A single intracerebroventricular Aβ25–35 infusion leads to prolonged alterations in arginine metabolism in the rat hippocampus and prefrontal cortex

Bergin, David H.; Yu, Jing; Zhang, H.; Liu, P.

doi:10.1016/j.neuroscience.2015.04.034

Cited by 14 publications

(10 citation statements)

References 71 publications

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“…Additionally, these patients demonstrate a reduced global arginine bioavailability ratio, the index, which is positively correlated with the Mini-Mental Status Examination score, making urinary arginine levels a potential diagnostic biomarker for MCI. Of note, numerous animal studies have further implicated altered arginine metabolism in the pathogenesis of AD (95,96).…”

Section: A Contribution Of the Urea Cycle And Polyamine Metabolic Patmentioning

confidence: 99%

A New Perspective on Alzheimer’s Disease as a Brain Expression of a Complex Metabolic Disorder

Polis

Samson

2019

Alzheimer’s Disease

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Alzheimer' s disease (AD) is an irredeemable chronic neurodegenerative disorder and the predominant cause of dementia. The disease progression is associated with the deposition of amyloid plaques and formation of neurofibrillary tangles in the brain, yet clinical dementia is the end and culminating stage of the enduring pathology. Recent evidence suggests that AD is characterized by distinctive abnormalities apparent on systemic, histological, macromolecular, and biochemical levels. Besides the well-described characteristic profuse neurofibrillary tangles, dystrophic neurites, and Aβ deposits, the AD pathology includes substantial neuronal loss, inflammation, extensive DNA damage, considerable mitochondrial malfunction, impaired energy metabolism, and chronic oxidative stress. Moreover, severe metabolic dysfunction leading to oxidative stress is a possible cause and hallmark of AD that is apparent decades before the disease manifestation. State-of-the-art metabolomics studies have proved that arginine and branched-chain amino acids metabolism disturbances accompany AD and contribute to its pathogenesis. Repetitive failures to find an efficient anti-amyloid or anti-Tau treatment, which would face the challenges of the complex AD pathology, led to the hypothesis that hyperphosphorylated Tau and deposited

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Section: A Contribution Of the Urea Cycle And Polyamine Metabolic Patmentioning

confidence: 99%

A New Perspective on Alzheimer’s Disease as a Brain Expression of a Complex Metabolic Disorder

Polis

Samson

2019

Alzheimer’s Disease

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“…However, in APP/PS1 mice putrescine is not reduced but raised, not only in brain but also in plasma (Pan et al, 2016). It has been demonstrated that intracerebroventricular infusion of pre-aggregated Aβ25-35 significantly decreases putrescine levels the prefrontal cortex of rats (Bergin et al, 2015). Contrastingly, Aβ1-41 upregulates of polyamine uptake and increases ornithine decarboxylase activity, which leads to increased polyamine levels in cultured neurons (Yatin et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Temporal Effects of Neuron-specific beta-secretase 1 (BACE1) Knock-in on the Mouse Brain Metabolome: Implications for Alzheimer's Disease

Pan

Green

2019

Neuroscience

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Highlights• Neuron-specific knockin of human BACE1 age-dependently affects the brain metabolome • More brain metabolites were significantly altered in 'old' PLB4 mice than 'young'• Leucine, creatinine, putrescine, various acylcarnitines and phospholipids were affected • Compared with other AD models (e.g. APP/PS1) fewer metabolites were affected • Oligomer versus plaque Aβ pathology may have divergent effects on some metabolites Abstract Beta secretase 1 (BACE1) is an enzyme involved in the pathogenesis of Alzheimer's disease (AD). PLB4 mice is a neuron-specific human BACE1 knockin mouse model characterised by the accumulation of extracellular Aβ and an AD-like phenotype. In this investigation brain hemispheres from 'young' (4-6 months) and 'old' (8 months) female PLB4 mice and age-matched wild-type littermates underwent targeted LC-MS/MS metabolomic profiling. Powdered lyophilized brain tissue was extracted in ethanol:PBS 85%:15% (v/v)) and a total of 187 metabolites were quantified using a targeted metabolomics methodology. Multivariate statistical analysis produced models that distinguished PLB4 from wild type (WT) mice regardless of their age group. Univariate analysis (t-test) found that more brain metabolites were perturbed in 'old' PLB4 mice than 'young'. Carnosine and 8 phosphatidylcholine species were significantly decreased (p<0.05) in 'young' PLB4 mouse brain. In 'old'PLB4 mice a total of 21 metabolites were perturbed including: leucine, creatinine, putrescine and species of acylcarnitines, lysophosphatidylcholines, phosphatidylcholines and sphingomyelin. Within the PLB4 genotype there were a range of age-dependent increases in metabolites. This study indicates that gender-specific responses occur in models of AD-like pathology, but importantly, when changes in PLB4 mice (where Aβ oligomers predominate) are compared with APP/PS1 mice (where Aβ plaques predominate) there are consistent and also divergent effects on the brain metabolome.

