Objective Cerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer’s disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive.
Design Using a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis.
Results Composition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid β plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice.
Conclusion These results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.
- Alzheimer’s disease
- gut microbiota
- fecal microbiota transfer
- hyperphosphorylated tau
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M-SK, YK and HC contributed equally.
Contributors IM-J, J-WB, M-SK, YK and HyC designed the study. M-SK, YK, HyC, DL, DKK, HJK, DW-H and J-YL performed the experiments. IM-J, J-WB, M-SK, YK and HyC analysed the data. WK, SP, HaC, EYC and DL carried out the FACS analysis. IM-J, J-WB, M-SK, YK and HyC wrote the manuscript. All authors reviewed and approved the manuscript.
Funding This work was supported by a grant from the Mid-Career Researcher Program (2016R1E1A1A02921587), SRC (NRF-2018R1A5A1025077) and the Collaborative Genome Program for Fostering New Post-Genome industry (2015M3C9A2054299) through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (MSIP) (to J-WB). It is also supported by grants from NRF (2018R1A2A1A19019062) and MRC (NRF-2018R1A5A2025964) (to IM-J) and NRF-2017R1A6A3A01004073 (to YK). The Basic Research Laboratory grant from NRF (2017R1A4A1015745) also supports this work (EYC and D-SL).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No data are available.
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