Inflammasomes & Alzheimer's Disease
Alzheimer's Disease is the most common form of dementia, affecting 5.7M people in the US and 1 in 10 people over 70 years of age. There are no satisfactory treatments for the disease.
It has long been recognized that in AD, amyloid-β and tangles of tau protein accumulate in the brain, triggering inflammation and nerve cell death, which then triggers further inflammation and amyloid-β accumulation.
Biochemically, AD is a multifactorial disease. Amyloid-β and tau protein tangles have long been therapeutic targets in the AD as they are present in the brains of patients with AD. Also present in brains of patients with the disease are elevated levels of Alu-RNA, complement, iron, and reactive oxygen species. These different factors all induce inflammasome activation, which triggers production of caspase-1 and the inflammatory cytokines, IL-1β and IL-18. In AD, inappropriate inflammasome activation causes nerve cell death.
In animal studies it has been found that inhibition of caspase-1 and inflammasome activation alleviates cognitive impairment and neuropathy in an Alzheimer’s disease mouse model.
References
- Ahmed M, Iyer S, Thangavel R, et al. Co-localization of glia maturation factor with NLRP3 inflammasome and autophagosome markers in human Alzheimer’s disease brain. J Alzheimer’s Dis. 2017; 60:1143-1160.
- Alzheimer’s Association. 2019 Alzheimer’s Disease Facts and Figures. Alzheimers Dement. 2019; 15:321-87.
- Chakraborty S, Kaushik DK, Gupta M, et al. Inflammasome signaling at heart of central nervous system pathology. J Neurosci Res. 2010; 88:1615-31.
- Cully M. Inflammasome protein seeds plaques in Alzheimer’s disease. Nature Rev Drug Discov. 2018; 17:96.
- Dempsey C, Rubio Araiz A, Bryson KJ, et al. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid and cognitive function in APP/PS1 mice. Brain Behav Immun. 2017; 61:306-16.
- Flores J, Noel A, LeBlanc AC et al. Caspase-1 inhibition alleviates cognitive impairment and neuropathy in an Alzheimer’s disease mouse model. Nat Commun. 2018;9:3916.
- Gold M and El-Khoury J. β-amyloid, microglia and the inflammasome in Alzheimer’s disease. Semin Immunopathol. 2015; 37:607-11.
- Halle A, Hornung V, Petzold GC, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol. 2008; 9:857-65.
- Heneka MT, Kummer MP, Stutz A, et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 2013; 493:674-8.
- Lane DR, Ayton S and Bush A. Iron and Alzheimer’s Disease: an update on emerging mechanisms. J Alzheimers Dis. 2018; 64(s1) s379-s395.
- Larsen PA, Lutz MW, Hunnicutt KE et al. The Alu neurodegeneration hypothesis: a primate specific mechanism of neuronal transcriptional noise, mitochondrial dysfunction and manifestation of neurodegenerative disease. Alzheimers Dement. 2017; 13:828-38.
- Liu L and Chan C. The role of inflammasome in Alzheimer’s disease. Aging Res Rev. 2014; 15:6-15.
- Morgan BP. Complement in the pathogenesis of Alzheimer’s disease. Semin Immunopathol. 2018; 40:113-24.
- Polesskaya O, Kananykhina E, Roy-Engel AM, et al. The role of Alu-derived RNAs in Alzheimer's and other neurodegenerative conditions. Med Hypotheses. 2018; 115:29-34.
- Saresella M, La Rosa F, Piancone F, et al. NLRP2 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol. Neurodegener. 2016; 3:11-23.
- Sheedy FJ, Grebe A, Rayner KJ, et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol. 2013; 14:812-20.
- Stancu IC, Cremers N, Vanrusselt H, et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol. 2019; 137:599-617.
- Tan MS, Yu JT, Jiang T, et al. NLRP3 polymorphisms are associated with late-onset Alzheimer's disease in Han Chinese. J Neuroimmunol. 2013; 265:91-5.
- Tejera D, Mercan D, Sanchez-Caro JM, et al. Systemic inflammation impairs microglial Aβ clearance through NLRP3 inflammasome. EMBO J. 2019;38:e101064.
- White CS, Lawrence CB, Brough D, et al. Inflammasomes as therapeutic targets for Alzheimer’s disease. Brain Pathol. 2017; 27:223-34.
Market Opportunity
In 2017 global Alzheimer's Disease revenue was $3.6B, driven by Aricept, Exelon and Razadyne. According to Zion Market Research the expected CAGR for AD drugs between 2017-2024 is 8% due to the growing aged population and the increasing prevalence/diagnosis of AD. However, PharmaPoint reports that additional AD treatments could increase market growth to 17% CAGR for a global market to exceed $12B by 2026.
- Alzheimer’s drug market 2017-2024, Zion Market Research
- PharmaPoint: Alzheimer’s disease global drug forecast and market analysis to 2026. GlobalData 2017