Microglia mediate NVU dysfunction via BBB dysfunction
The influence of microglia on the BBB is largely dependent on the activation phenotypes of microglia. Aβ-activated M1 microglia have increased secretion of inflammatory factors and chemokines, including tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-12 (IL-12), CCL-2, CXCL-10, reactive oxygen species (ROS) and nitric oxide (NO), which exacerbate damage to the BBB [19-22]. In contrast, M2 microglia are characterized by alternative activation and acquired inactivation and play an important role in the protection and repair of the BBB by suppressing neuroinflammation in the CNS [20].
Microglia affect tight junctions (TJs) and adhesion junctions (AJs) between BMECs to modulate the permeability of the BBB. Under physiological conditions or in the early stage of AD, resting microglia maintain the integrity of the BBB. These cells improve the expression of TJ proteins such as zonula occludens 1 (ZO-1) and occludin on BMECs in vitro [21]. Moreover, microglia in a resting state directly provide the essential proteins for TJs, such as claudin-5, to protect the integrity of the BBB [23].
However, microglia destroy the BBB in the late stage of AD, which may be a therapeutic target for AD. First, proinflammatory factors derived from M1 microglia, including IL-1β, TNF-α and CCL2, affect BMECs and directly destroy the BBB in AD. Aβ-activated microglia secrete IL-1β by upregulating the expression of P2X7 receptor (P2X7R) [18]. IL-1β increases the expression of IL-6, interleukin-8 (IL-8) and TNF-α and decreases the expression of ZO-1, enhancing BBB paracellular permeability. A study also showed that IL-1β upregulated the expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) to increase the transmigration of peripheral white blood cells (WBCs) into the CNS [24]. Aβ-activated M1 microglia release NO and TNF-α via the poly (ADP-ribose) polymerase-1 (PARP-1) pathway to downregulate the expression of TJ proteins, including ZO-1 and occludin, increasing BBB paracellular permeability in vitro [21]. CCL2 decreases AJs and increases platelet endothelial cell adhesion molecule-1 (PECAM-1) on BMECs by inducing the phosphorylation and transference of β-Catenin from AJs to PECAM-1, which may contribute to BBB dysfunction and increase WBC recruitment [25]. Aβ-activated M1 microglia also release matrix metalloproteinases-9 (MMP-9) and ROS to damage BMECs and TJs [26]. Second, Aβ-activated microglia activate astrocytes by releasing inflammatory factors, further contributing to the indirect destruction of the BBB [27-29]. Third, Aβ-activated microglia secrete proinflammatory factors to induce pericyte loss [21, 30-32], potentially leading to BBB destruction [33-35]. Overall, M1 microglia can destroy TJs and AJs between BMECs by mediating neuroinflammation, astrocyte dysfunction and pericyte loss, leading to BBB and NVU dysfunction (Fig. 1).
Increased infiltration of peripheral WBCs in the CNS exacerbates neuroinflammation and BBB dysfunction. Aβ-activated microglia and cerebral macrophages secrete chemokines and cytokines to induce peripheral monocytes to accumulate in the CNS and transform into resident macrophages to exacerbate BBB and NVU dysfunction [36]. Microglial inflammatory factors mediate peripheral WBC migration in complex ways. Proinflammatory factors (IL-1β, TNF-α, IL-6 and IL-12) and chemokines (monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), macrophage inflammatory protein-1β (MIP-1β) and IL-8 secreted by Aβ-activated M1 microglia increase the permeability of the BBB and the infiltration of monocytes into the CNS in vitro [36]. Specifically, IL-1β induceds the migration of peripheral WBCs and exacerbated the destruction of the BBB by increasing the release of proinflammatory factors, including CCL2, CCL20 and CXCL2 [37]. Then, CCL2 was shown to cooperate with monocytes and lymphocytes to reduce the expression of TJs [38] and induce the disruption of AJs, destroying the integrity of the BBB. Increased PECAM-1 was also shown to recruit peripheral WBCs [25]. Finally, microglia-derived TNF-α plays an important role in peripheral WBC migration. Aβ-activated microglia secrete TNF-α, which is essential for CXCR2-dependent transmigration of T cells across the BBB [39]. These cells induce T cells and monocytes to transmigrate into the CNS by upregulating the expression of major histocompatibility complex (MHC-1) and vascular cell adhesion molecule-1 (VCAM-1) on BMECs [40, 41] (Fig. 1).