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“…Recent research using human post-mortem brain tissue has demonstrated an altered metabolic profile of L-arginine, including its downstream polyamines, in AD 6 , 8 . Experimentally, a single central administration of pre-aggregated Aβ 25–35 peptide leads to impaired behavioural performance and altered L-arginine metabolic profile in the brain, and the latter appears to be associated with the degree of cognitive impairment 29 , 40 . Moreover, there are also altered brain arginine metabolic profiles and cognitive deficits with age in rats, as part of the normal ageing process 44 , 47 , 48 , 50 , 52 , 68 – 70 .…”

Section: Discussionmentioning

confidence: 99%

“…The use of animal models has begun to reveal relationships between Aβ and arginine metabolism in the brain. For example, we have demonstrated that a single intracerebroventricular injection of Aβ 25–35 (the proposed toxic domain of Aβ) alters L-arginine metabolism in the rat prefrontal cortex and hippocampus at 8, 42 and 97 days post infusion 29 , 30 . In another model of AD, APPswe/PSEN1ΔE9 (APP/PS1) transgenic mice display progressive brain Aβ accumulation and behavioural impairments from 4 months of age, which become progressively apparent up to and beyond 12 months of age 31 – 35 .…”

Section: Introductionmentioning

confidence: 99%

Altered plasma arginine metabolome precedes behavioural and brain arginine metabolomic profile changes in the APPswe/PS1ΔE9 mouse model of Alzheimer’s disease

Bergin

Mockett

et al. 2018

Transl Psychiatry

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While amyloid-beta (Aβ) peptides play a central role in the development of Alzheimer’s disease (AD), recent evidence also implicates altered metabolism of L-arginine in the pathogenesis of AD. The present study systematically investigated how behavioural function and the brain and plasma arginine metabolic profiles changed in a chronic Aβ accumulation model using male APPswe/PS1ΔE9 transgenic (Tg) mice at 7 and 13 months of age. As compared to their wild-type (WT) littermates, Tg mice displayed age-related deficits in spatial water maze tasks and alterations in brain arginine metabolism. Interestingly, the plasma arginine metabolic profile was markedly altered in 7-month Tg mice prior to major behavioural impairment. Receiver operating characteristic curve analysis revealed that plasma putrescine and spermine significantly differentiated between Tg and WT mice. These results demonstrate the parallel development of altered brain arginine metabolism and behavioural deficits in Tg mice. The altered plasma arginine metabolic profile that preceded the behavioural and brain profile changes suggests that there may be merit in an arginine-centric set of ante-mortem biomarkers for AD.

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A single intracerebroventricular Aβ25–35 infusion leads to prolonged alterations in arginine metabolism in the rat hippocampus and prefrontal cortex

Cited by 14 publications

References 71 publications

A New Perspective on Alzheimer’s Disease as a Brain Expression of a Complex Metabolic Disorder

A New Perspective on Alzheimer’s Disease as a Brain Expression of a Complex Metabolic Disorder

Temporal Effects of Neuron-specific beta-secretase 1 (BACE1) Knock-in on the Mouse Brain Metabolome: Implications for Alzheimer's Disease

Altered plasma arginine metabolome precedes behavioural and brain arginine metabolomic profile changes in the APPswe/PS1ΔE9 mouse model of Alzheimer’s disease

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