Protein restriction slows the development and progression of Alzheimer's disease in mice
Ontology highlight
ABSTRACT:
INSTRUMENT(S): 6495C Triple Quadrupole LC/MS
ORGANISM(S): Mus Musculus (ncbitaxon:10090)
SUBMITTER: 
Judith Simcox
PROVIDER: MSV000094816 | MassIVE | Tue May 21 09:22:00 BST 2024
REPOSITORIES: MassIVE
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Project description:Untargeted lipidomics of 3xTg and non-transgenic mouse brain on protein restricted diet
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Project description:Targeted lipidomics of 3xTg and non-transgenic mouse brain on protein restricted diet
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Project description:Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. Here, we show that PR promotes leanness and glycemic control in 3xTg mice, specifically rescuing the glucose intolerance of 3xTg females. PR induces sex-specific alterations in circulating and brain metabolites, downregulating sphingolipid subclasses in 3xTg females. PR also reduces AD pathology and mTORC1 activity, increases autophagy, and improves the cognition of 3xTg mice. Finally, PR improves the survival of 3xTg mice. Our results suggest that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.
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Project description:Alzheimer's disease (AD) affects an estimated 5.8 million Americans, and advanced age is the greatest risk factor. AD patients have altered intestinal microbiota. Accordingly, depleting intestinal microbiota in AD animal models reduces amyloid-beta (Aβ) plaque deposition. Age-related changes in the microbiota contribute to immunologic and physiologic decline. Translationally relevant dietary manipulations may be an effective approach to slow microbiota changes during aging. We previously showed that calorie restriction (CR) reduced brain Aβ deposition in the well-established Tg2576 mouse model of AD. Presently, we investigated whether CR alters the microbiome during aging. We found that female Tg2576 mice have more substantial age-related microbiome changes compared to wildtype (WT) mice, including an increase in Bacteroides, which were normalized by CR. Specific gut microbiota changes were linked to Aβ levels, with greater effects in females than in males. In the gut, Tg2576 female mice had an enhanced intestinal inflammatory transcriptional profile, which was reversed by CR. Furthermore, we demonstrate that Bacteroides colonization exacerbates Aβ deposition, which may be a mechanism whereby the gut impacts AD pathogenesis. These results suggest that long-term CR may alter the gut environment and prevent the expansion of microbes that contribute to age-related cognitive decline.
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Project description:plasma metabolomics done after restriction of dietary protein in AD mice.
2024-06-11 | MSV000094992 | MassIVE
Project description:Neuroinflammation is an important contributor to neuronal pathology and death in neurodegenerative diseases and neuronal injury. Therapeutic interventions blocking the activity of the inflammatory kinase IKKβ, a key regulator of neuroinflammatory pathways, is protective in several animal models of neurodegenerative disease and neuronal injury. In Huntington's disease (HD), however, significant questions exist as to the impact of blocking or diminishing the activity of IKKβ on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKβ phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKβ to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKβ knockout mice with R6/1 HD mice. Behavioral assays in these mice showed a significant worsening of HD pathological phenotypes. The increased behavioral pathology correlated with reduced levels of endogenous mouse full-length phospho-S13 HTT, supporting the importance of IKKβ in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKβ knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKβ is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKβ is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKβ may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset.
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Project description:plasma metabolomics done after restriction of dietary protein in AD mice.
