Alzheimer’s disease: amino acid levels and brain metabolic status

Gueli, Maria Concetta; Taibi, Gennaro

doi:10.1007/s10072-013-1289-9

Cited by 121 publications

(80 citation statements)

References 37 publications

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“…This pathway is required for the production of S ‐adenosylmethionine (SAM), the major DNA methylating agent, using methionine and folate as precursors. In AD, abnormal transmethylation mechanisms have been associated with polymorphisms of genes participating in the cycle and reduced levels of folate , SAM and methionine , in agreement with our findings. Other three potential markers found in the present study could be related to vascular disorders: homocysteine‐cysteine disulfide (Hcy‐Cys), asymmetric dimethyl‐arginine (ADMA) and phenylalanyl‐phenylalanine (Phe‐Phe).…”

Section: Resultssupporting

confidence: 92%

Metabolomic profiling of serum in the progression of Alzheimer's disease by capillary electrophoresis–mass spectrometry

et al. 2014

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There is high interest in the discovery of early diagnostic biomarkers of Alzheimer's disease, for which metabolomics exhibits a great potential. In this work, a metabolomic approach based on ultrafiltration and analysis by CE-MS has been used to obtain representative fingerprints of polar metabolites from serum samples in order to distinguish between patients with Alzheimer's disease, mild cognitive impairment, and healthy controls. By the use of partial least squares discriminant analysis it was possible to classify patients according to the disease stage and then identify potential markers. Significant increase was observed with progression of disease in levels of choline, creatinine, asymmetric dimethyl-arginine, homocysteine-cysteine disulfide, phenylalanyl-phenylalanine, and different medium chain acylcarnitines. On the other hand, asparagine, methionine, histidine, carnitine, acetyl-spermidine, and C5-carnitine were reduced in these serum samples. In this way, multiple essential pathways were found implicated in the underlying pathology, such as oxidative stress or defects in energy metabolism. However, the most interesting results are related to the association of several vascular risk factors with Alzheimer's disease.

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Section: Resultssupporting

confidence: 92%

Metabolomic profiling of serum in the progression of Alzheimer's disease by capillary electrophoresis–mass spectrometry

et al. 2014

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“…Although GABA loss has been variably demonstrated in AD, disruption and significantly reduced GABA transmission are widely observed in AD patients. [52][53][54] We also observed remarkable reduction of 5-HIAA and HVA, the metabolites of 5-HT and DA in dialysates of the htau-expressing mice (data not shown). The hippocampus CA3 has enriched GABAergic inputs and outputs, whereas the serotoninergic and dopaminergic neurons are scarcely seen.…”

Section: Discussionmentioning

confidence: 72%

Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice

Wang

Tan

et al. 2017

Molecular Therapy

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Patients with Alzheimer's disease (AD) commonly show anxiety behaviors, but the molecular mechanisms are not clear and no efficient intervention exists. Here, we found that overexpression of human wild-type, full-length tau (termed htau) in hippocampus significantly decreased the extracellular g-aminobutyric acid (GABA) level with inhibition of g oscillation and the evoked inhibitory postsynaptic potential (eIPSP). With tau accumulation, the mice show age-dependent anxiety behaviors. Among the factors responsible for GABA synthesis, release, uptake, and transport, we found that accumulation of htau selectively suppressed expression of the intracellular vesicular GABA transporter (vGAT). Tau accumulation increased miR92a, which targeted vGAT mRNA 3 0 UTR and inhibited vGAT translation. Importantly, we found that upregulating GABA tones by intraperitoneal injection of midazolam (a GABA agonist), ChR2-mediated photostimulating and overexpressing vGAT, or blocking miR92a by using specific antagomir or inhibitor efficiently rescued the htau-induced GABAergic dysfunctions with attenuation of anxiety. Finally, we also demonstrated that vGAT level decreased while the miR92a increased in the AD brains. These findings demonstrate that the AD-like tau accumulation induces anxiety through disrupting miR92a-vGAT-GABA signaling, which reveals molecular mechanisms underlying the anxiety behavior in AD patients and potentially leads to the development of new therapeutics for tauopathies.

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“…These neurotransmitters (along with acetylcholine) are important for learning, memory and cognition (Riederer and Hoyer, 2006), and are decreased in regions of the AD brain compared to normal controls (Gueli and Taibi, 2013). …”

Section: Discussionmentioning

confidence: 99%

Metabolomic analysis of exercise effects in the POLG mitochondrial DNA mutator mouse brain

Clark-Matott

Saleem

Dai

et al. 2015

Neurobiology of Aging

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Mitochondrial DNA (mtDNA) mutator mice express a mutated form of mtDNA polymerase gamma (PolgA) that results an accelerated accumulation of somatic mtDNA mutations in association with a premature aging phenotype. An exploratory metabolomic analysis of cortical metabolites in sedentary and exercised mtDNA mutator mice and wild-type (WT) littermate controls at 9–10 months of age was performed. Pathway analysis revealed deficits in the neurotransmitters acetylcholine, glutamate and aspartate that were ameliorated by exercise. Nicotinamide adenine dinucleotide (NAD+) depletion and evidence of increased Poly [ADP-ribose] polymerase 1 (PARP-1) activity were apparent in sedentary mtDNA mutator mouse cortex, along with deficits in carnitine metabolites and an upregulated antioxidant response that largely normalized with exercise. These data highlight specific pathways that are altered in the brain in association with an accelerated age-related accumulation of somatic mtDNA mutations. These results may have relevance to age-related neurodegenerative diseases associated with mitochondrial dysfunction, such as Alzheimer’s disease and Parkinson’s disease, and provide insights into potential mechanisms of beneficial effects of exercise on brain function.

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Alzheimer’s disease: amino acid levels and brain metabolic status

Cited by 121 publications

References 37 publications

Metabolomic profiling of serum in the progression of Alzheimer's disease by capillary electrophoresis–mass spectrometry

Metabolomic profiling of serum in the progression of Alzheimer's disease by capillary electrophoresis–mass spectrometry

Correcting miR92a-vGAT-Mediated GABAergic Dysfunctions Rescues Human Tau-Induced Anxiety in Mice

Metabolomic analysis of exercise effects in the POLG mitochondrial DNA mutator mouse brain

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