The Preventive Effect of Exercise and Oral Branched-Chain Amino Acid Supplementation on Obesity-Induced Brain Changes in Ldlr-/-.Leiden Mice.

Exercise and dietary interventions are promising approaches to tackle obesity and its obesogenic effects on the brain. We investigated the impact of exercise and possible synergistic effects of exercise and branched-chain amino acids (BCAA) supplementation on the brain and behavior in high-fat-diet (HFD)-induced obese Ldlr-/-.Leiden mice. Baseline measurements were performed in chow-fed Ldlr-/-.Leiden mice to assess metabolic risk factors, cognition, and brain structure using magnetic resonance imaging. Thereafter, a subgroup was sacrificed, serving as a healthy reference. The remaining mice were fed an HFD and divided into three groups: (i) no exercise, (ii) exercise, or (iii) exercise and dietary BCAA. Mice were followed for 6 months and aforementioned tests were repeated. We found that exercise alone changed cerebral blood flow, attenuated white matter loss, and reduced neuroinflammation compared to non-exercising HFD-fed mice. Contrarily, no favorable effects of exercise on the brain were found in combination with BCAA, and neuroinflammation was increased. However, cognition was slightly improved in exercising mice on BCAA. Moreover, BCAA and exercise increased the percentage of epididymal white adipose tissue and muscle weight, decreased body weight and fasting insulin levels, improved the circadian rhythm, and transiently improved grip strength. In conclusion, BCAA should be supplemented with caution, although beneficial effects on metabolism, behavior, and cognition were observed.

Hypertension Impairs Cerebral Blood Flow in a Mouse Model for Alzheimer's Disease.

AIMS: Hypertension, a risk factor for Alzheimer's disease (AD), is a treatable condition, which offers possibilities for prevention of AD. Elevated angiotensin II (AngII) is an important cause of essential hypertension. AngII has deleterious effects on endothelial function and cerebral blood flow (CBF), which may contribute to AD. AngII blocking agents can thus provide potential candidates to reduce AD risk factors in hypertensive patients. METHODS: We studied the effect of 2 months induced hypertension (AngII-infusion via osmotic micropumps) on systolic blood pressure (SBP) and CBF in 10 months-old wild-type (WT) C57bl/6j and AßPPswe/PS1ΔE9 (AßPP/PS1) mice, and treatment with two different antihypertensives, 1) eprosartan mesylate (EM, 0.35mg/kg) or 2) hydrochlorotiazide (HCT, 7.5mg/kg), after 1 month of induced-hypertension. SBP was monitored twice each month via tail cuff plethysmography. CBF was measured with MR by flow-sensitive alternating inversion recovery. RESULTS: Chronic AngII-infusion induced an increase in SBP in both AßPP/PS1 and WT mice accompanied by a decrease in hippocampal and thalamic CBF only in the AßPP/PS1 mice. An additional difference between the AßPP/PS1 mice and WT mice was that SBP was much higher in AßPP/PS1 mice in both hypertensive and normotensive conditions. Moreover, both antihypertensives were less effective in reducing AngII-induced hypertension to normal levels in AßPP/PS1 mice, while being effective in WT mice. CONCLUSIONS: It can be concluded that AngII-induced elevated SBP results in impaired CBF and a decreased response to blood pressure lowering treatment in a transgenic model of AD. Our findings suggest a relation between midlife hypertension and decreased CBF in an AD mouse model, similar to the relation which has been found in AD patients. This translational mouse model could be used to investigate possible prevention and treatment strategies for AD.

Impact of dietary n-3 polyunsaturated fatty acids on cognition, motor skills and hippocampal neurogenesis in developing C57BL/6J mice.

