CoChat
Sign Up
Cited by 180Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchAmino Acid Enzymes and Metabolism

Alzheimer’s disease: Targeting the glutamatergic system

Open access
Conway, Myra E.·2020·Biogerontology
DOI 10.1007/s10522-020-09860-4PMC PMC7196085
Open this paper in CoChat — free accountOpen PDF

Abstract

Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that causes a progressive decline in memory, language and problem solving. For decades mechanism-based therapies have primarily focused on amyloid β (Aβ) processing and pathways that govern neurofibrillary tangle generation. With the potential exception to Aducanumab, a monotherapy to target Aβ, clinical trials in these areas have been challenging and have failed to demonstrate efficacy. Currently, the prescribed therapies for AD are those that target the cholinesterase and glutamatergic systems that can moderately reduce cognitive decline, dependent on the individual. In the brain, over 40% of neuronal synapses are glutamatergic, where the glutamate level is tightly regulated through metabolite exchange in neuronal, astrocytic and endothelial cells. In AD brain, Aβ can interrupt effective glutamate uptake by astrocytes, which evokes a cascade of events that leads to neuronal swelling, destruction of membrane integrity and ultimately cell death. Much work has focussed on the post-synaptic response with little insight into how glutamate is regulated more broadly in the brain and the influence of anaplerotic pathways that finely tune these mechanisms. The role of blood branched chain amino acids (BCAA) in regulating neurotransmitter profiles under disease conditions also warrant discussion. Here, we review the importance of the branched chain aminotransferase proteins in regulating brain glutamate and the potential consequence of dysregulated metabolism in the context of BCAA or glutamate accumulation. We explore how the reported benefits of BCAA supplementation or restriction in improving cognitive function in other neurological diseases may have potential application in AD. Given that memantine, the glutamate receptor agonist, shows clinical relevance it is now timely to research related pathways, an understanding of which could identify novel approaches to treatment of AD.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that dysregulated brain glutamate handling—especially failed astrocytic glutamate uptake and altered branched-chain amino acid (BCAA)/branched-chain aminotransferase (BCAT) metabolism—contributes to Alzheimer’s disease (AD) excitotoxicity and cognitive decline. It highlights BCAT and glutamate as candidate biomarkers/targets and suggests BCAA supplementation or restriction may merit study in AD, though current evidence is largely indirect.

Key findings

  • Over 40% of neuronal synapses are glutamatergic; synaptic cleft glutamate is about 0.6 μM at rest and rises to 10 μM during excitation. In AD, Aβ interrupts astrocytic glutamate uptake, evoking neuronal swelling, membrane damage, and cell death; in vitro, toxic glutamate left Ca²⁺ elevated for about 1 h and 84% of neurons died over 24 h.
  • ¹H MRS studies show lower glutamate/glutamine (Glx) in the posterior cingulate cortex in AD, reduced NAA in posterior cingulate and bilateral hippocampus (p < 0.005), decreased NAA/Cr and increased mI/Cr ratios, and reduced GABA/Glx/NAA in amnestic MCI correlated with CERAD word-learning performance.
  • Human BCATc is neuron-specific, strongest in parietal cortex, with hippocampal CA3 staining more intense than CA1; AD brain shows regional increases in BCATc in hippocampus CA1/CA4 and more widespread BCATm increases in frontal and temporal regions, also reported in dementia with Lewy bodies and vascular dementia. Serum BCAT was higher in AD than age-matched controls, and a combined BCAT/glutamate/MoCA model distinguished control from AD with sensitivity 1.00 and specificity 0.978.
  • Tracing studies indicate about 30% of the nitrogen in glutamate/glutamine derives from leucine alone; BCAT2 mutations cause mild cognitive impairment and brain lesions, MSUD involves toxic BCAA/BCKA accumulation, and TBI is associated with decreased plasma BCAAs with BCAA supplementation improving cognition in some cases. In SH-SY5Y cells, leucine reduced BCATc-induced autophagy and Aβ accumulation.

Methods

  • Narrative review; no systematic review protocol, meta-analysis, or primary experimental design is stated. It synthesizes published literature and the authors’ prior human, animal, and in vitro work.
  • Evidence discussed includes human post-mortem brain immunohistochemistry, serum biomarker/cognitive/MRI studies, ¹H MRS studies, rodent and in vitro models, and genetic disorder case reports.
  • Main analysis is qualitative synthesis linking BCAT/BCAA metabolism to brain glutamate regulation, excitotoxicity, and AD pathology, with proposed mechanistic models.