Microglia mediate NVU dysfunction via neurovascular uncoupling
Neurovascular uncoupling is one of the most important reasons for CBF reductions in AD [42, 43]. Reduced CBF is a sign of the early stage of AD, which leads to neuronal death and neurodegeneration through metabolic dysfunction in neurons and glial cells. Microglia-mediated neuroinflammation has been observed in the early stages of AD [44, 45], and studies have shown a close correlation between microglia and neurovascular uncoupling in AD. Multiple lines of evidence have shown that microglia modulate neurovascular coupling via the P2Y12 receptor (P2Y12R) under physiological conditions. The expression of P2Y12R on microglia is significantly decreased in AD, impairing cellular communication and the response of cerebral vessels to neuronal activity [16, 46].
Damage to neuronal mitochondria has been proven to contribute to metabolic dysfunction in neurons and neurovascular uncoupling [47]. In fact, gp91phox, a catalytic subunit of NADPH oxidase (NOX), is significantly upregulated in microglia and neurons in mild cognitive impairment (MCI) patients [48]. A study showed that ROS derived from NOX containing gp91phox were essential for Aβ-induced neurovascular uncoupling [49]. Therefore, the interaction between microglia and neurons plays a crucial role in neurovascular uncoupling in AD. It was reported that Aβ-activated microglia upregulated the expression of P2X7R to promote the release of IL-1β and the activation of NOX in an AD mouse model [18]. Increases in H2O2, NO and proinflammatory factors led to structural and functional damage to neuronal mitochondria, contributing to increased ROS. TNF-α induced neuronal mitochondrial dysfunction via neuron-derived EVs, leading to increased oxygen consumption and gradual ROS release from neurons [50]. As a result, increased ROS activate NOD-like receptor protein 3 (NLRP3) inflammasomes to exacerbate oxidative stress, neuroinflammation, insulin resistance and metabolic abnormalities [42, 47], leading to neurovascular uncoupling in AD.
Recent studies have shown that the primary mechanism of neurovascular uncoupling in AD is cerebrovascular component dysfunction [51]. First, activated microglia promote VSMC and pericyte dysfunction, leading to neurovascular uncoupling. On the one hand, microglia can directly mediate pericyte degeneration. Activated microglia can secrete proinflammatory factors to induce pericyte loss [21, 30-32]. LPS-activated microglia directly increased the release of ROS from pericytes by secreting TNF-α and IL-1β, leading to death in rat retinal microglia and pericytes [52]. Then, pericyte degeneration reduces the capillary response to neuronal activity, resulting in neurovascular uncoupling [53]. We think a similar mechanism by which activated microglia induce pericyte loss leading to neurovascular uncoupling is present in AD. On the other hand, activated microglia indirectly induce cerebral vessels to contract by exacerbating Aβ accumulation. Aβ-activated microglia upregulate cyclooxygenase 2 (COX-2) to increase the expression of IL-1β. Then, IL-1β upregulates β-site APP-cleaving enzyme (BACE-1) in neuron-like cells (SH-SY5Y cells) to exacerbate Aβ accumulation [54]. Increased Aβ deposition mediates the hypercontractive phenotype of VSMCs in small arteries in the CNS and decreases CBF via high levels of serum response factor (SRF)/myocardin (MYOCD) [55, 56]. In human and mouse models of AD, Aβ also induced pericytes around brain capillaries to contract through NADPH-oxidase-4 (NOX4)-derived ROS [57]. However, some researchers believe that VSMCs can directly contract cerebral vessels, while pericytes cannot. In contrast, pericytes influence CBF only by indirectly regulating cellular interactions [58]. Finally, the end-feet of astrocytes on cerebral vessels are very important for communication between blood vessels and neurons. The expression of aquaporin-4 (AQP-4) in astrocytic end-feet on the vessels is significantly reduced in AD and is accompanied by a prominent increase in microglial activation and proliferation [59]. Excessive activated microglia may be involved in astrocyte-mediated neurovascular uncoupling, but the exact mechanism is still unknown. Overall, microglia can mediate neurovascular uncoupling in AD by downregulating the expression of P2Y12R, increasing ROS and proinflammatory factors to induce neuronal mitochondrial dysfunction, exacerbating Aβ accumulation to attenuate the response of cerebral vessels to neuronal activity and inducing dysfunction of pericytes and astrocytes (Fig. 2).
