Dietary intake of branched‐chain amino acids in a mouse model of Alzheimer's disease: Effects on survival, behavior, and neuropathology

Tournissac, Marine; Vandal, Milène; Tremblay, Cyntia; Bourassa, Philippe; Vancassel, Sylvie; Émond, Vincent; Gangloff, Anne; Calon, Frédéric

doi:10.1016/j.trci.2018.10.005

Cited by 51 publications

(30 citation statements)

References 46 publications

(77 reference statements)

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“…In AD patient cerebral spinal fluid (CSF), histidine was identified as a possible disease progression biomarker 53 . One potential therapeutic strategy for AD patients is to supplement low protein diets with high levels of branched-chain amino acids, such as histidine, glutamine, and threonine 54 .…”

Section: Discussionmentioning

confidence: 99%

Divergence in the metabolome between natural aging and Alzheimer’s disease

Hunsberger

Greenwood

Tolstikov

et al. 2020

Sci Rep

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Alzheimer's disease (AD) is a progressive and debilitating neurodegenerative disorder and one of the leading causes of death in the United States. Although amyloid plaques and fibrillary tangles are hallmarks of AD, research suggests that pathology associated with AD often begins 20 or more years before symptoms appear. Therefore, it is essential to identify early-stage biomarkers in those at risk for AD and age-related cognitive decline (ARCD) in order to develop preventative treatments. Here, we used an untargeted metabolomics analysis to define system-level alterations following cognitive decline in aged and APP/PS1 (AD) mice. At 6, 12, and 24 months of age, both control (Ctrl) and AD mice were tested in a 3-shock contextual fear conditioning (CFC) paradigm to assess memory decline. AD mice exhibited memory deficits across age and these memory deficits were also seen in naturally aged mice. Prefrontal cortex (PFC), hippocampus (HPC), and spleen were then collected and analyzed for metabolomic alterations. A number of significant pathways were altered between Ctrl and AD mice and naturally aged mice. By identifying systems-level alterations following ARCD and AD, these data could provide insights into disease mechanisms and advance the development of biomarker panels. Alzheimer's disease (AD), a progressive and debilitating neurodegenerative disorder, characterized by senile amyloid plaques and tau fibrillary tangles, is the leading cause of dementia 1. Amyloid plaques are aggregates of various amyloid peptides derived from the amyloid precursor protein (APP). APP accumulates when presenilin 1 and 2 mutant genes (PS1 and PS2) enhance the γ-secretase-mediated processing of APP 2. Therefore, we have chosen the APP/PS1 AD mouse model to best replicate the human amyloid cascade. This amyloid accumulation then promotes the spread of tau tangles, consisting of hyperphosphorylated tau protein, inevitably leading to cognitive decline 3. However, research suggests that the pathology associated with AD often begins 20 or more years before symptoms appear 4 , which makes this a critical time window for possible preventative treatments. Because aging is the greatest risk factor for developing AD 5 , it is also important to examine age-related brain changes and age-related cognitive decline (ARCD). ARCD is a normal process of aging where conceptual reasoning, memory, and processing speed gradually decline over time (fluid intelligence) 6-8. However, ARCD differs from AD in that certain abilities, such as vocabulary or other skills that have accumulated throughout life, are resilient to brain aging (crystallized intelligence) 9. It is important to understand how metabolites influence ARCD and AD, as our current aging population is expected to double in the next 40 years 10. One of the biggest problems facing AD research is the lack of biomarkers for diagnosis and treatment. Currently, there are only 3 FDA-approved diagnostic tests for AD, all of which are positron emission tomography (PET) neuroimaging scans for amyloid 11-1...

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Section: Discussionmentioning

confidence: 99%

Divergence in the metabolome between natural aging and Alzheimer’s disease

Hunsberger

Greenwood

Tolstikov

et al. 2020

Sci Rep

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“…This intervention suggests that BCAA and fatty acids are not limiting to energy production and that excess levels are pathologic, but systemic stress could also be important, independent of brain metabolism. Conversely, a low BCAA diet was found to improve recognition memory in 18-month-old 3xTg-AD mice [83]. Taken together, the BCAA metabolites levels in plasma may serve as a biomarker for an AD metabolic switch and pathology.…”

