Trimethylamine N-Oxide (TMAO) links peripheral insulin resistance and cognitive deficiencies in a senescence accelerated mouse model

It has been established that ageing is the major risk factor for cognitive deficiency or neurodegenerative diseases such as Alzheimer's disease (AD) and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. The dysfunction of the insulin signaling system and glucose metabolism has been proposed to be responsible for brain aging. Normal insulin signaling in the brain is required to mediate growth, metabolic functions, and the survival of neurons and glia. Insulin receptors are densely expressed in the olfactory bulb, the cerebral cortex and the hippocampus and regulate neurotransmitter release and receptor recruitment. In normal elderly individuals, reduced glucose tolerance and decreased insulin levels in the aged brain are typically observed. Furthermore, insulin signaling is aberrantly activated in the AD brain, leading to non-responsive insulin receptor signaling. The senescence accelerated mouse (SAMP8) mouse was one of the accelerated senescence strains that spontaneously developed from breeding pairs of the AKR/J series. The SAMP8 mouse develops early learning and memory deficits (between 6 and 8 months) together with other characteristics similar to those seen in Alzheimer's disease. The present project proposes the investigation of the missing link between aging, insulin resistance and dementia. Peripheral but not central insulin resistance was found in SAMP8 mice accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state (i.e. significantly higher adipose tissue TNF-[alpha]; and IL6 levels) were observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across a aging-disrupted BBB. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment inhibits the transformation of choline, carnitine and crotonobetaine, decreaseing TMAO levels. The ever-increasing incidence of neurodegenerative diseases not only limits the life quality of the affected individuals and their families but also poses an enormous demand on the societies. Thus, it is instrumental to pursue novel promising approaches to prevent and treat it at the highest possible speed to rapidly translate them to clinical practice. From this point of view, data obtained from this project will be instrumental to validate the principle approach of microbial dysbiosis and increased TMAO secretion as a key link between aging, insulin resistance and dementia. Collectively, the proposed experiments ideally integrate the aim to promote a novel approach to improve the lives of those suffering from cognitive disturbances.

Erinacine A-Enriched Hericium erinaceus Mycelium Delays Progression of Age-Related Cognitive Decline in Senescence Accelerated Mouse Prone 8 (SAMP8) Mice

There have been many reports on the neuroprotective effects of Hericium erinaceus mycelium, in which the most well-known active compounds found are diterpenoids, such as erinacine A. Previously, erinacine A-enriched Hericeum erinaceus mycelium (EAHEM) was shown to decrease amyloid plaque aggregation and improve cognitive disability in Alzheimer’s disease model APP/PS1 mice. However, its effects on brain aging have not yet been touched upon. Here, we used senescence accelerated mouse prone 8 (SAMP8) mice as a model to elucidate the mechanism by which EAHEM delays the aging of the brain. Three-month-old SAMP8 mice were divided into three EAHEM dosage groups, administered at 108, 215 and 431 mg/kg/BW/day, respectively. During the 12th week of EAHEM feeding, learning and memory of the mice were evaluated by single-trial passive avoidance and active avoidance test. After sacrifice, the amyloid plaques, induced nitric oxidase synthase (iNOS) activity, thiobarbituric acid-reactive substances (TBARS) and 8-OHdG levels were analyzed. We found that the lowest dose of 108 mg/kg/BW EAHEM was sufficient to significantly improve learning and memory in the passive and active avoidance tests. In all three EAHEM dose groups, iNOS, TBARS and 8-OHdG levels all decreased significantly and showed a dose-dependent response. The results indicate that EAHEM improved learning and memory and delayed degenerative aging in mice brains.