Microglia mediate NVU dysfunction through dysfunction of the cellular components of the NVU
The NVU is a structural and functional complex [4]. Dysfunction of the cellular components of the NVU has been observed in AD, including changes in the distribution of capillaries, pericyte diminishment, astrocyte activation and proliferation, and the relocation of microphages [60]. Furthermore, studies indicates these changes may be mediated by microglia and potentially lead to NVU dysfunction in AD.
Microglia mediate NVU dysfunction via astrocyte dysfunction
As an important constituent of the NVU, astrocytes are reactive cells in the CNS that can rapidly and simultaneously exchange information with several synapses. Astrocytes maintain the integrity of the BBB and regulate CBF with BMECs, pericytes and VSMCs [61]. Additionally, reactive astrocytes accelerate AD progression by significantly affecting Aβ and tau pathology via the β-site APP-cleaving enzyme (BACE-1) and IL-3 pathways [62, 63].
Microglia induce excitotoxicity in astrocytes and disturb the communication among astrocytes and surrounding cells to mediate astrocyte dysfunction, ultimately leading to NVU dysfunction in AD [64]. First, microglia play an important role in severe neuronal excitotoxicity induced by the release of calcium ion-dependent gliotransmitters such as glutamate from astrocytes [65]. TNF-α, which is mainly secreted by microglia, was shown to be essential for calcium-dependent release of glutamate by astrocytes [66, 67]. TNF-α mediates calcium ion-dependent glutamate release by activating prostaglandin E2 (PGE2) in astrocytes, which leads to neuronal apoptosis in an AD mouse model [68]. The expression of intermediate conductance calcium-activated potassium channels (KCa3.1 channels) on reactive astrocytes and activated microglia was enhanced in AD patients and SAMP8 mice [69, 70]. Some researchers found that microglia-derived TGF-β upregulated astrocyte KCa3.1 channels to induce astrogliosis and increased the level of calcium ions to mediate the release of glutamate during AD [65, 69, 71]. Second, a high number of gap junctions is important for intercellular communication among astrocytes. In particular, Aβ-activated microglia suppress the expression of astrocyte gap junctions by secreting TNF-α and IL-1β, contributing to astrogliosis [72]. Third, activated microglia are involved in the regulation of astrocyte complement-dependent intercellular communication leading to NVU dysfunction. Specifically, activated microglia release C1q to activate the nuclear factor-kappa B (NF-κB) pathway in astrocytes, which release C3 [27, 73]. C3 has been reported to compromise neuronal synapses and cognitive function by acting on neuronal C3R and destroying the BBB by acting on BMECs [29, 74]. Finally, C3 attenuated microglial phagocytosis of Aβ [75].
Aβ-activated microglia induce NVU dysfunction by mediating astrocyte activation and neuroinflammation. Microglia are more sensitive to pathological changes than astrocytes [20], and the activation of astrocytes is highly dependent on microglia [76]. This finding indicates the initial role of microglia and the amplified role of astrocytes in neuroinflammation [77, 78]. In addition, microglia can mediate the phenotypic conversion of astrocytes. Similar to microglia, there are A1 and A2 astrocytes in AD. Aβ-activated M1 microglia secrete IL-1β, TNF-α, C1q and NO to induce A1 astrocytes [22, 27]. A1 astrocytes have increased release of proinflammatory factors, chemokines and complement to amplify neuroinflammation, leading to BBB destruction and neuronal injury [27-29, 79]. Moreover, IL-1β indirectly enhances the permeability of the BBB in vitro by suppressing the expression of sonic hedgehog (SHH) in astrocytes, which was neuroprotective [37]. IL-1β also mediates the destruction of the BBB by increasing the expression of proinflammatory chemokines and vascular endothelial growth factors (VEGFs) in astrocytes [37, 79]. Moreover, it was reported that chronic neuroinflammation induced degeneration and death in astrocytes [80]. However, as M1 microglia are converted to M2 microglia, they secrete IL-10 to induce the activation of A2 astrocytes, which increases the expression of anti-inflammatory factors [20, 81] (Fig. 3).
