Chapter 1: Introduction
1.9 Neuroinflammation and cognitive disorders
Microglia in the elderly brain or under inflammatory situations produced higher inflammatory cytokines, continuous activation of microglia cells and chronic
inflammation increase the quantity of tau by stimulating kinases that regulate the expression of tau and cause it to aggregate more readily in neurons, which leads to neuroinflammation that results in neurodegeneration (Gorlovoy et al., 2009; Ritzel et al., 2015).
Adulthood and aging cause a continuous activation of microglia which results in a significant decline in neurogenesis. In rodents, this is manifested as a decrease in the rate of proliferation. Reduced neurogenesis may impact hippocampus function and at least in part account for decreased learning and memory as well as cognitive degeneration in the elderly (Galvan & Jin, 2007). While neurogenesis varies dramatically with age, synaptic structure changes less subtly (Lazarov & Hollands, 2016). In comparison to rats which replace 10% of their DG, humans exchange around 35% of their neurons (Lepousez et al., 2015). Also, as the brain matures, the blood-brain barrier becomes more permeable
allowing unresolved inflammatory cells to penetrate. Also, neuroinflammation leads to an increase in permeability of the blood-brain barrier.
1.9.1 Neuroinflammation and dementia
Dementia is a condition in which the brain's cognitive and behavioral functions deteriorate over time making it difficult to carry out daily tasks (Salardini, 2019).
Microglia activation will cause the release of pro-inflammatory mediators, which will lead to overexpression of apoptosis by disrupting the PI3K-AKT-GSK-3β pathway as well as neurotoxic stimuli impacting neurotransmitter release, which will cause LTP to change resulting in neuroinflammation and dementia. These variables exacerbate synaptic excitation and brain network connectivity, hastening synaptic malfunction and neurodegeneration (Giacobbo et al., 2019).
1.9.2 Neuroinflammation and Alzheimer’s disease (AD)
While there is no known etiology for Alzheimer's disease, it is known that persistent inflammatory processes play a role in the development of amyloid plaques, which result in additional accumulation and inflammatory processes affecting neuronal connections because it triggers a pro-inflammatory response in which microglia increase the release of cytokines (Interleukins and TNF-α), chemokines (NF-kB), and peptides (bradykinin) (Gorlovoy et al., 2009). The failure to resolve this reaction leads to
pathology since chronic inflammation puts microglia in danger of losing their ability to clear an infection due to a lack of phagocytic activity in microglia resulting in plaque formation and neurodegeneration (Wendeln et al., 2018).
A recent piece of evidence demonstrating that microglia have either positive or harmful effects throughout the onset and progression of AD is a critical issue in the scientific discussion. This is closely tied to the nature of the primary activities: (I)
amyloid plaques clearing or (II) proinflammatory mediator release amyloid oligomer and fibril clump together in the extracellular space during early AD pathogenesis triggering a pathogenic cascade that results in neuronal death and depletion (Hickman et al., 2018).
Microglia use phagocytosis to remove amyloid peptides and dead cells. Apart from clearing amyloid oligomers and fibrils, microglia likely form a physical barrier around
plaques and fibrils preventing their spread and toxicity (Wang & Colonna, 2019). The release of several proteases involved in Amyloid breakdown also promotes amyloid plaque clearance (Hickman et al., 2018; Simard et al., 2006; Wang & Colonna, 2019).
Despite the benefits of early microglia cell activation, persistent activation by amyloid plaques is harmful and causes chronic inflammation and excessive amyloid plaque accumulation hastening neurodegeneration (Simard et al., 2006). The production and release of proinflammatory cytokines and other harmful components are increased during AD pathogenesis. In addition, microglia's usual phagocytic activity has reduced resulting in neuroinflammation and neurodegeneration (Businaro et al., 2018; Ledo et al., 2016).
Clinical trials examining the efficacy of various medications in the treatment of Alzheimer's disease specifically by targeting the neuroinflammation process are in various stages. The clinical trial for indomethacin is in its (iii) phase. An archetypal ligand-activated nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPAR-gamma), is activated by the medication. The activity of amyloid precursor protein cleaving enzyme 1 is reduced because of this activation resulting in decreased amyloid plaque formation (Deardorff & Grossberg, 2017; Rawat et al., 2019). Simufilam is another medicine that is in its (ii) phase of clinical studies. In preclinical studies it reduces inflammation and tau phosphorylation (Eratne et al., 2018). while candesartan reduces microglia hyperactivation in the hippocampus area of AD mice (Torika et al., 2018). Minocycline protects the brain by lowering the levels of inflammatory markers including IL-6 as well as microglial activation (Cheng et al., 2015). On the other hand, Pioglitazone influences the phagocytosis process that helps in the removal of
accumulated amyloid plaques and reduces the production of inflammatory cytokines.
1.9.3 Neuroinflammation and Parkinson's disease (PD)
Parkinson's disease (PD) is brought on by a steady depletion of dopaminergic neurons located in the substantia nigra. Less dopamine is released into the striatum as dopaminergic neurons die, leading to movement disorders like tremors, stiffness, and bradykinesia, cognitive impairment like dementia, and even mental symptoms like
sadness, apathy, and anxiety, along with bowel problems and sleep issues (Forno, 1996;
Toulouse & Sullivan, 2008).
The innate immune systems mediators such as chemokines and cytokines that released by microglia were discovered to be elevated in the brains of PD patients. As putative PD biomarkers TNF-α, IL-1, and IL6 were especially proposed (Scalzo et al., 2009). It is interesting to note that the severity and progression of Parkinson's disease may have an impact on the levels of these markers in peripheral tissues. TNF-α levels in the blood were shown to be higher in PD patients with more severe cognitive
impairment, depression, sleep problems, and fatigue (Dobbs et al., 1999; B. Liu et al., 2003; Scalzo et al., 2009).