Neuroprotective effect of novel Rho kinase inhibitor FSD-C10 on a mouse model of Alzheimer disease

AIM: To explore the neuroprotective effect of novel Rho kinase inhibitor FSD-C10 on Alzheimer disease (AD) model of APP/PS1 double transgenic (Tg) mice. METHODS: Male APP/PS1 Tg mice (n=20) at 8 months of age were randomly divided into 2 groups:model group and FSD-C10 treatment group. The mice were treated with normal saline or FSD-C10 (25 mg·kg^-1·d^-1) by intraperitoneal injection, once daily for 2 months. Age-and sex-matched wild-type (WT) mice without treatment were used as the control. The Morris water maze (MWM) test and SMART 3.0 behavioral record system were applied to examine and analyze the spatial cognitive function of the mice. The protein levels and distribution of Aβ, p-tau and synapse-associated proteins such as synaptophysin, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and postsynaptic density protein 95 (PSD-95) were determined by immunofluorescence staining. The protein levels of phosphorylated amyloid precursor protein at Thr668[p-APP(Thr668)], beta-site APP-cleaving enzyme 1 (BACE1) and synapse-associated proteins in the brain were analyzed by Western blot. RESULTS: Compared with model group, FSD-C10 treatment significantly improved the cognitive function of the APP/PS1 Tg mice, accompanied by reduced Aβ deposition and p-tau level, increased protein level of p-APP (Thr668) in the central nervous system, decreased expression of BACE1, and increased expression of synapse-associated proteins in the brain of the mice (P<0.05). CONCLUSION: FSD-C10 has neuroprotective potential in the APP/PS1 Tg mice. The mechanism may be related to enhancing the non-amyloidogenic APP cleavage pathway, reducing the production of Aβ oligomers, the deposition of senile plaques and the amount of tau protein, up-regulating synapse-associated proteins, and increasing synaptic plasticity.