The contribution of neuroinflammation to amyloid toxicity in Alzheimer's disease

• Published in: Journal of neurochemistry 2016-02, Vol.136 (3), p.457-474
• Main Authors: Minter, Myles R., Taylor, Juliet M., Crack, Peter J.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - complications; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Alzheimers disease; amyloid; Amyloidogenic Proteins - metabolism; Animals; Chemokines; Cytokines; Cytokines - metabolism; Encephalitis - complications; Humans; Hypotheses; Immunity, Innate; Neurodegeneration; Neuroglia - pathology; neuroinflammation; Neurotoxicity; Pathogenesis; Toxicity
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.13411

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. Deposition of amyloid‐β (Aβ) remains a hallmark feature of the disease, yet the precise mechanism(s) by which this peptide induces neurotoxicity remain unknown. Neuroinflammation has long been implicated in AD pathology, yet its contribution to disease progression is still not understood. Recent evidence suggests that various Aβ complexes interact with microglial and astrocytic expressed pattern recognition receptors that initiate innate immunity. This process involves secretion of pro‐inflammatory cytokines, chemokines and generation of reactive oxygen species that, in excess, drive a dysregulated immune response that contributes to neurodegeneration. The mechanisms by which a neuroinflammatory response can influence Aβ production, aggregation and eventual clearance are now becoming key areas where future therapeutic intervention may slow progression of AD. This review will focus on evidence supporting the combined neuroinflammatory‐amyloid hypothesis for pathogenesis of AD, describing the key cell types, pathways and mediators involved. Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. Deposition of intracellular plaques containing amyloid‐beta (Aβ) is a hallmark proteinopathy of the disease yet the precise mechanisms by which this peptide induces neurotoxicity remains unknown. A neuroinflammatory response involving polarized microglial activity, enhanced astrocyte reactivity and elevated pro‐inflammatory cytokine and chemokine load has long been implicated in AD and proposed to facilitate neurodegeneration. In this issue we discuss key receptor systems of innate immunity that detect Aβ, drive pro‐inflammatory cytokine and chemokine production and influence Aβ aggregation and clearance. Evidence summarized in this review supports the combined neuroinflammatory‐amyloid hypothesis for pathogenesis of AD and highlights the potential of immunomodulatory agents as potential future therapies for AD patients. Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. Deposition of intracellular plaques containing amyloid‐beta (Aβ) is a hallmark proteinopathy of the disease yet the precise mechanisms by which this peptide induces neurotoxicity remains unknown. A neuroinflammatory response involving polarized microglial activity, enhanced as