2.1. Microglia

Microglia are the CNS’s immune cells [98] and are different from peripheral and other tissue-resident macrophages [99,100,101,102,103,104]. They arise from yolk-sac fetal macrophages and are unique in their capacity for self-renewal [105,106,107]. Other tissue macrophages develop from precursors that emerge later in life [103,104]. They constantly survey their milieu and assess ongoing synaptic activity, mediate synaptic pruning, clear debris, and provide trophic support for neurons [108]. In pathological situations such as chronic stress, the blood brain barrier (BBB) may become compromised, allowing peripheral hematopoietic cells to cross into neural tissue and become part of the parenchymal microglia/macrophage pool [109,110]. In response to CNS insults such as neuronal injury or infection, microglia become activated to produce pro-inflammatory factors (M1 phenotype) or anti-inflammatory factors (M2 phenotype) [111]. An exquisite balance of anti-inflammatory mediators to heal and repair tissues and pro-inflammatory mediators to clear cellular debris and aggregated misfolded proteins is essential for the maintenance of a healthy CNS [27,111]. With advancing age, microglia acquire an activated phenotype and release pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6 [112,113,114]. In AD, microglia react to pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) [115,116,117] to assume a M1 phenotype, leading to an exacerbation of inflammation and an acceleration of disease progression [88] (Figure 1). Preliminary findings implicate a link between Aβ and neuroinflammation [118]. In AD brain slices, activated microglia surround both extracellular Aβ plaques and neurons containing neurofibrillary tangles (NFTs) [119,120]. It is thought that Aβ activate microglia, which then secrete IL1β, IL6, and TNFα, as well as (C-C motif) ligand (CCL 2/4/11), which lead to the recruitment of more microglia and astrocytes to the Aβ locus [121]. Microglia phagocytize Aβ through a range of cell surface receptors, including cluster of differentiation (CD)-14, toll-like receptor (TLR)-2, TLR4, α6β1 integrin, CD47, and scavenger receptors such as CD36 [122,123,124,125]. In AD, the accumulation of Aβ throughout the brain results partly from the failure of microglia to remove extracellular Aβ [126,127,128] and AD cortical specimens reveal that the microglia surrounding plaques have impaired Aβ uptake [127,129,130]. It has been shown in human and animal studies that inflammation influences APP processing overall [131,132]. Initially, microglial activation may serve to eliminate Aβ [126,133,134,135], but their chronic activation may amplify the amyloid cascade [133,136] and lead to neurotoxicity [137,138]. In rat intraventricular hemorrhage (IVH) model of AD, Aβ accumulation tracks with neuroinflammation and may contribute to the cognitive impairment [139].There is no consensus, however, regarding the relationship between in vivo microglial activation and Aβ plaque burden [140,141,142,143,144]. Aβ has recently been suggested to be an antimicrobial peptide that fibrilizes in order to activate the innate immune defense system and protect the host from a wide range of infectious agents [145].

Figure 1. Schematic representation of the proposed causes of neuroinflammation in Alzheimer’s disease (AD). Age-related release of damage-associated molecular patterns (DAMPs) such as Aβ, extracellular ATP, and cell debris such as circulating mitochondrial DNA, which are capable of interacting with the Nod-like receptor 3 (NLRP3), creates an oxidative and neuroinflammatory environment through the excessive production and release of pro-inflammatory cytokines and reactive oxygen and nitrogen species (RONS). Further, mitochondrial reactive oxygen species (mtROS) and senescence-associated secretory phenotype (SASP) factors from the senescent cells, which also drive senescence in nearby cells, produce pro-inflammatory cytokines. This culminates in neuroinflammation and neuronal apoptosis.

2.2. Astrocytes

Astrocytes are the most abundant cell type in the CNS and a critical part of the tripartite synapse [146]. They are highly sensitive to their environment and rapidly respond to CNS needs and insults [147]. 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]. They hypertrophy upon activation and upregulate glial fibrillary acidic protein (GFAP) expression [153,154]. Reactive astrocytes are a distinct trait of AD patient brains [155] and are also a feature of AD mouse model brains [156,157,158]. Intralaminar astrocytes are atrophied and severely disrupted in post-mortem AD brains [159]. In the 3xTg, which contain three mutations associated with a familial AD (APP Swedish, MAPT P301L, and PSEN1 M146V) mouse model, atrophic astrocytes appear in the entorhinal cortex (EC) as early as 30 days and are present until Aβ plaques begin to emerge at 12 months of age [160]. This phenomenon also occurs in other AD mouse models including the 5xTG-AD, PDAPP-J20, and Swiss 3 mice [161,162,163,164]. When astrocytes are created from familial and sporadic AD-induced pluripotent stem cells (iPSC), they have an atrophic phenotype in vitro [165]. Inhibiting astrogliosis in AD mouse brains results in Aβ accumulation with increased histopathology [166] and they are associated with cognition [167]. This may result in a breach of the blood brain barrier (BBB), leading to an infiltration of peripheral immune cells, aggravating neuroinflammation and inducing neurotoxicity by impairing glutamate homeostasis [168,169], and generating altered Ca²⁺ signaling [170].

2.3. Oligodendrocytes

The main function of oligodendrocytes is to provide support and insulation to the axons by forming myelin sheaths around nerve fibers. Their involvement in AD is not fully understood, although emerging evidence implicates their potential role in pathogenesis and progression of AD [171]. Tsai et al. recently reported that oligodendrocytes are severely impaired in AD [172] and, indeed, there is focal loss of oligodendrocytes and a reduction in myelin proteins near Aβ plaques [173,174,175]. Aβ not only impairs the survival and maturation of oligodendrocyte progenitor cells (OPCs), but also hampers the formation of the myelin sheath [176]. Neuroinflammation and oxidative stress may also contribute to oligodendrocyte dysfunction and death [175].

2.4. Myeloid Cells Other Than Microglia

The other monocytic cells found in the CNS include perivascular macrophages that line blood vessels of the brain, macrophages within the choroid plexus, and meningeal macrophages in the leptomeninges [177]. Dendritic cells, monocytes, and granulocytes are found in the meninges and are recruited to the brain during or after an insult or other pathology [178,179]. The CNS-resident macrophages express scavenger receptors (SR) and TLRs that facilitate phagocytosis and degradation of Aβ [180,181]. In SR knock out mouse models of AD, Aβ accumulates in the parenchyma and the animals have cognitive deficits [124,182]. In the CD11c-DNR mouse model of AD, which expresses a dominant-negative form of the TGF-β receptor under the control of the CD11c promoter, the brain levels of Aβ are reduced by up to 90%, the Aβ plaques and cerebral vasculature are surrounded by macrophages [183], and the behavior of the animals is significantly improved [183]. The migration of peripheral monocytes is dependent on C-C chemokine receptor type 2 (CCR2) [184]. Blocking transforming growth factor (TGF)-β signaling increases peripheral myeloid cell infiltration into the CNS and significantly reduces Aβ burden [183]. It is still not exactly clear how myeloid infiltration into the brain contributes to damage or clearance of pathological proteins.