Serum Amino Acid Profiles in Normal Subjects and in Patients with or at Risk of Alzheimer Dementia

Corso, Gaetano; Cristofano, Adriana; Sapere, Nadia; Marca, Giancarlo la; Angiolillo, Antonella; Vitale, Michela; Fratangelo, Roberto; Lombardi, Teresa; Porcile, Carola; Intrieri, Mariano; Costanzo, Alfonso Di

doi:10.1159/000466688

Cited by 60 publications

(34 citation statements)

References 65 publications

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“…Unfortunately, apart from ketone bodies, astrocyte-neuron lactate shuttle, the pentose phosphate pathway (PPP), and glycogenolysis, there are no clear-cut data that support other energy compensatory mechanisms to balance the bioenergetic deficits in AD brain. Several findings substantiate that plasma levels of certain amino acids are significantly altered in mild cognitive impairment (MCI) and AD patients compared to control individuals [ 21 – 23 ]. The BBB restricts the entry of glutamate and other anionic excitatory amino acids from the circulation [ 24 ], although it allows selective transport of certain amino acids to support neuronal functions through transporters [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 80%

Possible Clues for Brain Energy Translation via Endolysosomal Trafficking of APP‐CTFs in Alzheimer’s Disease

Sivanesan

Mundugaru

Rajadas

2018

Oxidative Medicine and Cellular Longevity

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Vascular dysfunctions, hypometabolism, and insulin resistance are high and early risk factors for Alzheimer's disease (AD), a leading neurological disease associated with memory decline and cognitive dysfunctions. Early defects in glucose transporters and glycolysis occur during the course of AD progression. Hypometabolism begins well before the onset of early AD symptoms; this timing implicates the vulnerability of hypometabolic brain regions to beta-secretase 1 (BACE-1) upregulation, oxidative stress, inflammation, synaptic failure, and cell death. Despite the fact that ketone bodies, astrocyte-neuron lactate shuttle, pentose phosphate pathway (PPP), and glycogenolysis compensate to provide energy to the starving AD brain, a considerable energy crisis still persists and increases during disease progression. Studies that track brain energy metabolism in humans, animal models of AD, and in vitro studies reveal striking upregulation of beta-amyloid precursor protein (β-APP) and carboxy-terminal fragments (CTFs). Currently, the precise role of CTFs is unclear, but evidence supports increased endosomal-lysosomal trafficking of β-APP and CTFs through autophagy through a vague mechanism. While intracellular accumulation of Aβ is attributed as both the cause and consequence of a defective endolysosomal-autophagic system, much remains to be explored about the other β-APP cleavage products. Many recent works report altered amino acid catabolism and expression of several urea cycle enzymes in AD brains, but the precise cause for this dysregulation is not fully explained. In this paper, we try to connect the role of CTFs in the energy translation process in AD brain based on recent findings.

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Section: Introductionmentioning

confidence: 80%

Possible Clues for Brain Energy Translation via Endolysosomal Trafficking of APP‐CTFs in Alzheimer’s Disease

Sivanesan

Mundugaru

Rajadas

2018

Oxidative Medicine and Cellular Longevity

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“…It should be noted that only a selection of promising biomarkers has been included in this review, and many other candidates are being studied at present. As well as other protein/peptide markers and panels [ 206 ], non-protein analytes such as lipids [ 8 ], amino acids [ 56 ], and microRNAs [ 120 , 328 ] are being explored. Advances in technologies such as mass spectrometry enable the precise measurement of analytes, helping to identify new candidate biomarkers [ 26 ] as well as supporting harmonization efforts for the core biomarkers [ 292 ].…”

Section: Discussionmentioning

confidence: 99%

Current state of Alzheimer’s fluid biomarkers

et al. 2018

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.

