial accumulate in the vicinity of amyloid plaque pathology, and that activated microglial burden correlates with declining cognition (Edison et al. , 2008). Genome-wide association studies have identified a number of risk variants for Alzheimer’s disease implicated in inflammatory responses (Bettens et al. , 2013); exome sequencing has revealed polymorphisms in the microglial receptor TREM2 gene as a rare but significant risk for Alzheimer’s disease (Guerreiro et al. , 2013; Jonsson et al. , 2013); and recently, the CD33 risk allele has been shown to inhibit microglial clearance of amyloid-β (Bradshaw et al. , 2013; Griciuc et al. , 2013). Finally, an integrative network-based genetic analysis of Alzheimer’s disease brain has implicated disturbance in immune/microglial networks in the pathogenesis of the disease (Zhang et al. , 2013). If inflammation, and microglial activation in particular, are core features of Alzheimer’s disease, the exact mechanisms involved, and the roles of the different inflammatory components are far less clear. Microglia—the predominant macrophage species within the brain—can express different cell-surface …