The first GSM was identified

The first GSM was identified from the discovery of non-steroidal anti-inflammatory drugs (NSAIDs). An amyloid reducing GSM that also suppresses inflammation is desirable. Inflammatory response is an invariable characteristic of AD pathogenesis, in part triggered by Aβ. During AD onset and progression, microglial cells and astrocytes are activated, and cytokines like TNFα are secreted by microglia [84]. In 3X Tg AD model, TNFα is upregulated as Aβ pathology appears, at about 3 months of age [85]. Most cytokines are expressed at very low levels in the healthy brain, and neuroinflammation can be detected years before neurons die. Previous studies have shown that Aβ can bind to scavenger receptors expressed on microglia like CD36 [86] and Scara1 [6], which enter microglia and activate inflammation. When microglia cells engulf extracellular gtpase inhibitor like Aβ, they trigger inflammasomes (such as NOD-like receptor family pyrin domain-containing 3 (NLRP3)) and activate caspases, and promote IL-1β release [87]. This pathway was validated in AD transgenic mice where NLRP3 was shown to contribute to AD like pathology in mouse brains [88]. Aβ generation and inflammatory response are thus concurrent events associated with Aβ clearance. Accordingly, genetic mutations found in the microglial receptor TREM2 (triggering receptor expressed on myeloid cells 2) triple a person’s risk for AD [89,90] and increased expression of CD33, which functions to suppress Aβ uptake and clearance, modifies AD risk [91,92]. Systems analysis of hundreds AD brain reveals changes in network related to immunologic molecules and microglial cells, including microglial protein TYROBP that binds TREM2 and may regulate CD33 [93]. Several classes of GSMs have been developed [94,95]. As discussed above, one class of GSMs includes a subset of NSAID-like carboxylic acids that specifically block cleavage of the γ-secretase substrates in the middle of their TM domains without affecting generation of the ICD of several type I transmembrane proteins, including APP, ErbB-4, and Notch [96]. These GSMs inhibit Aβ42 production with a concurrent increase of Aβ38 and no effect on Aβ40 production or Notch processing. Dosing cultured cells and transgenic mice revealed that NSAIDs directly modulate the γ-secretase complex [78,[97], [98], [99], [100], [101]], independent of their inhibitory effects on cyclooxygenase (COX) and Rho activity in the Rho-Rock pathway [102]. Another GSM that suppress neuroinflammation is CHF5074. In cultured cells, CHF5074 exhibits IC50s of 18.4 and 3.6 μM for Aβ40 and Aβ42, respectively (6-fold selectivity for Aβ42). In HEK293 cells expressing Notch substrate, Notch cleavage by γ-secretase was not inhibited by CHF5074 at 5 μM [103,104]. In 10-month old Tg2576 mice (expressing the Swedish mutant of APP), steady state brain and plasma concentrations of CHF5074 reached 6.4 μM and 228 μM, respectively, with a ∼50% reduction in both the number of plaques and the area occupied by plaques in brain was observed. This corresponded to a ∼50% reduction of total brain Aβ and Aβ42 (49% and 42%, respectively). A third reduction of Aβ was found in a second transgenic mouse line expressing both Swedish and London mutant APP after chronic exposure with CHF5074, with brain and plasma drug exposure at 3 and 281 μM respectively [104]. CHF5074 showed reversal of contextual memory deficit and restoration of hippocampal neurogenesis potential [105]. CHF5074 is not only a GSM but also a neuroinflammation modulator [106,107]. Ross et al. reported that subjects on CHF5074 showed linear decreases in levels of inflammatory marker TNFα and soluble CD40 ligand in CSF [106]. Apparently, CHF5074 is the first GSM that shows positive cognitive outcomes in humans with clear decrease in CSF TNFα. TNFα is a major marker of neuroinflammation in AD. It is produced in glial cells and neurons during normal aging and in patients suffering brain trauma, neurodegenerative disorder or excitotoxic insults, and TNFα has detrimental effects on synaptic transmission and plasticity [108]. It is not specific for AD, as most neurodegenerative diseases are accompanied by a cytokine-mediated inflammatory response. Binding of TNFα to Tumor necrosis factor receptor 1 (TNFR1) leads to activation of NFƙB and MAPK pathways, and induction of death signaling [109]. CHF5074 is devoid of anticyclooxygenase (COX) and Notch-interfering activities in vitro [110]. It is likely that CHF5074 has a direct anti-inflammatory effect that is mediated by its interaction with the γ-secretase complex.