Microglia mediate NVU dysfunction via pericyte dysfunction
Brain pericytes, which are important cellular components of cerebral capillaries, have features similar to those of VSMCs and form the BBB with BMECs, astrocytic end-feet and the basement membrane [82]. The coverage ratio of pericytes was proven to be associated with the permeability of the BBB [33]. Evidence has demonstrated that microglia and neuroinflammation can mediate pericyte dysfunction and loss in various ways, leading to NVU dysfunction in AD. First, Aβ-activated microglia induce BBB destruction via pericyte-derived MMP-9. Aβ-activated microglia secrete TNF-α in AD [21], and TNF-α promotes pericytes to release MMP-9, which leads to BBB breakdown by destroying TJs and extracellular matrix between BMECs and promoting the migration of pericytes surrounding vessels to other regions in the brain, leading to pericyte loss in vitro [30]. Second, microglial cytokines participate in pathways that lead to pericyte loss from cerebral vessels in AD. Pericyte loss contributes to neurovascular uncoupling and BBB dysfunction. It was reported that microglia presented Aβ to Th1 cells and promoted Th1 cells to secrete IFN-γ in vitro [31]. Then, IFN-γ promoted the phosphorylation, internalization and degradation of platelet-derived growth factor receptor-β (PDGFR-β) in pericytes to prevent PDGF-BB-associated proliferation and migration [32], leading to the loss of pericytes. Moreover, TGF-β, which is mainly derived from microglia, induced pericyte loss and NVU dysfunction [67]. [83]. TGF-β attenuated the phagocytic capacity of pericytes and increased the expression of classic proinflammatory factors, leading to pericyte loss [84]. The loss of pericytes reduced the cerebral capillary response to neuronal activity and increased basal blood flow rates in cerebral capillaries, providing less nutrients and oxygen for neurons [53, 85] and destroying the metabolic balance and neurovascular coupling in AD. Moreover, pericyte loss enhanced the permeability of the BBB in several ways. In PDGFR-β -/- mice, the loss of pericytes increased paracellular permeability and the migration of peripheral WBCs by downregulating TJs and upregulating leukocyte adhesion molecules (LAMs) [33]. Then, in PDGFR-β variant mice, the loss of pericyte increased BBB permeability by enhancing the phagocytosis of BMECs and dysfunction in astrocytic end-feet [34]. Moreover, in PDGFR-β ret/ret mice, pericyte loss mediated endothelial arteriovenous zonation, angiogenic quiescence and impaired functions of the BBB [86]. Third, it was reported that activated microglia exacerbated Aβ-induced abnormal pericyte contraction and neurovascular uncoupling in AD, which has been elucidated [54, 57, 87].
Overall, it has been proven that Aβ-activated microglia induce pericyte dysfunction and loss by releasing TNF-α, IFN-γ and TGF-β. Pericyte dysfunction and loss lead to BBB breakdown and neurovascular uncoupling in several ways. However, evidence is still needed to determine whether microglia directly mediate NVU dysfunction by regulating pericyte function in AD.
Microglia mediate NVU dysfunction via injury to neurons and interneurons
A decrease in neurons is one of the important factors in the progressively declining cognitive and memory function of AD patients, which is mediated by microglia through phagocytosis and the secretion of inflammatory factors, EVs and ROS. First, abnormal microglial phagocytosis induces neuronal damage in AD. It was reported that enhanced microglial phagocytosis damaged neuronal synapses in the early stage of AD in TREM2-variant mice, but phagocytosis was neuroprotective in the late stage of AD by engulfing Aβ [88]. Aβ-induced microglial phagocytosis of synapses was proven to be dependent on the complement pathway [73, 89]. M1 microglia secrete inflammatory factors and C1q to increase the release of C3 by A1 astrocytes, leading to the rapid death of neurons [27, 73]. Increased C3 enhances microglial phagocytosis of synapses by binding to C3R on microglia [89]. Second, microglia-mediated neuroinflammation and oxidative stress regulate neuronal function. Aβ-activated microglia have increased release of TNF-α, glutamate and ROS, leading to excessive neuronal activation and death [18, 90-92]. In addition, Aβ-activated microglia damage neurons via Toll-like receptor-2/3 (TLR-2/3) by releasing IL-6, TNF-α and ROS [93, 94]. Third, ATP-activated microglia produce EVs that convert aggregated Aβ to soluble Aβ, which is more neurotoxic [95]. Finally, activated microglia affect the function of interneurons and neural networks. In 5XFAD and 3x-TgAD mice, activated microglia were closely associated with damage to interneurons in AD [96]. In addition, damage to interneurons leads to dysfunction of neural networks and cognition by inducing imbalance between suppression and excitation in the CNS [97].
