Inflammasomes, hormesis, and antioxidants in neuroinflammation: Role of NRLP3 in Alzheimer disease

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Alzheimer disease (AD) is a progressive neurodegenerative disorder leading to cognitive decline, neuropsychiatric symptoms, disability, caregiver burden, and premature death. It represents the most prevalent cause of dementia, and its incidence rates exponentially increase with age (Ziegler‐Graham et al., 2008). The number of Americans living with AD is growing fast. An estimated 5.4 million Americans of all ages have AD in 2016. Of the 5.4 million Americans with AD, an estimated 5.2 million people are aged 65 and older, and approximately 200,000 individuals are under age 65 (early‐onset AD). One in nine people aged 65 and older has AD, and by midcentury, someone in the United States will develop the disease every 33 sec. These numbers will escalate rapidly in the coming years, as the baby boom generation has begun to reach age 65 and beyond, the age range of greatest risk of AD. By 2050, the number of people aged 65 and older with AD may nearly triple from 5.2 million to a projected 13.8 million, barring the development of medical breakthroughs to prevent or cure the disease. Previous estimates based on high range projections of population growth provided by the U.S. Census suggest that this number may be as high as 16 million. The disease is predicted to affect 1 in 85 people globally worldwide by 2050 (Brookmeyer et al., 2007). The neuropathological hallmarks of AD, in mouse models and postmortem patient brains, are diffuse amyloid plaques—which are frequently surrounded by dystrophic neurites—and intracellular neurofibrillary tangles (NFTs), respectively constituted by amyloid β (Aβ) and hyperphosphorylated microtubule‐associated protein tau (Lalla and Donmez, 2013). In addition, dominant mutations were found in the amyloid precursor protein (APP) gene and in the presenilin 1 and 2 genes (PSEN1 and PSEN2), which encode for components of gamma‐secretase, leading to early‐onset AD (Giri et al., 2016). APP is cleaved by beta‐secretase and gamma‐secretase sequentially to generate Aβ1–40 and Aβ1–42 amyloid peptides, respectively, which accumulate and form the amyloid plaques (Huang et al., 2016; Mendiola‐Precoma et al., 2016). Research since the discoveries of Aβ and tau has provided detailed information about molecular pathogenetic events, yet little is known about the cause of AD, and no cure is available (Scheltens et al., 2016). Emerging evidence suggests that inflammation has a pivotal role in the pathogenesis of various neurological disorders, and understanding of interactions between the immune system and the nervous system might be key to the prevention or delay of most late‐onset central nervous system (CNS) diseases. Neuroinflammation, a specialized immune response of the nervous system, has been related to the onset of some chronic degenerative diseases of the CNS characterized by a progressive neuronal death in specific regions of the CNS. This neuronal loss seems to be the cause of motor and cognitive deficits that characterize neurodegenerative diseases. Brain inflammation has been linked to many of these diseases, including amyotrophic lateral sclerosis, multiple sclerosis (MS), Parkinson disease (PD), and, in particular, AD (Calabrese V et al., 2010a; Trovato et al., 2016). An increasing number of studies have proposed a strong correlation between reactive oxygen species (ROS)‐induced oxidative stress dysfunction of protein metabolism and the pathogenesis of AD. Indeed, the brain has a large potential oxidative capacity but a limited ability to counteract oxidative stress (Cobb and Cole, 2015; Chiurchiù et al., 2016; Tramutola et al., 2016a). One possible vehicle for deposition and accumulation of Aβ in AD is oxidative stress, mediated by the production of ROS.

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