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“…A transgenic animal model of AD demonstrated a falling Glu level ( Nilsen et al, 2012 ), and the serum and plasma metabolomics also indicated a decrease of Trp, 5-HT, Glu, Phe, Tyr in AD model mice or patients ( Vermeiren et al, 2014 ; González-Domínguez et al, 2015 ; Weng et al, 2015 ; Corso et al, 2017 ; Li et al, 2018 ). Correspondingly, our results proved that the scopolamine-induced dementia was accompanied by the decrease of ACh, L -Trp, 5-HT, L -Glu, L -Phe, L -Tyr and the elevation of Ch and γ-GABA, which is in agreement with the previous studies ( Scali et al, 1999 ; Nilsen et al, 2012 ; Lee et al, 2014 ; Vermeiren et al, 2014 ; González-Domínguez et al, 2015 ; Kumar and Singh, 2015 ; Weng et al, 2015 ; Zhou et al, 2016 ; Corso et al, 2017 ; Liu et al, 2017 ). Neurotransmitters play an important role in the brain circuit involved in many aspects of learning and memory, especially the cholinergic, serotonergic, glutametargic, and GABAergic neurotransmitters ( Vermeiren et al, 2014 ; Kumar and Singh, 2015 ; Zhou et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Analogous β-Carboline Alkaloids Harmaline and Harmine Ameliorate Scopolamine-Induced Cognition Dysfunction by Attenuating Acetylcholinesterase Activity, Oxidative Stress, and Inflammation in Mice

Wang

et al. 2018

Front. Pharmacol.

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The analogous β-carboline alkaloids, harmaline (HAL) and harmine (HAR), possess a variety of biological properties, including acetylcholinesterase (AChE) inhibitory activity, antioxidant, anti-inflammatory, and many others, and have great potential for treating Alzheimer’s disease (AD). However, studies have showed that the two compounds have similar structures and in vitro AChE inhibitory activities but with significant difference in bioavailability. The objective of this study was to comparatively investigate the effects of HAL and HAR in memory deficits of scopolamine-induced mice. In the present study, mice were pretreated with HAL (2, 5, and 10 mg/kg), HAR (10, 20, and 30 mg/kg) and donepezil (5 mg/kg) by intragastrically for 7 days, and were daily intraperitoneal injected with scopolamine (1 mg/kg) to induce memory deficits and then subjected to behavioral evaluation by Morris water maze. To further elucidate the underlying mechanisms of HAL and HAR in improving learning and memory, the levels of various biochemical factors and protein expressions related to cholinergic function, oxidative stress, and inflammation were examined. The results showed that HAL and HAR could effectively ameliorate memory deficits in scopolamine-induced mice. Both of them exhibited an enhancement in cholinergic function by inhibiting AChE and inducing choline acetyltransferase (ChAT) activities, and antioxidant defense via increasing the antioxidant enzymes activities of superoxide dismutase and glutathione peroxidase, and reducing maleic diadehyde production, and anti-inflammatory effects through suppressing myeloperoxidase, tumor necrosis factor α, and nitric oxide as well as modulation of critical neurotransmitters such as acetylcholine (ACh), choline (Ch), L-tryptophan (L-Trp), 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (γ-GABA), and L-glutamic acid (L-Glu). Furthermore, the regulations of HAL on cholinergic function, inflammation, and neurotransmitters were more striking than those of HAR, and HAL manifested a comparable antioxidant capacity to HAR. Remarkably, the effective dosage of HAL (2 mg/kg) was far lower than that of HAR (20 mg/kg), which probably due to the evidently differences in the bioavailability and metabolic stability of the two analogs. Taken together, all these results revealed that HAL may be a promising candidate compound with better anti-amnesic effects and pharmacokinetic characteristics for the treatments of AD and related diseases.

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Serum Amino Acid Profiles in Normal Subjects and in Patients with or at Risk of Alzheimer Dementia

Cited by 60 publications

References 65 publications

Possible Clues for Brain Energy Translation via Endolysosomal Trafficking of APP‐CTFs in Alzheimer’s Disease

Possible Clues for Brain Energy Translation via Endolysosomal Trafficking of APP‐CTFs in Alzheimer’s Disease

Current state of Alzheimer’s fluid biomarkers

Analogous β-Carboline Alkaloids Harmaline and Harmine Ameliorate Scopolamine-Induced Cognition Dysfunction by Attenuating Acetylcholinesterase Activity, Oxidative Stress, and Inflammation in Mice

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