Maternal intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) is critical during perinatal development of the brain. Docosahexaenoic acid (DHA) is the most abundant n-3 PUFA in the brain and influences neuronal membrane function and neuroprotection. The present study aims to assess the effect of dietary n-3 PUFA availability during the gestational and postnatal period on cognition, brain metabolism and neurohistology in C57BL/6J mice. Female wild-type C57BL/6J mice at day 0 of gestation were randomly assigned to either an n-3 PUFA deficient diet (0.05% of total fatty acids) or an n-3 PUFA adequate diet (3.83% of total fatty acids) containing preformed DHA and its precursor α-linolenic acid. Male offspring remained on diet and performed cognitive tests during puberty and adulthood. In adulthood, animals underwent (31)P magnetic resonance spectroscopy to assess brain energy metabolites. Thereafter, biochemical and immunohistochemical analyses were performed assessing inflammation, neurogenesis and synaptic plasticity. Compared to the n-3 PUFA deficient group, pubertal n-3 PUFA adequate fed mice demonstrated increased motor coordination. Adult n-3 PUFA adequate fed mice exhibited increased exploratory behavior, sensorimotor integration and spatial memory, while neurogenesis in the hippocampus was decreased. Selected brain regions of n-3 PUFA adequate fed mice contained significantly lower levels of arachidonic acid and higher levels of DHA and dihomo-γ-linolenic acid. Our data suggest that dietary n-3 PUFA can modify neural maturation and enhance brain functioning in healthy C57BL/6J mice. This indicates that availability of n-3 PUFA in infant diet during early development may have a significant impact on brain development.

Multinutrient diets improve cerebral perfusion and neuroprotection in a murine model of Alzheimer's disease.

Nutritional intervention may retard the development of Alzheimer's disease (AD). In this study we tested the effects of 2 multi-nutrient diets in an AD mouse model (APPswe/PS1dE9). One diet contained membrane precursors such as omega-3 fatty acids and uridine monophosphate (DEU), whereas another diet contained cofactors for membrane synthesis as well (Fortasyn); the diets were developed to enhance synaptic membranes synthesis, and contain components that may improve vascular health. We measured cerebral blood flow (CBF) and water diffusivity with ultra-high-field magnetic resonance imaging, as alterations in these parameters correlate with clinical symptoms of the disease. APPswe/PS1dE9 mice on control diet showed decreased CBF and changes in brain water diffusion, in accordance with findings of hypoperfusion, axonal disconnection and neuronal loss in patients with AD. Both multinutrient diets were able to increase cortical CBF in APPswe/PS1dE9 mice and Fortasyn reduced water diffusivity, particularly in the dentate gyrus and in cortical regions. We suggest that a specific diet intervention has the potential to slow AD progression, by simultaneously improving cerebrovascular health and enhancing neuroprotective mechanisms.

Effects of specific multi-nutrient enriched diets on cerebral metabolism, cognition and neuropathology in AßPPswe-PS1dE9 mice.

Recent studies have focused on the use of multi-nutrient dietary interventions in search of alternatives for the treatment and prevention of Alzheimer's disease (AD). In this study we investigated to which extent long-term consumption of two specific multi-nutrient diets can modulate AD-related etiopathogenic mechanisms and behavior in 11-12-month-old AßPPswe-PS1dE9 mice. Starting from 2 months of age, male AßPP-PS1 mice and wild-type littermates were fed either a control diet, the DHA+EPA+UMP (DEU) diet enriched with uridine monophosphate (UMP) and the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), or the Fortasyn® Connect (FC) diet enriched with the DEU diet plus phospholipids, choline, folic acid, vitamins and antioxidants. We performed behavioral testing, proton magnetic resonance spectroscopy, immunohistochemistry, biochemical analyses and quantitative real-time PCR to gain a better understanding of the potential mechanisms by which these multi-nutrient diets exert protective properties against AD. Our results show that both diets were equally effective in changing brain fatty acid and cholesterol profiles. However, the diets differentially affected AD-related pathologies and behavioral measures, suggesting that the effectiveness of specific nutrients may depend on the dietary context in which they are provided. The FC diet was more effective than the DEU diet in counteracting neurodegenerative aspects of AD and enhancing processes involved in neuronal maintenance and repair. Both diets elevated interleukin-1ß mRNA levels in AßPP-PS1 and wild-type mice. The FC diet additionally restored neurogenesis in AßPP-PS1 mice, decreased hippocampal levels of unbound choline-containing compounds in wild-type and AßPP-PS1 animals, suggesting diminished membrane turnover, and decreased anxiety-related behavior in the open field behavior. In conclusion, the current data indicate that specific multi-nutrient diets can influence AD-related etiopathogenic processes. Intervention with the FC diet might be of interest for several other neurodegenerative and neurological disorders.