Microglia mediate NVU dysfunction via dysfunction of other cellular components in the NVU
First, microglia mediate dysfunction of BMECs and the BBB in AD by destroying TJs and AJs and increasing the entry of peripheral WBCs into the CNS. Second, microglia exacerbate Aβ accumulation [87] to affect the communication between BMECs and astrocytic end-feet [35], which contributes to neurovascular uncoupling in AD and alters calcium signalling in BMECs [98]. Third, microglia mediate the hypercontractive phenotype of VSMCs by exacerbating Aβ accumulation, leading to neurovascular uncoupling in AD. Finally, oligodendrocytes, which are the myelin-forming cells in the CNS, play a significant role in the conduction of action potentials and neuronal protection [99]. In 5XFAD mice, TREM2-variant microglia were associated with the phagocytosis of myelin and lipid metabolism in the CNS, and reactive oligodendrocytes were always accompanied by damage to axonal myelin and metabolic imbalance [100-102]. This finding indicates the potential correlation between microglia and oligodendrocytes in AD, although there is no direct evidence to support it.
Medications for restoring the function of microglia and the NVU in AD
Accompanied by studies about microglia-mediated NVU dysfunction in AD, many medications have been developed. These treatments restore microglial and NVU function to alleviate AD progression and improve cognitive function (Table 1).
First, inhibiting neuroinflammation is most likely helpful in improving BBB function to restore NVU function in AD. Annexin A1 (ANXA1) not only inhibits neuroinflammation by increasing IL-10 and decreasing TNF-α [103] but also alleviates Aβ-induced BBB breakdown by suppressing the RhoA-Rock pathway [104]. Second, multiple-target drugs, including dabigatran, L-norvaline and quercetin, regulate the function of several types of cells in the NVU to reduce BBB permeability in AD mouse models [105-107]. Third, a clinical trial demonstrated that resveratrol reduced the concentration of MMP-9 in CSF to preserve BBB integrity and improved the cognitive function of AD patients [108]. Finally, the mammalian/mechanistic target of rapamycin (mTOR) inhibitor rapamycin was proven to upregulate TJs and inhibit the activity of MMP-9 to maintain BBB integrity in an AD mouse model [109].
Medications have also been designed to restore neurovascular coupling and increase CBF in AD. First, NAD+ intermediates have been shown to restore NAD+ concentrations to alleviate ageing-associated neurovascular uncoupling. Nicotinamide mononucleotide (NMN) rescued cerebral vessel responses to neuronal activity and cognitive function in a mouse model of ageing by increasing endothelial NO-derived relaxation in cerebral microvessels and alleviating mitochondrial dysfunction [110]. NMN has also been reported to be beneficial for the cognitive function in AD mice by attenuating Aβ accumulation, synaptic loss and neuroinflammation [111]. Second, the PARP-1 inhibitor PJ-34 was shown to improve neurovascular coupling and cognitive function by regulating endothelial-mediated vasodilation in an ageing mouse model [112]. Third, twendee X has been proven to alleviate tau and α-synuclein pathology and neurovascular uncoupling in APP23+ CCH mice [113]. Furthermore, sildenafil increased CBF and improved NVU function in AD patients in clinical trials [114, 115].