2024-06-11 | MSV000094992 | GNPS
Project description:Background & Aims: In this study, we investigated metabolic and molecular effects of weekly intervening 30% calorie restriction on long term natural progression of non-alcoholic fatty liver disease (NAFLD), which was induced by a medium fat diet. Methods: Male C57BL/6J mice of 9 weeks old received either (1) a control (C), (2) a calorie restricted (CR), (3) a medium fat (MF; 25%fat) or (4) an intermittent diet (ID), a weekly alternating diet consisting of calorie restriction and medium fat diet ad libitum until sacrifice at the age of 12 months. Various metabolic and molecular features of the liver were examined. Results: The ID regimen improved the status of a range of metabolic parameters and showed no progression to NAFLD: proper glucose tolerance, low hepatic triglyceride content, low plasma alanine aminotransferase and no abnormalities in its liver morphological features; similarly to that of CR. In contrast, the metabolic parameters in a number of the C and MF animals indicated development of NAFLD and hepatic fibrosis, which was positively correlated with body weight. Despite the metabolic phenotypes similarity, the liver gene expression profile of ID-fed mice did not reflect that of CR mice and resembled more to C and MF-fed mice with similar low body weight. Conclusions: Our study reveals that ID is beneficial for metabolic health and prevents the development of NAFLD in mice, with a gene expression profile similar to C and MF diet in a body weight-dependent manner.
2018-05-09 | GSE53188 | GEO
Project description:Alzheimer's disease (AD), currently the single leading cause of death still on the rise, almost always coexists alongside vascular cognitive impairment (VCI). In fact, the ischemic disease affects up to 90% of AD patients, with strokes and major infarctions representing over a third of vascular lesions. Studies also confirmed that amyloid plaques, typical of AD, are much more likely to cause dementia if strokes or cerebrovascular damage also exist, leading to the term "mixed pathology" cognitive impairment. Although its incidence is expected to grow, there are no satisfactory treatments. There is hence an urgent need for safe and effective therapies that preserve cognition, maintain function, and prevent the clinical deterioration that results from the progression of this irreversible, neurodegenerative disease. To our knowledge, this is the first study to investigate the effects of long-term treatment with C21, a novel angiotensin II type 2 receptor (AT2R) agonist, on the development of "mixed pathology" cognitive impairment. This was accomplished using a unique model that employs the fundamental elements of both AD and VCI. Treatment with C21/vehicle was started 1 h post-stroke and continued for 5 weeks in mice with concurrent AD pathology. Efficacy was established through a series of functional tests assessing various aspects of cognition, including spatial learning, short-term/working memory, long-term/reference memory, and cognitive flexibility, in addition to the molecular markers characteristic of AD. Our findings demonstrate that C21 treatment preserves cognitive function, maintains cerebral blood flow, and reduces Aβ accumulation and toxic tau phosphorylation in AD animals post-stroke.
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Project description:BackgroundDuchenne muscular dystrophy results from mutation of the dystrophin gene, causing skeletal and cardiac muscle loss of function. The mdx mouse model of Duchenne muscular dystrophy is widely utilized to evaluate the potential of therapeutic regimens to modulate the loss of skeletal muscle function associated with dystrophin mutation. Importantly, progressive loss of diaphragm function is the most consistent striated muscle effect observed in the mdx mouse model, which is the same as in patients suffering from Duchenne muscular dystrophy.MethodsUsing the mdx mouse model, we have evaluated the effect that corticotrophin releasing factor 2 receptor (CRF2R) agonist treatment has on diaphragm function, morphology and gene expression.ResultsWe have observed that treatment with the potent CRF2R-selective agonist PG-873637 prevents the progressive loss of diaphragm specific force observed during aging of mdx mice. In addition, the combination of PG-873637 with glucocorticoids not only prevents the loss of diaphragm specific force over time, but also results in recovery of specific force. Pathological analysis of CRF2R agonist-treated diaphragm muscle demonstrates that treatment reduces fibrosis, immune cell infiltration, and muscle architectural disruption. Gene expression analysis of CRF2R-treated diaphragm muscle showed multiple gene expression changes including globally decreased immune cell-related gene expression, decreased extracellular matrix gene expression, increased metabolism-related gene expression, and, surprisingly, modulation of circadian rhythm gene expression.ConclusionTogether, these data demonstrate that CRF2R activation can prevent the progressive degeneration of diaphragm muscle associated with dystrophin gene mutation.
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