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

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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-beta (A beta) 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-kappa B pathway. Overall, our in vitro and in vivo investigations on efficacies andmolecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral A beta 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.
Publisher
NATL ACAD SCIENCES
Issue Date
2019-11
Language
English
Article Type
Article
Citation

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.116, no.47, pp.23426 - 23436

ISSN
0027-8424
DOI
10.1073/pnas.1916318116
URI
http://hdl.handle.net/10203/268885
Appears in Collection
CH-Journal Papers(저널논문)
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