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Review
. 2017 Mar;27(2):223-234.
doi: 10.1111/bpa.12478.

Inflammasomes as therapeutic targets for Alzheimer's disease

Claire S White  1 , Catherine B Lawrence  1 , David Brough  1 , Jack Rivers-Auty  1
Affiliations
Review

Inflammasomes as therapeutic targets for Alzheimer's disease

Claire S White et al. Brain Pathol. 2017 Mar.

Abstract

Alzheimer's disease is the most common form of progressive dementia, typified initially by short term memory deficits which develop into a dramatic global cognitive decline. The classical hall marks of Alzheimer's disease include the accumulation of amyloid oligomers and fibrils, and the intracellular formation of neurofibrillary tangles of hyperphosphorylated tau. It is now clear that inflammation also plays a central role in the pathogenesis of the disease through a number of neurotoxic mechanisms. Microglia are the key immune regulators of the CNS which detect amyloidopathy through cell surface and cytosolic pattern recognition receptors (PRRs) and respond by initiating inflammation through the secretion of cytokines such as interleukin-1β (IL-1β). Inflammasomes, which regulate IL-1β release, are formed following activation of cytosolic PRRs, and using genetic and pharmacological approaches, NLRP3 and NLRP1 inflammasomes have been found to be integral in pathogenic neuroinflammation in animal models of Alzheimer's disease. Therefore, the inflammasomes are very promising novel pharmacological targets which merit further research in the continued endeavor for efficacious therapeutics for Alzheimer's disease.

Keywords: Alzheimer's disease; inflammasomes; inflammation.

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Figures

Figure 1
Figure 1
Inflammation has an integral role in the pathogenesis of AD and can be influenced through a number of genetic and environmental factors. Amyloidopathy has been demonstrated to induce neurotoxic inflammation which has been shown to cause and propagate tauopathy. Neuronal damage caused by these processes could result in further inflammation in an unresolved feedback pattern. Many risk factors for AD such as inflammatory gene variants, brain injury, midlife obesity, diabetes, ageing and infection all have an inflammatory component; this supports the critical role inflammation has in AD and highlights the therapeutic potential of targeting inflammation.
Figure 2
Figure 2
Amyloid oligomers and monomers cause the expression of NLRP3 and proIL‐1β through TLR mediated NFκB activation. The NLRP3 inflammasome is then activated by amyloid oligomers and fibrils through phagosomal disruption or cell surface K+ channels. Both pathways result in K+ efflux and cell swelling leading to Cl− efflux through VRAC. This, through an unknown mechanism, leads to deubiquitination of NLRP3 and ASC, and the binding of NEK7 to NLRP3 resulting in NLRP3 inflammasome activation. The NLRP3‐ASC speck then recruits and activates caspase‐1 which then cleaves gasdermin D and proIL‐1β into their active forms. The N‐terminus cleavage product of gasdermin D then forms pores in the cell membrane allowing the leaderless IL‐1β to leave the cell.
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