Synergistic effects of an innovative combination therapy on treating Alzheimer's disease involving modulation of gut dysbiosis

Abstract

Background Chronic neuro‐inflammation leading to excessive neuronal damages predates the presence of clinical manifestations of Alzheimer’s disease (AD) by many years. Due to the complex pathogenesis of AD, a multi‐target regimen using a combination therapy is proposed to be essential to the effectiveness of AD therapy. Method An innovative combination therapy using a newly developed multi‐functional Aβ antibody (NP106) and a novel curcumin derivative (TML‐6) was applied to treat APP/PS1 mice. To investigate whether synergistic effects of combination therapy on reducing AD‐like pathology in APP/PS1 mice alter fecal microbiome, high‐throughput 16S rRNA sequencing was performed. Result Here, we demonstrate that monotherapy with either weekly intraperitoneal injection of low‐dose NP106 or TML‐6‐supplemented diet for four months showed beneficial effects on counteracting AD‐like pathology in APP/PS1 mice, while combination therapy using these two drugs outperformed monotherapy and exerted synergistic effects on improving behavioral abnormality and reducing cerebral Aβ accumulation. Data from microbiome indicate that the gut bacterial community structure of APP/PS1 mice was different from those of wt littermates. Intriguingly, relative abundant genera of APP/PS1 mice can be restored by either monotherapy or combination therapy to levels similar to wt littermates, indicating that these treatments possessed prebiotic effects against gut dysbiosis. Importantly, analyses of samples diversity further reveal that combination therapy might lead to better normalization of microbiota. Conclusion Combination therapy exerted synergistic effects on attenuating AD‐like pathological features and behavioral deficits in APP/PS1 mice. Furthermore, the synergistic effects of combination therapy were concurrent with the normalization of gut microbiota.