Oral tributyrin supplementation attenuates Alzheimer’s disease‐associated neuropathology and prevents cognitive and behavioral deficits in the 3xTg‐AD mouse model

Abstract

AbstractBackgroundDysbiosis of the gut microbiome is associated with various diseases, including Alzheimer’s Disease (AD). A decrease in intestinal butyrate‐producing bacteria has been indicated by pre‐clinical and clinical studies in AD; therefore, we assessed the effects of long‐term oral administration of tributyrin (TB: a butyrate pro‐drug) on the development of memory and neuromuscular deficits, and CNS pathology in 3xTg‐AD (3xTg) mice.MethodOral gavage with tributyrin (2 mg/kg) was given twice weekly to female 3xTg mice between 6‐ and 17‐months of age. Treatment was stopped and mice were tested for spatial memory (Y‐maze and novel object recognition test‐NORT) and neuromuscular function (RotaRod and grip tests). Brains from untreated (2‐, 12‐, or 18‐month‐old untreated or TB treated 18‐month‐old mice were formalin‐fixed, paraffin‐embedded for microscopic analysis of AD‐associated pathology, neuroinflammation, and oxidative stress markers.ResultShort‐term, episodic memory and spatial memory along with balance and coordination and grip strength were all significantly decreased in untreated 3xTg mice at 17‐months of age compared to 2‐ or 10‐month‐old mice. TB treatment, however, attenuated these effects in 17‐month mice. TB treatment did not affect the accumulation of either Aβ or Tau in the subiculum at 18‐months. However, pTau hyperphosphorylation—as indicated by co‐staining with both pTau(Ser404) and AT‐8 pTau (Ser202/Thr205) mAb—was effectively prevented with TB treatment. Similarly, significant age‐dependent neuroinflammation indicated by IBA1 (microglia) and GFAP (astrocytes) staining was increased in the hippocampus of 18‐month 3xTg mice and was effectively prevented by TB treatment. Additionally, markers of oxidative stress, 4‐HNE and acrolein adducts, were also increased in the molecular layer of the hippocampus and attenuated in TB treated mice.ConclusionThese studies demonstrate that TB treatment after initiation of Aβ deposition in the subiculum dramatically abrogates the loss of neurologic function in 3xTg mice as demonstrated by increased memory, cognition, and neuromuscular function. Moreover, these increases coincide with attenuated AD‐associated pathology in the hippocampus of TB‐treated 3xTg mice. Importantly, these data indicate that treatment with a butyrate pro‐drug can be integrated into treatment strategies to preserve cognitive and neuromuscular functions in patients in the prodromal phase of AD.