Limitations

  • Paper-stated: the serum BCAT/glutamate biomarker study was limited by its timeframe, and a longitudinal study is needed to define utility as biomarkers. Further studies are required to determine the impact of increased BCAT levels in AD brain.
  • Paper-stated: mechanisms underlying brain damage in patients with BCAT2 mutations are not well established; few studies report Aβ aggregates measured by PET and their association with ¹H MRS; debate exists about the actual synaptic glutamate concentration.
  • Evident: as a narrative review, it lacks systematic search/quality appraisal and new primary data; many mechanistic claims rely on cited models and the authors’ own prior studies, so the causal role of BCAT changes in AD remains proposed rather than established.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s10522-020-09860-4

Cites

142 of 142 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 68 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    A more widespread increase in the level of BCATm was reported throughout the frontal and temporal regions of AD brain.

    “A more widespread increase in the level of BCATm was also reported that extended throughout the frontal and temporal regions of AD brain.”
    Quote in the paperNot a substantial claim
  • Findingcitation

    Serum BCAT was higher in AD individuals relative to healthy age-matched controls.

    “More recently, we reported that serum BCAT was also higher in AD individuals relative to healthy age-matched controls (Hudd et al. 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hudd et al. 2019 source

      Not checked in the free run.

  • Findingcitation

    Our group found a regional increase in BCATc in the hippocampus, specifically the CA1 and CA4 region, in AD brain.

    “Our focus was on the main regions of the brain affected by AD pathology where we found a regional increase in BCATc in the hippocampus (Hull et al. 2015a, b), specifically the CA1 and CA4 region, the area first targeted by AD pathology (Fig. 5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hull et al. 2015a, b

      Not checked in the free run.

  • Findingown data

    BCATc-mediated autophagy is regulated through PKC-mediated phosphorylation, modulated by the redox state of BCATc.

    “Here, BCATc-mediated autophagy was shown to be regulated through PKC-mediated phosphorylation, modulated by the redox state of BCATc.”
    Quote in the paperSubstantial claim
  • Findingown data

    In the SH-SY5Y cell model, overexpression of BCATc (as observed in AD brain) resulted in Aβ accumulation through an increase in autophagosome synthesis.

    “Using the SH-SY5Y cell model, we showed that overexpression of BCATc, as observed in AD brain, resulted in Aβ accumulation through an increase in autophagosome synthesis.”
    Quote in the paperSubstantial claim
  • May combine two claims. 38
  • Classified as probably not a substantial claim. 10

  • May combine two claims.

    Findingcitation

    In human brain, BCATc was found in all brain regions and was neuron-specific, with strongest labelling in the parietal cortex.

    “Our group subsequently mapped BCATc to the human brain, where it was found in all brain regions and consistent with the rat model was neuron-specific, with strongest labelling reported in the parietal cortex (Hull et al. 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hull et al. 2012

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Wherever BCATc staining occurred, BCATm was absent and vice versa.

    “What was clear was that wherever BCATc staining occurred BCATm was absent and vice versa (Fig. 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The model showed that BCAT and glutamate accurately distinguish between control and AD participants and, in combination with the Montreal Cognitive Assessment, improved overall sensitivity to 1.00 and specificity to 0.978.

    “Our model showed that BCAT and glutamate accurately distinguish between control and AD participants and in combination with the neurophysiological test Montreal Cognitive Assessment, improved the overall sensitivity to 1.00 and specificity to 0.978.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    The hippocampus showed intense immunoreactivity for BCATc of pyramidal cells (approximately 70% of neuronal cells) in the pyramidal cell layer, with moderate BCATc staining in the cell bodies of interneurons.

    “The hippocampus showed intense immunoreactivity for BCATc of pyramidal cells (approximately 70% of neuronal cells) in the pyramidal cell layer, with moderate BCATc staining in the cell bodies of interneurons (GABAergic or glycine).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    BCATm immunopositive staining was vessel and capillary in nature, evident in all major anatomical regions of the brain assessed except the parietal lobe and medulla.

    “Immunopositive staining for BCATm was vessel and capillary in nature. This staining was evident in all major anatomical regions of the brain assessed with the exception of the parietal lobe and medulla.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Leucine significantly reduced BCATc-induced autophagy and consequently Aβ.

