Systemic and CNS Inflammation Crosstalk: Implications for Alzheimer’s Disease

Abstract

After years of failed therapeutic attempts targeting beta-amyloid (Aβ) in AD, there is now increasing evidence suggesting that inflammation holds a pivotal role in AD pathogenesis and immune pathways can possibly comprise primary therapeutic targets. Inflammation is a key characteristic of numerous diseases including neurodegenerative disorders and thus not surprisingly suppression of inflammation frequently constitutes a major therapeutic strategy for a wide spectrum of disorders. Several brain-resident and peripherally-derived immune populations and inflammatory mediators are involved in AD pathophysiology, with microglia comprising central cellular player in the disease process. Systemic inflammation, mostly in the form of infections, has long been observed to induce behavioral alterations and cognitive dysfunction, suggesting for a close interaction of the peripheral immune system with the brain. Systemic inflammation can result in neuroinflammation, mainly exhibited as microglial activation, production of inflammatory molecules, as well as recruitment of peripheral immune cells in the brain, thus shaping a cerebral inflammatory milieu that may seriously impact neuronal function. Increasing clinical and experimental studies have provided significant evidence that acute (e.g. infections) or chronic (e.g. autoimmune diseases like rheumatoid arthritis) systemic inflammatory conditions may be associated with increased AD risk and accelerate AD progression. Here we review the current literature that links systemic with CNS inflammation and the implications of this interaction for AD in the context of acute and chronic systemic pathologies as acute infection and rheumatoid arthritis. Elucidating the mechanisms that govern the crosstalk between the peripheral and the local brain immune system may provide the ground for new therapeutic approaches that target the immune-brain interface and shed light on the understanding of AD.

Chronic Oral Palmitoylethanolamide Administration Rescues Cognitive Deficit and Reduces Neuroinflammation, Oxidative Stress, and Glutamate Levels in A Transgenic Murine Model of Alzheimer’s Disease

“…In the present study we only observed that um-PEA treatment failed to modulate the increased plasma TNF-α levels in 3×Tg-AD mice. However, it cannot be ruled out that the compound could reduce other markers of systemic inflammation, thus modulating the systemic and CNS inflammation crosstalk [61].…”

Distinct Gut Microbiota Composition and Functional Category in Children With Cerebral Palsy and Epilepsy

“…Further analysis of microbial functions revealed the increased risks of immune systemic diseases and neurodegenerative diseases in CPE patients, and that neuroinflammation probably played a key role in the pathology of CPE (34). The elevated risk of immune system diseases was mainly attributed to the higher proportion of Akkermnsia in CPE patients.…”

Chronic Systemic Inflammation Exacerbates Neurotoxicity in a Parkinson’s Disease Model

“…High levels of systemic TNFα can cross the blood-brain barrier (BBB), stimulating the microglia to secrete more TNFα as well as other proinflammatory factors and thus creating persistent and self-generated neuroinflammation [15]. Metabolic diseases such as obesity, hypertension, dyslipidemia, diabetes, and insulin resistance are associated with chronic systemic inflammation and a higher risk of developing neurodegenerative diseases such as Alzheimer's disease and PD [17][18][19][20][21][22][23]. Due to the importance of peripheral inflammatory processes in PD development [24][25][26], it is relevant to investigate more thoroughly the mechanisms involved.…”