β-Alanyl-L-Histidine Rescues Cognitive Deficits Caused by Feeding a High Fat Diet in a Transgenic Mouse Model of Alzheimer's Disease

Abstract

Abstract. Our goal in this study was to determine whether or not feeding young (4 months old) Alzheimer's disease model transgenic mice with a high fat diet (HFD), consisting of 32% fat, is capable of causing cognitive decline and whether treatment with ␤-alanyl-L-histidine (carnosine) is capable of reducing these effects. Carnosine is an endogenous antioxidant and antiglycating agent that is abundantly present in the brain and muscle tissues of vertebrates. After 8 weeks of feeding with HFD, we observed a significant decline in the contextual memory in transgenic mice fed with HFD as compared to transgenic mice fed with a normal diet as well as to normal diet-wild type mice. Treatment with carnosine at a dose of 5 mg/day for 6 weeks was effective in preventing cognitive decline, as the transgenic group fed with HFD and treated with carnosine displayed a level of cognition comparable to controls. No differences in senile plaque load were observed between all groups. However, we observed an increase in the expression of RAGE in blood vessels as well as increased microglial activation in the hippocampus of animals fed with HFD, effects that were reversed when treated with carnosine. Given these results, there is a possibility that inflammation and cerebrovascular abnormalities might be the cause of cognitive decline in this model.

High-fat diet-induced memory impairment in triple-transgenic Alzheimer's disease (3xTgAD) mice is independent of changes in amyloid and tau pathology

“…Microglia are the brain-resident “immune” cells and are proposed to play a key role in many neurodegenerative conditions and particularly in AD (Wyss-Coray and Rogers, 2012). Microglial activation was increased in response to a high-fat diet seen here in both 3xTgAD and non-Tg control mice, and also in other mouse models of AD (Herculano et al., 2013). Vascular inflammation might also be important in the effects of obesity on cognition as diets high in fat also increase expression of vascular inflammatory markers in AD mice (Herculano et al., 2013).…”

“…Microglial activation was increased in response to a high-fat diet seen here in both 3xTgAD and non-Tg control mice, and also in other mouse models of AD (Herculano et al., 2013). Vascular inflammation might also be important in the effects of obesity on cognition as diets high in fat also increase expression of vascular inflammatory markers in AD mice (Herculano et al., 2013). Furthermore, when AD transgenic mice (APP23) are crossed with an obese mouse model ( ob/ob ) the resulting offspring (APP + - ob/ob ) show worse cognitive deficits and vascular inflammation that appear before significant Aβ deposition (Takeda et al., 2010).…”

“…Altered metabolism has also been demonstrated in the 3xTgAD mouse as after the age of 12 months, these mice are no longer heavier than the control non-Tg mice even though food intake is still increased, an observation that might be because of a higher metabolic rate (Adebakin et al., 2012; Knight et al., 2012). However, it is likely that body weight and/or obesity per se may not be the main cause for cognitive deficits as memory deficits in high-fat fed AD mice can be reduced (with an antioxidant) without an effect on body weight (Herculano et al., 2013). Furthermore, when body weight is normalized after the high-fat diet is replaced with control diet, AD mice still experience cognitive deficits (Maesako et al., 2012b).…”

Possible Benefit of Dietary Carnosine towards Depressive Disorders

“…Nevertheless it is possible that a common molecular entity exists whose activities link aging, telomeres, cortisol and behaviour. It is suggested here that carnosine could provide a therapeutic link between these phenomena because, as noted above, carnosine (i) can act as an anti-aging agent (mimicking rapamycin) including exerting beneficial effects on animal models of age-related brain dysfunction [23][24][25][26][27][28], (ii) can help to maintain telomere length [12], (iii) may enhance cortisol metabolism, at least in mice [36], (iv) ameliorates stress-induced changes in metabolism in restrained mice [37] and (v), when complexed with zinc, suppress the effects of cortisol on rat bone metabolism [38]. Interestingly, it has been suggested that carnosine's anti-stress effects in mice are mediated by modulating the stress-activated hypothalamic-pituitary-adrenal axis [37], whilst it has recently been shown that raised cortisol levels are present in Alzheimer's disease patients' cerebrospinal fluid, possibly arising from dysregulation of the hypothalamic-pituitary-adrenal axis [39].…”

“…Carnosine can inhibit many deleterious biochemical phenomena thought to be associated with generation of the aged phenotype, these include protein damage (including cross-linking [13]) induced by reactive oxygen species [14], reactive nitrogen species [15,16], reducing sugars [13] and reactive carbonyl species such as malondialdehyde [17], 4-hydroxynonenal [18,19] and methylglyoxal [20]. Model animal studies show beneficial effects of the dipeptide towards a number of age-related physiological conditions including impaired wound healing [21,22], Alzheimer's disease [23,24], Parkinson's disease [25,26], stroke [27,28], atherosclerosis [29,30], cataracts [31,32] and diabetic kidney disease [33,34]. In fact it has been claimed that carnosine may be a rapamycin mimetic (a well-recognized anti-aging agent) because many of their respective properties are so similar [35], and recent evidence supports this proposal [10].…”