Dysregulation of Systemic Immunity in Aging and Dementia

Abstract

Neuroinflammation and the tissue-resident innate immune cells, the microglia, respond and contribute to neurodegenerative pathology. Although microglia have been the focus of work linking neuroinflammation and associated dementias like Alzheimer’s Disease, the inflammatory milieu of brain is a conglomerate of cross-talk amongst microglia, systemic immune cells and soluble mediators like cytokines. Age-related changes in the inflammatory profile at the levels of both the brain and periphery are largely orchestrated by immune system cells. Strong evidence indicates that both innate and adaptive immune cells, the latter including T cells and B cells, contribute to chronic neuroinflammation and thus dementia. Neurodegenerative hallmarks coupled with more traditional immune system stimuli like infection or injury likely combine to trigger and maintain persistent microglial and thus brain inflammation. This review summarizes age-related changes in immune cell function, with special emphasis on lymphocytes as a source of inflammation, and discusses how such changes may potentiate both systemic and central nervous system inflammation to culminate in dementia. We recap the understudied area of AD-associated changes in systemic lymphocytes in greater detail to provide a unifying perspective of inflammation-fueled dementia, with an eye toward evidence of two-way communication between the brain parenchyma and blood immune cells. We focused our review on human subjects studies, adding key data from animal models as relevant.

Expression of Immune Related Genes and Possible Regulatory Mechanisms in Alzheimer’s Disease

“…Pathologically, AD brains harbor neurofibrillary tangles (NFTs) formed by excessive intracellular hyperphosphorylation and misfolded tau and amyloid plaques of extracellular amyloid b (Ab) (1). In recent years, neuroinflammation and tissue-resident immune cells have been increasingly recognized as critical contributors to AD pathogenesis (2,3).…”

High-Fat and Resveratrol Supplemented Diets Modulate Adenosine Receptors in the Cerebral Cortex of C57BL/6J and SAMP8 Mice

“…All these data point out a potential role of 5′-NT-A 2A R signaling in the HFD-induced cognitive deterioration. Neuroinflammation is a key factor that may contribute to the progression of neurodegenerative disorders [ 73 , 74 , 75 ]. Microglial 5′-NT-A 2A R-mediated signaling modulates microglial immune-response in the brain [ 72 , 76 ], hence, this functional axis may represent a potential target to control neuroinflammation.…”

Leukocyte-derived ratios are associated with late-life any type dementia: a cross-sectional analysis of the Mugello study

“…Converging evidence supports the hypothesis that both central and peripheral inflammation play a pivotal role in the pathogenesis of dementia [3]. The central nervous system (CNS) inflammation process has polyhedric manifestations, occurring in the continuum of the different stages of dementia [4]; moreover, different forms of dementia might share inflammation as an etiopathological trigger and a common pathway [5]. In older individuals, due to multiple systemic inflammatory events [6], and in the earliest silent dementia phase, in response to intraneuronal accumulation of oligomeric peptides, neurotoxic cytokines are released [7]: in this inflammatory scenario, microglia are activated [8], driving further proinflammatory conditions which in turn induce an anti-inflammatory response [9].…”

“…The recent COVID-19 pandemic has renewed the interest in leukocyte countderived indexes, which are easily available at no extra cost, and represent possible markers of inflammation with predictive value for disease outcome, not only in the elderly. The leukocytes derived ratio, as a combined inflammatory biomarker, integrates information from innate and adaptive immunity [5]. It avoids the disadvantage of an absolute value of a single leukocyte subtype, which may be affected by infection or dehydration, and has higher clinical significance than the other independent inflammatory biomarkers [12].…”