Glial Cell-Mediated Neuroinflammation in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder; it is the most common cause of dementia and has no treatment. It is characterized by two pathological hallmarks, the extracellular deposits of amyloid beta (Aβ) and the intraneuronal deposits of Neurofibrillary tangles (NFTs). Yet, those two hallmarks do not explain the full pathology seen with AD, suggesting the involvement of other mechanisms. Neuroinflammation could offer another explanation for the progression of the disease. This review provides an overview of recent advances on the role of the immune cells’ microglia and astrocytes in neuroinflammation. In AD, microglia and astrocytes become reactive by several mechanisms leading to the release of proinflammatory cytokines that cause further neuronal damage. We then provide updates on neuroinflammation diagnostic markers and investigational therapeutics currently in clinical trials to target neuroinflammation.

Neuroprotective Epigenetic Changes Induced by Maternal Treatment with an Inhibitor of Soluble Epoxide Hydrolase Prevents Early Alzheimer′s Disease Neurodegeneration

“…Neuroinflammation was detected at the age of 2 months as a trend towards an increase in the microglial activation marker gene Trem2 . However, neuroinflammation was a prominent sign in the 7-month-old 5XFAD mice, in agreement with its relevance in AD triggering and progression [ 53 , 54 ]. Therefore, polarization of microglia to a reactive phenotype is an early event after Aβ 42 accumulation in these mice.…”

Anti-Neuroinflammatory Potential of Natural Products in the Treatment of Alzheimer’s Disease

“…More and more research evidence shows that the development of AD is closely related to neuroinflammation [ 55 ]. In the early stage of AD, Aβ activates microglia by promoting the expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), IL-1β and IL-6 and then results in a neuroinflammatory environment to induce astrocyte activation and neuronal damage [ 56 ]. Neuron damage acts as damage-associated molecular patterns (DAMPs) [ 5 ], and in turn promotes the continuous activation of microglia and astrocytes to produce persistent chronic neuroinflammation.…”

“…M1 plays a pro-inflammatory role by secreting pro-inflammatory mediators, while M2 secretes anti-inflammatory mediators and nutritional factors to exert neuroprotective effects and remove apoptosis-related Aβ aggregation through phagocytosis [ 66 , 67 ]. In the early stage of AD, increased levels of Aβ, ATP and ROS lead to activation of the purinergic receptor P2X7 receptor (P2X7R) and down-regulation of myeloid cell trigger receptor 2 (TREM2), increasing calcium influx and, thus, activating microglia [ 56 ]. Furthermore, the BBB operates within the neurovascular unit (NVU).…”

“…M2 microglia can clear Aβ through phagocytosis and prevent the formation of Aβ plates. Over time, the efficiency of Aβ clearance decreases and then results in the formation of extracellular Aβ plaques [ 56 ], when M2 microglia recognize pathogen-associated molecular patterns (PAMPs) or PRRs-induced DAMPs [ 70 ]. As shown in Figure 2 , activated microglia are switched from the M2 to the M1 and eventually replaced by M1 in the later stages of brain injury [ 10 ].…”

“…It loses the ability to protect neuronal survival and promote synapse formation and phagocytosis and releases pro-inflammatory factors that cause neuronal damage [ 67 ]. Astrocytes can mediate Aβ uptake and clearance through transporters and receptors such as low-density lipoprotein receptor-associated protein 1 (LRP1) and scavenger receptor class B member 1 (SCARB1); however, the Aβ clearance ability of reactive astrocytes decreased, causing Aβ aggregation [ 56 ], resulting in decreased Ach levels, which in turn leads to synaptic dysfunction.…”