**6. The prospect of treatment of AD**

For a long time, it is considered that Aβ accumulation is the central and initial event in the pathological process of AD. The famous amyloid cascade hypothesis thinks that the increase of Aβ levels leads to the pathological events of AD [124, 125]. Extensive clinical medicine trials of Aβ finally come to an end, and results showed that reduced Aβ load does not affect the cognitive ability of patients with AD [126, 127]. So, finding a new target rather than Aβ may be our priority. Microglia play pivotal roles in the pathological process, and interfering with their detrimental process in AD can become our next focus.

Microglia are shown to maintain the function of neurons by clearing toxic damage in the early stage of AD [128]. Consequently, interfering with the activation of microglia to lengthen the period of anti-inflammatory seems to be a therapy for AD [129]. Other anti-inflammatory cytokines such as IL-2, IL-4, and IL-33 have

### *Microglia, TREM2, and Therapeutic Methods of Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.100203*

the potential to ameliorate AD pathology by regulating microglial activation [128], despite its results are not decisive [130].

Moreover, TREM2 is shown to be a positive target for treating AD. Recently, AL002c, an anti-human TREM2 agonistic monoclonal antibody (mAb), gives a positive outcome in 5xFAD mice expressing both the R47H variant and the common variant (CV). Prolonged administration of AL002c ameliorates filamentous plaques, causes neurodystrophy, and regulates microglial inflammation. AL002 is a derivative product of AL002c, which is modified for clinical use. AL002 is proven safe and well-tolerated in a first-in-human phase I clinical trial [131]. Overexpression of TREM2 can attenuate the pro-inflammatory effect caused by LPS, which can contribute to the increase of NO, LDH, TNF-α, IL-1b, and the activation of AKT [132]. Thus, relative experiments can be conducted in CNS.

Another way to increase TREM2 expression in microglia is by preventing ADAM10/17 family proteases from shedding extracellular domain [133, 134]. To stabilize TREM2 on the cell surface and enhance its activity, a specific mAb against TREM2 called 4D9 was screened to selectively compete for α-secretase-mediated shedding [133]. Shedding is considered to end cell-autonomous TREM2 signaling, and data show an increased phagocytic capacity of cells that express TREM2 by inhibiting ADAM proteases [135]. Combined with another research, Aβ clearance is TREM2-dependant [136], and future treatments can combine anti-Aβ antibodies with microglia-stimulating antibodies (4D9). This view opens a new door to the treatment of AD. Another study evaluated aducanumab as another antibody that may treat AD, but clinical trial results are still unsatisfactory [137]. In addition to cross-linking and activating the TREM2-DAP12 signal, 4D9 also inhibits the shedding of TREM2, resulting in the decrease of soluble TREM2 *in vitro* and the increase of total TREM2 in the brain [133]. This research may consider the role of sTREM2 in AD [91]. Since TREM2 is expressed in peripheral myeloid cells, any effects of treatment for TREM2 should be evaluated for peripheral adipose tissue in liver, lung, bone, and spleen. However, this has not been thoroughly investigated [91].

A novel property, cyclocreatine, the creatine analog, which can generate a supply chain for ATP demand regardless of the TREM2-mTOR pathway [138], is found to ameliorate autophagy, induce microglia around Aβ, and decrease neuronal dystrophy during dietary administration in 5xFAD mice [63]. Based on metabolism, this is a new era for treating AD.

Another research provides a creative angle in treating AD. It is known that meningeal lymphatic vessels drain macromolecular substances from the brain into the deep cervical lymph nodes [139], in which meningeal lymphatic serves as a channel to transport substances such as an antibody. But ablation of meningeal lymphatic vessels in 5xFAD mice can lead to a switch of microglia from homeostasis to DAM [140] and inhibit the transportation of antibodies to specific locations, thus exacerbating the cognitive ability of AD patients. It may bring unexpected clinical effects to patients with AD, if the treatment is placed in the early stage, thus enhancing the meningeal lymphatic function and combined with immunotherapy, to better play the role of meningeal lymphatic vessels.

Recently, tau pathology is the study focus. Tau hyperphosphorylation causes abnormal aggregation and neurodegeneration in AD brains [141], and protein phosphatase 2A (PP2A) has the most robust dephosphorylation activity to tau protein *in vitro* and *in vivo* [142]. A novel DEPho-sphorylation Targeting Chimaera (DEPTAC) was designed to enhance the combination of tau and PP2A-Bα, which shows high efficiency in preventing tau accumulation *in vitro* and *in vivo* [143]. Further studies showed that DEPAC significantly improved the microtubule assembly, neurite plasticity, and hippocampus-dependent learning and memory in transgenic mice [143].
