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Alzheimer-associated A? oligomers impact the central nervous system to induce peripheral metabolic deregulation.

ABSTRACT: Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated A? oligomers (A?Os) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected A?Os failed to induce glucose intolerance, suggesting A?Os target brain regions involved in peripheral metabolic control. Accordingly, we show that A?Os affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2? phosphorylation (eIF2?-P). A?Os further induced eIF2?-P and activated pro-inflammatory IKK?/NF-?B signaling in the hypothalamus of mice and macaques. A?Os failed to trigger peripheral glucose intolerance in tumor necrosis factor-? (TNF-?) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that A?Os act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that A?Os affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD.

SUBMITTER: Clarke JR

PROVIDER: S-EPMC4328648 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Alzheimer-associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation.

Clarke Julia R JR Lyra E Silva Natalia M NM Figueiredo Claudia P CP Frozza Rudimar L RL Ledo Jose H JH Beckman Danielle D Katashima Carlos K CK Razolli Daniela D Carvalho Bruno M BM Frazão Renata R Silveira Marina A MA Ribeiro Felipe C FC Bomfim Theresa R TR Neves Fernanda S FS Klein William L WL Medeiros Rodrigo R LaFerla Frank M FM Carvalheira Jose B JB Saad Mario J MJ Munoz Douglas P DP Velloso Licio A LA Ferreira Sergio T ST De Felice Fernanda G FG

EMBO molecular medicine 20150201 2

Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AβOs failed to induce glucose intolerance, suggesting AβOs target brain regions involved in peripheral metabolic ...[more]

PMID: 25617315

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Project description:Purpose of reviewPeripheral nervous system vasculitides (PNSV) are a heterogeneous group of disorders with a clinical subset that may differ in prognosis and therapy. We provide a comprehensive update on the clinical assessment, diagnosis, complications, treatment, and follow-up of PNSV.Recent findingsProgress in neuroimaging, molecular testing, and peripheral nerve biopsy has improved clinical assessment and decision-making of PNSV, also providing novel insights on how to prevent misdiagnosis and increase diagnostic certainty. Advances in imaging techniques, allowing to clearly display the vessel walls, have also enhanced the possibility to differentiate inflammatory from non-inflammatory vascular lesions, while recent histopathology data have identified the main morphological criteria for more accurate diagnosis and differential diagnoses. Overall, the identification of peculiar morphological findings tends to improve diagnostic accuracy by defining a clearer boundary between systemic and non-systemic neuropathies. Therefore, the definition of epineurium vessel wall damage, type of vascular lesion, characterization of lymphocyte populations, antibodies, and inflammatory factors, as well as the identification of direct nerve damage or degeneration, are the common goals for pathologists and clinicians, who will both benefit for data integration and findings translation. Nevertheless, to date, treatment is still largely empiric and, in some cases, unsatisfactory, thus often precluding precise prognostic prediction. In this context, new diagnostic techniques and multidisciplinary management will be essential in the proper diagnosis and prompt management of PNSV, as highlighted in the present review. Thirty to fifty percent of all patients with vasculitis have signs of polyneuropathy. Neuropathies associated with systemic vasculitis are best managed according to the guidelines of the underlying disease because appropriate workup and initiation of treatment can reduce morbidity. Steroids, or in severe or progressive cases, cyclophosphamide pulse therapy is the standard therapy in non-systemic vasculitic neuropathies. Some patients need long-term immunosuppression. The use of novel technologies for high-throughput genotyping will permit to determine the genetic influence of related phenotypes in patients with PNSV.

Project description:BACKGROUND:Metabolic alterations, related to cerebral glucose metabolism, brain insulin resistance, and age-induced mitochondrial dysfunction, play an important role in Alzheimer's disease (AD) on both the systemic and central nervous system level. To study the extent and significance of these alterations in AD, quantitative metabolomics was applied to plasma and cerebrospinal fluid (CSF) from clinically well-characterized AD patients and cognitively healthy control subjects. The observed metabolic alterations were associated with core pathological processes of AD to investigate their relation with amyloid pathology and tau-related neurodegeneration. METHODS:In a case-control study of clinical and biomarker-confirmed AD patients (n = 40) and cognitively healthy controls without cerebral AD pathology (n = 34) with paired plasma and CSF samples, we performed metabolic profiling, i.e., untargeted metabolomics and targeted quantification. Targeted quantification focused on identified deregulated pathways highlighted in the untargeted assay, i.e. the TCA cycle, and its anaplerotic pathways, as well as the neuroactive tryptophan and kynurenine pathway. RESULTS:Concentrations of several TCA cycle and beta-oxidation intermediates were higher in plasma of AD patients, whilst amino acid concentrations were significantly lower. Similar alterations in these energy metabolism intermediates were observed in CSF, together with higher concentrations of creatinine, which were strongly correlated with blood-brain barrier permeability. Alterations of several amino acids were associated with CSF Amyloidβ1-42. The tryptophan catabolites, kynurenic acid and quinolinic acid, showed significantly higher concentrations in CSF of AD patients, which, together with other tryptophan pathway intermediates, were correlated with either CSF Amyloidβ1-42, or tau and phosphorylated Tau-181. CONCLUSIONS:This study revealed AD-associated systemic dysregulation of nutrient sensing and oxidation and CNS-specific alterations in the neuroactive tryptophan pathway and (phospho)creatine degradation. The specific association of amino acids and tryptophan catabolites with AD CSF biomarkers suggests a close relationship with core AD pathology. Our findings warrant validation in independent, larger cohort studies as well as further investigation of factors such as gender and APOE genotype, as well as of other groups, such as preclinical AD, to identify metabolic alterations as potential intervention targets.

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Alzheimer-associated A? oligomers impact the central nervous system to induce peripheral metabolic deregulation.

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Alzheimer-associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation.

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