Cholinergic Modulation of Glial Function During Aging and Chronic Neuroinflammation

Abstract

Aging is a complex biological process that increases the risk of age-related cognitive degenerative diseases such as dementia, including Alzheimer's disease (AD), Lewy Body Dementia (LBD), and mild cognitive impairment (MCI). Even non-pathological aging of the brain can involve chronic oxidative and inflammatory stress, which disrupts the communication and balance between the brain and the immune system. There has been an increasingly strong connection found between chronic neuroinflammation and impaired memory, especially in AD. While microglia and astrocytes, the resident immune cells of the central nervous system (CNS), exerting beneficial effects during the acute inflammatory phase, during chronic neuroinflammation they can become more detrimental. Central cholinergic circuits are involved in maintaining normal cognitive function and regulating signaling within the entire cerebral cortex. While neuronal-glial cholinergic signaling is anti-inflammatory and anti-oxidative, central cholinergic neuronal degeneration is implicated in impaired learning, memory sleep regulation, and attention. Although there is evidence of cholinergic involvement in memory, fewer studies have linked the cholinergic anti-inflammatory and anti-oxidant pathways to memory processes during development, normal aging, and disease states. This review will summarize the current knowledge of cholinergic effects on microglia and astroglia, and their role in both anti-inflammatory and anti-oxidant mechanisms, concerning normal aging and chronic neuroinflammation.

Neuroinflammation in Alzheimer’s Disease

“…They also regulate the maturation of neurons and help maintain their function [ 147 , 148 ]. They are found in various states of activation and can be neuroprotective (reducing inflammation and stimulating repair) or neurotoxic (promoting inflammation that may result in neurodegeneration) [ 149 , 150 ]. They respond to inflammatory molecules such as cytokines and chemokines and are able to detect aggregated proteins such as Aβ [ 148 , 151 , 152 ].…”

Central Activation of Alpha7 Nicotinic Signaling Attenuates LPS-Induced Neuroinflammation and Sickness Behavior in Adult but Not in Aged Animals

“…Levels of IL-6 in plasma were determined using BD OptEIA Mouse IL-6 ELISA according to the manufacturer’s instructions (BD Biosciences, San Jose, CA, USA), as previously described [ 33 ]. Briefly, 96-well plates were coated with anti-mouse IL-6 capture antibody at 4 °C overnight.…”

“…Moreover, evidence of the anti-inflammatory role of α7 nAChR has also been addressed in vivo, were activation of the receptor showed protective effect in a model of chronic stress via inhibition of TLR4 and microglial activity [ 31 ]. All together, these findings point at α7 nAChR as an interesting target for neuroprotection, reviewed in [ 32 , 33 ]. Thus, in this study, we aim to evaluate how central α7 nAChR signaling controls the microglial response upon LPS peripheral challenge in adult and aged animals.…”

PET Neuroimaging of Alzheimer's Disease: Radiotracers and Their Utility in Clinical Research

“…Early differentiation of MCI due to AD is crucial since early therapeutic intervention is indicated to be beneficial at least in slowing disease progression (Vellas et al, 2007;Molinuevo et al, 2011). It should be noted, though, that the etiology of MCI is heterogeneous, meaning that approximately half of the patients convert to dementia other than AD, or do not convert at all (Rowe et al, 2010;Bennett et al, 2012;Frisoni et al, 2017). Therefore, whether FDG PET has discriminative and predictive ability for MCI patients is of great clinical relevance.…”

“…PET imaging studies with tracers for both pre- and post-synaptic cholinergic targets have confirmed the abnormalities of cholinergic transmission in vivo , in AD, as manifested in altered levels of AChE, VAChT, and α 4 β 2 and α 7 nAChR's, and their correlations with Aβ deposition and cognitive functions. The α 7 nAChR is a target gaining increasing focus in recent years, due to its newly discovered participation in preventing amyloid toxicity and tau hyper-phosphorylation, in increasing synaptic strength and stability, and in modulating neuroinflammation by acting on non-neuronal cells (Wang et al, 2003 ; Conejero-Goldberg et al, 2008 ; Halff et al, 2014 ; de Oliveira et al, 2016 ; Maurer and Williams, 2017 ; Gamage et al, 2020 ). Renewed interests have also been seen in the mAChR, especially the M1 and M4 subtypes, for therapeutic development for AD (Levey, 1996 ; Schliebs and Arendt, 2011 ; Melancon et al, 2013 ).…”