Section: Branched Chain Amino Acidsmentioning

confidence: 88%

“…The important question is whether this is protective or pathologic. In the 3xTg-AD mouse fed with a BCAA-supplemented high-fat diet for 2 months, tau and amyloid pathologies worsened leading to an increase in the mortality of two-thirds of the mice from 6 to 16 months [83]. This intervention suggests that BCAA and fatty acids are not limiting to energy production and that excess levels are pathologic, but systemic stress could also be important, independent of brain metabolism.…”

Section: Branched Chain Amino Acidsmentioning

confidence: 97%

Global Metabolic Shifts in Age and Alzheimer’s Disease Mouse Brains Pivot at NAD+/NADH Redox Sites

Dong

Brewer

2019

JAD

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Age and Alzheimer's disease (AD) share some common features such as cognitive impairments, memory loss, metabolic disturbances, bioenergetic deficits, and inflammation. Yet little is known on how systematic shifts in metabolic networks depend on age and AD. In this work, we investigated the global metabolomic alterations in non-transgenic (NTg) and triple-transgenic (3xTg-AD) mouse brain hippocampus as a function of age by using untargeted Ultrahigh Performance Liquid Chromatography-tandem Mass Spectroscopy (UPLC-MS/MS). We observed common metabolic patterns with aging in both NTg and 3xTg-AD brains involved in energy-generating pathways, fatty acids oxidation, glutamate, and sphingolipid metabolism. We found age-related downregulation of metabolites from reactions in glycolysis that consumed ATP and in the TCA cycle, especially at NAD + /NADH-dependent redox sites, where age-and AD-associated limitations in the free NADH may alter reactions. Conversely, metabolites increased in glycolytic reactions in which ATP is produced. With age, inputs to the TCA cycle were increased including fatty acid ␤-oxidation and glutamine. Overall age-and AD-related changes were > 2-fold when comparing the declines of upstream metabolites of NAD + /NADH-dependent reactions to the increases of downstream metabolites (p = 10 −5 , n = 8 redox reactions). Inflammatory metabolites such as ceramides and sphingosine-1phosphate also increased with age. Age-related decreases in glutamate, GABA, and sphingolipid were seen which worsened with AD genetic load in 3xTg-AD brains, possibly contributing to synaptic, learning-and memory-related deficits. The data support the novel hypothesis that age-and AD-associated metabolic shifts respond to NAD(P) + /NAD(P)H redox-dependent reactions, which may contribute to decreased energetic capacity.

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“…Hyperphosphorylation of Tau is recapitulated following BCAT knockdown in neurons of AD mouse brains in mTOR-dependent manner [128]. In keeping with these results, 50% BCAA restriction significantly lowers plasma BCAAs and improves memory function in both regular chow and HFD-fed 3xTg AD mice [129]. Similarly, protein restriction cycling in 3xTg AD mice also has shown to improve memory function [130].…”

Section: Alzheimer's Diseasementioning

confidence: 90%

Recent Progress on Branched-Chain Amino Acids in Obesity, Diabetes, and Beyond

2019

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Branched-chain amino acids (BCAAs) are essential amino acids that are not synthesized in our body; thus, they need to be obtained from food. They have shown to provide many physiological and metabolic benefits such as stimulation of pancreatic insulin secretion, milk production, adipogenesis, and enhanced immune function, among others, mainly mediated by mammalian target of rapamycin (mTOR) signaling pathway. After identified as a reliable marker of obesity and type 2 diabetes in recent years, an increasing number of studies have surfaced implicating BCAAs in the pathophysiology of other diseases such as cancers, cardiovascular diseases, and even neurodegenerative disorders like Alzheimer's disease. Here we discuss the most recent progress and review studies highlighting both correlational and potentially causative role of BCAAs in the development of these disorders. Although we are just beginning to understand the intricate relationships between BCAAs and some of the most prevalent chronic diseases, current findings raise a possibility that they are linked by a similar putative mechanism.

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Dietary intake of branched‐chain amino acids in a mouse model of Alzheimer's disease: Effects on survival, behavior, and neuropathology

Cited by 51 publications

References 46 publications

Divergence in the metabolome between natural aging and Alzheimer’s disease

Divergence in the metabolome between natural aging and Alzheimer’s disease

Global Metabolic Shifts in Age and Alzheimer’s Disease Mouse Brains Pivot at NAD+/NADH Redox Sites

Recent Progress on Branched-Chain Amino Acids in Obesity, Diabetes, and Beyond

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