N , N ′-Diacetyl- p -phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer’s disease transgenic mice

Abstract

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N′-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-β (Aβ) species and significantly improving cognitive function in the brains of 2 types of Alzheimer’s disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aβ clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

Dexmedetomidine Ameliorates Hippocampus Injury and Cognitive Dysfunction Induced by Hepatic Ischemia/Reperfusion by Activating SIRT3-Mediated Mitophagy and Inhibiting Activation of the NLRP3 Inflammasome in Young Rats

“…The process is a proinflammatory form of programmed cell death termed as pyroptosis [85][86][87]. Accumulating evidence suggests that the NLRP3 inflammasome plays an important role in inflammation in the central nervous system [88,89] and cognitive deficits [90]. Moreover, a previous study demonstrated that the NLRP3 inflammasome could be regulated by ROS and mitophagy in the reverse direction [13].…”

Epoxy fatty acid dysregulation and neuroinflammation in Alzheimer’s disease is resolved by a soluble epoxide hydrolase inhibitor

“…The availability of the Ephx2 conditional allele(38) allows deciphering the cell-type specific effect and central-peripheral interactions. Additionally, the NLRP3 inflammasome activation has been implicated in producing harmful chronic inflammatory reactions and impairing microglial Aβ clearance and cognitive function in AD(8,44,45). Indeed, we found that Nlrp3 and Casp1 were both upregulated in Tg mice and downregulated by TPPU treatment.…”

TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions

“…These findings and new insights lead to the interesting proposal of the feedback hypothesis instead of the prevailing amyloid cascade hypothesis of AD. There is increasing evidence to suggest that breaking such positive feedback loops is a promising approach to intervene in the pathogenesis and progression of AD [ 212 ]. Currently, there are no effective treatments, or a substantial unmet clinical need, for many debilitating diseases or conditions of which the TRPM2 channel plays an important part in the pathogenesis and progression.…”