Instead of restoring BBB function and neurovascular coupling alone, medications have also been designed to simultaneously regulate the function of multiple cells in the NVU to improve NVU function in AD. First, anserine can improve NVU function in AD. It was reported that anserine and carnosine improved brain perfusion and verbal episodic memory in elderly people [116, 117], although the effect of anserine on AD patients is still unclear. A recent study demonstrated the role of anserine in maintaining NVU integrity by suppressing astrocyte-mediated neuroinflammation and improving the coverage ratio of pericytes in a mouse model of AD [118]. Second, stains, including atorvastatin and pitavastatin, restored NVU function by inhibiting the activity of MMP-9 in neurons and attenuating astrogliosis, leading to improved behavioural memory and a reduction in senile plaques (SPs) in an AD mouse model [119]. Third, pinocembrin was reported to suppress neuroinflammation and protect the cholinergic system to restore the function of the NVU [120]. Fourth, adipoRon, an adiponectin receptor agonist, enhanced the effects of adiponectin, whose deficiency was proven to increase Aβ-induced microglial activation and neuroinflammation. AdipoRon treatment suppressed neuroinflammation, restored microglial phagocytosis of Aβ, rescued neuronal and synaptic function and improved spatial memory function in AD mice [121, 122]. Finally, rapamycin plays a crucial role in NVU protection. Rapamycin increases CBF, decreases BBB permeability and maintains neuronal function in vivo. Moreover, rapamycin alleviates Aβ pathology and normalizes glucose metabolism. Most importantly, rapamycin was demonstrated to improve the cognitive function of AD mice [109, 123, 124].
Due to the close correlation between microglia and astrocytes, many medications have been designed to regulate the function of microglia and astrocytes to improve NVU function and delay AD progression. First, suppressing the activation of microglia and astrocytes and neuroinflammation may be helpful in delaying AD progression. For example, methystictin activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway; Nrf2 is an anti-inflammatory transcription factor that significantly reduces microgliosis, astrogliosis, proinflammatory cytokines and oxidative stress in APP/PS1 mice [125]. Low molecular weight GILZ analogues (GAs), which are the peptide analogues of the p65 binding domain of glucocorticoid-induced leucine zipper (GILZ), suppress the NF-κB pathway. GA decreases Aβ accumulation, reduces activated microglia and astrocytes, and inhibits inflammatory cytokines and TLR expression in 5xFAD mice [126]. TPPU, a specific small-molecule soluble epoxide hydrolase (sEH) inhibitor, improves the concentration and anti-inflammatory activity of epoxy fatty acids (EpFAs). TPPU significantly reversed microglia and astrocyte activation and suppressed neuroinflammation in 5xFAD mice [127]. Second, pantethine not only suppressed glial neuroinflammation in mice but also suppressed the expression of complement genes and other inflammatory genes in astrocytes [128]. Third, boldine suppresses the activity of hemichannels between microglia and astrocytes without influencing the function of gap junctions to reduce calcium ion and ATP-induced glutamate release [129].
Medications regulate microglial function to treat AD in various ways. First, medications suppress microglia-associated inflammatory pathways and cytokines to prevent the progression of AD. For example, dapansutrile and edaravone suppress microglia-mediated neuroinflammation by inhibiting the NLRP3 inflammasome in AD [130, 131]. Artemether and tiliroside suppress microglia-mediated neuroinflammation in AD by activating the anti-inflammatory Nrf2 pathway [132, 133]. Second, some medications alleviated the accumulation of Aβ and apoptotic cells to maintain NVU homeostasis by enhancing microglial phagocytic capacity. For instance, K161 improves microglial phagocytosis of Aβ and apoptotic neurons by suppressing the Pan-SHIP1/2 pathway [134]. Magnolol improves microglial phagocytosis and the degradation of Aβ and suppresses microglia-mediated neuroinflammation [135]. TREM2 monoclonal antibodies improve cognitive function by promoting acute microglial activation and microglial phagocytosis of Aβ and suppressing chronic microglia-mediated inflammation [136]. Third, microglial phenotypic transformation from M1 to M2 is also important in AD. For example, DHCR24, TPP-MoS2QDs, naringenin, and Dendrimer-tesaglitazar were reported to induce M1 microglia to convert to M2 microglia to suppress neuroinflammation and improve microglial phagocytosis [137-140]. Eventually, there are many mutant genes in microglia in AD, and some have been proven to be associated with AD, including TREM2, CD33, PILRA, and CR [141]. Interestingly, the TREM2-activated antibody AL002c has been proven to be efficient and safe for delaying the AD in mouse models and phase 1 clinical trials [142]. The TREM2 monoclonal antibody promoted the acute activation of protective microglia and suppressed microglia-associated chronic neuroinflammation to attenuate AD pathology in vivo and in vitro [136].