ABSTRACT

Gut microbiota is closely involved with the pathogenesis of Alzheimer’s disease (AD). Oral administration of NK4146, a live biotherapeutic composed of Limosilactobacillus mucosae NK41 and Bifidobacterium longum NK46, alleviated cognitive impairment-like behaviors in 5xFAD-transgenic mice, accompanied by reduction in Aβ accumulation, amyloid precursor protein, β-secretase, γ-secretase, caspase-3, and TNF-α expression in both the brain and intestine and . NK4146 treatment also significantly improved gut dysbiosis. Notably, fecal microbiota transplantation (FMT) from NK4146-treated 5xFAD-transgenic mice to antibiotics-treated mice did not induce cognitive impairment-related symptoms, while FMT from saline-treated 5xFAD-transgenic mice caused cognitive impairment.

Lecanemab treatment alone alleviated cognitive impairment-like behaviors and reduced Aβ accumulation, but not Aβ-biosynthesizing enzymes, in 5xFAD-transgenic mice. Treatment with Donepezil alone alleviated cognitive impairment-like behaviors in 5xFAD-transgenic mice, while the Aβ accumulation was not reduced. Combined treatment of NK4146 and Lecanemab (NL) synergistically reduced cognitive impairment-related behaviors, Aβ accumulation, and the expression of amyloid precursor protein (APP), Aβ-biosynthesizing enzymes, and proinflammatory cytokines in 5xFAD-transgenic mice. Orally administered NK4146 or NL reduced the total abundance of gram-negative Verrucomicrobiota, Cyanobacteria, and Pseudomonadota populations in 5xFAD-transgenic mice.

Combined treatment of NK4146 and donepezil additively reduced cognitive impairment-related behaviors, donepezil did not increase NK4146-dependent suppression of Aβ accumulation and Aβ-biosynthesizing enzyme expression.

CONCLUSION