Anti-Inflammatory Action of Donepezil Ameliorates Tau Pathology, Synaptic Loss, and Neurodegeneration in a Tauopathy Mouse Model

Abstract

Acetylcholinesterase inhibitors (AChEIs) are widely used to compensate for acetylcholine (ACh) depletion in the Alzheimer's disease (AD) brain. Some clinical and experimental studies, however, have suggested that AChEIs also provide neuroprotection. To assess the effect of AChEIs on neurodegeneration, donepezil (DZ), an AChEI, was administered to FTDP-17 model mice with a P301S tau mutation (line PS19). Eight months of DZ treatment resulted in amelioration of neuroinflammation, tau pathology, synaptic loss, and neuronal loss, as well as decreased tau insolubility and phosphorylation. Tau kinase activity analysis demonstrated significantly suppressed c-Jun N-terminal kinase (JNK) in the brains of DZ-treated PS19 mice. Recently, ACh has been shown to suppress inflammation, which plays a role in neurodegeneration. To confirm the anti-inflammatory effect of DZ, PS19 mice were injected with lipopolysaccharide, in combination with or without DZ, for one month. Results demonstrated that DZ suppressed IL-1β and COX-2 expression in the brain, as well as the spleen, suggesting that DZ directly prevents systemic inflammation. These data indicated that ACh did not act just as a cognition-linking neurotransmitter, but might suppress pathological mechanisms of neurodegeneration via anti-inflammatory action.

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“…Over the years, many different ChE inhibitors (ChEIs) have been developed to boost the central cholinergic transmission, but approved ChEIbased treatments have proven to provide only transitory and modest recovery in cognitive impairment without affecting the natural progres sion or the ultimate outcome of the disease. 12 Multitarget diseasemodifying drugs, in which a single molecule is directed to bind multiple sites, have been de signed as drug candidates with potential to halt the progres sion of the disease. 13 The pivotal role of Aβ in the pathogen esis of Alzheimer disease and the proven cognitive benefit of cholinergic system augmentation support the development of multitarget molecules targeting both the cholinergic sys tem and Aβ deposits.…”

Does Anticholinergic Activity Affect Neuropathology Implication of Neuroinflammation in Alzheimer's Disease

“…However, a few studies have analyzed the effects of cholinergic agents on neuropathological changes using laboratory animals. Here, we re-analyzed the joint data from 2 studies from our group using a tauopathy mouse model (PS19), one administering 2 anticholinergic drugs [16] and the other administering a cholinergic drug [17]. These 2 studies were performed at the same time, but we previously analyzed these data separately.…”

“…The cholinergic agent used was donepezil (Arisept™, DZ). All drugs were administered to mice from the age of 2 to 10 months, namely before development of synaptic loss and microglial activation are thought to occur in the brain (see details of samples and methods [16,17]).…”

“…However, Western blot analysis of tau kinases demonstrated that DZ strongly suppressed JNK activity, but TP and PP did not enhance it [16,17]. An experiment using cell culture and adenoviral infection of tau demonstrated that tau overexpression in COS-7 cells induced JNK activation followed by excessive phosphorylation of tau, although JNK activation alone was insufficient to induce insoluble tau aggregation [26].…”

“…Thus, suppression of JNK activity by DZ might relate not only to suppression of tau phosphorylation and aggregation, but also to neuronal survival. Additionally, glycogen synthase kinase 3β and cyclin-dependent kinase 5, major tau kinases, were activated with TP and PP, but were unchanged with DZ [16,17]. Thus, we cannot simply conclude that the effects of anticholinergic activity act directly opposite to the effects induced by cholinergic activity.…”