Folate and vitamin B-12 deficiencies additively impaire memory function and disturb the gut microbiota in amyloid-β infused rats

Folate and vitamin B12(V-B12) deficiencies are associated with metabolic diseases that may impair memory function. We hypothesized that folate and V-B12 may differently alter mild cognitive impairment, glucose metabolism, and inflammation by modulating the gut microbiome in rats with Alzheimer's disease (AD)-like dementia. The hypothesis was examined in hippocampal amyloid-beta infused rats, and its mechanism was explored. Rats that received an amyloid-beta(25-35) infusion into the CA1 region of the hippocampus were fed either control (2.5 mg folate plus 25 mu g V-B12/kg diet; AD-CON, n = 10), no folate(0 folate plus 25 mu g V-B12/kg diet; AD-FA, n = 10), no V-B12(2.5 mg folate plus 0 mu g V-B12/kg diet: AD-V-B12, n = 10), or no folate plus no V-B12(0 mg folate plus 0 mu g V-B12/kg diet: AD-FAB12, n = 10) in high-fat diets for 8 weeks. AD-FA and AD-VB12 exacerbated bone mineral loss in the lumbar spine and femur whereas AD-FA lowered lean body mass in the hip compared to AD-CON(P < 0.05). Only AD-FAB12 exacerbated memory impairment by 1.3 and 1.4 folds, respectively, as measured by passive avoidance and water maze tests, compared to AD-CON(P < 0.01). Hippocampal insulin signaling and neuroinflammation were attenuated in AD-CON compared to Non-AD-CON. AD-FAB12 impaired the signaling (pAkt -> pGSK-3(3) and serum TNE-alpha and IL-1 beta levels the most among all groups. AD-CON decreased glucose tolerance by increasing insulin resistance compared to Non-AD-CON. AD-VB12 and AD-FAB12 increased insulin resistance by 1.2 and 1.3 folds, respectively, compared to the AD-CON. AD-CON and Non-AD-CON had a separate communities of gut microbiota. The relative counts of Bacteroidia were lower and those of Clostridia were higher in AD-CON than Non-AD-CON. AD-FA, but not V-B12, separated the gut microbiome community compared to AD-CON and AD-VB12(P = 0.009). In conclusion, folate and B-12 deficiencies impaired memory function by impairing hippocampal insulin signaling and gut microbiota in AD rats.

Automated summary

Folate and vitamin B12 deficiencies impair memory function, glucose metabolism, and inflammation, and exacerbate bone mineral loss in rats with Alzheimer's disease-like dementia by modulating gut microbiota.