Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.
Highlights
In the 3xTg, which contain three mutations associated with a familial Alzheimer’s disease (AD) (APP Swedish, MAPT P301L, and PSEN1 M146V) mouse model, atrophic astrocytes appear in the entorhinal cortex (EC) as early as 30 days and are present until Aβ plaques begin to emerge at 12 months of age [160]
While multiple mechanisms likely contribute to the etiology and progression of neurodegeneration in AD, the pathogenic role of neuroinflammation is well recognized and accepted
A sedentary lifestyle and unhealthy diet can accelerate the aging-associated chronic low-grade inflammatory process linked to neurodegeneration in AD
Summary
Aging is characterized by dysregulated immune [1] and metabolic homeostasis [2,3]. where there is chronic sterile low-grade inflammation or inflammaging [4] that involves cellular senescence [5,6], immunosenescence [7,8,9,10], mitochondrial dysfunction [11,12], defective autophagy [13,14] and mitophagy [15,16], dysregulation of the ubiquitin–proteasome system [17,18], activation of the DNA damage response [19,20], meta-inflammation or metaflammation from chronic overnutrition or obesity [21,22], and gut microbiota dysbiosis [5,23,24,25]. Recent large scale studies of AD genetics, employing genome-wide association studies (GWAS), whole exome sequencing (WES), and whole genome sequencing (WGS), have defined additional genes whose variants contribute to increased risk [53,54] These include Clusterin (CLU), Sortilin-related receptor-1 (SORL1), ATP-binding cassette subfamily A member 7 (ABCA7), Bridging integrator 1 (BIN1), phosphatidylinositol binding clathrin assembly protein (PICALM), CD2 associated protein (CD2AP), Complement component (3b/4b) receptor 1 (CR1), CD33, triggering receptor expressed on myeloid cells 2 (TREM2), and phospholipase D3 (PLD3) [55,56,57]. The sustained inflammatory response in AD brains [85,86,87] extends beyond a reaction to neuronal loss [88] and involves microglia, astrocytes, oligodendrocytes, mast cells, cytokines, and chemokines, as well as complement [89] These collectively play an integral role in the onset and progression of the disease [88,90,91]. We focus on recent progress made in understanding the role of inflammation in the etiopathogenesis of AD and describe a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without interfering with the defense mechanisms against pathogens and tissue damage
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