    “Importantly, leucine, a key regulator of autophagic flux, significantly reduced BCATc-induced autophagy and consequently Aβ.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    BCAT moonlighting functions are fundamental in regulating autophagy and play a fundamental role in regulating Aβ.

    “Our most recent study offers evidence that these ‘moonlighting’ functions are fundamental in regulating autophagy and play a fundamental role in regulating Aβ (Harris et al. 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Harris et al. 2020

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Currently prescribed AD treatments offer only modest and temporary improvement, indicating that the heterogeneity of the disease calls for a stratified approach for effective treatment.

    “Whilst these treatments offer some reprive to symptoms, the improvement is modest and temporary, indicating that like Aβ targeted approaches, the heterogenity of the disease calls for a stratified approach for effective treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Oxidation inhibits the redox switch, inactivates BCAT, and destabilises the metabolic complexes.

    “This is inhibited through oxidation that not only inactivates BCAT but also destabilises the metabolic complexes (Islam et al. 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Islam et al. 2010

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The canonical role of the BCAT proteins is the transamination of the BCAAs leucine, isoleucine and valine with α-keto glutarate to form Glu and their respective branched chain α-keto acids (BCKA), regenerating the pyridoxal phosphate (PLP) form of the enzyme.

    “The canonical role of the BCAT proteins is the transamination of the BCAAs, leucine, isoleucine and valine with α-keto glutarate to form Glu and their respective branched chain α-keto acids (BCKA) (α-ketoisocaproate (KIC), α-keto-β-methylvalerate (KMV) and α-ketoisovalerate (KIV)) regenerating the pyridoxal phosphate (PLP) form of the enzyme (Ichihara and Koyama 1966) (Fig. 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ichihara and Koyama 1966

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In AD brain, Aβ can interrupt effective glutamate uptake by astrocytes, which evokes a cascade of events that leads to neuronal swelling, destruction of membrane integrity and ultimately cell death.

    “In AD brain, Aβ can interrupt effective glutamate uptake by astrocytes, which evokes a cascade of events that leads to neuronal swelling, destruction of membrane integrity and ultimately cell death.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Huang et al. 2018

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pathological accumulation of Glu results in this amino acid becoming a potent neurotoxin, in part by overstimulating the post-synaptic response and causing an increase in calcium entry into neurons.

    “Whilst an important neurotransmitter, pathological accumulation of Glu results in this amino acid becoming a potent neurotoxin (Choi et al. 1987; Mattson and Chan 2003). This is in part due to the time-related exposure, overstimulating the post synaptic response causing an increase in the entry of calcium into neurons (Sattler and Tymianski 2000; Mattson and Chan 2003).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Choi et al. 1987

      Not checked in the free run.

    • cites Mattson and Chan 2003

      Not checked in the free run.

    • cites Sattler and Tymianski 2000

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The intensity of BCATc labelling in both cell bodies and dendrites was most pronounced in the hippocampus, a region susceptible to excitotoxic neuronal injury at an early stage of AD, highlighting that a sustained increase in BCATc may contribute to injury.

    “Importantly, the immunohistochemistry data, showed that the intensity of BCATc labelling in both cell bodies and dendrites was most pronounced in the hippocampus, a region that is known to be particularly susceptible to excitotoxic neuronal injury at an early stage of AD, highlighting that sustained increase in BCATc may contribute to injury.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The authors propose that if transamination in the direction of Glu synthesis persists, it could exacerbate toxicity and contribute to neuronal degeneration.

    “We assigned a neuroprotective role to BCATc but proposed that should transamination in the direction of Glu synthesis persist it could exacerbate toxicity contributing to neuronal degeneration (Fig. 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Uptake of Glu from the blood is minimal, but precursors to its synthesis such as the BCAAs are easily taken up, in particular leucine.

    “The regulation of brain Glu is important as uptake from the blood is minimal, however, precursors to its synthesis such as the BCAAs are easily taken up, in particular leucine (Oldendorf et al. 1977; Smith et al. 1987).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Oldendorf et al. 1977

      Not checked in the free run.

    • cites Smith et al. 1987

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    A limitation of the study was the timeframe; a longitudinal study would better define the utility of BCAT and glutamate as biomarkers.

    “However, a limitation to this study was the timeframe, where a longitudinal study would better define the utility of BCAT and glutamate as biomarkers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    BCAT is a redox-sensitive protein subject to oxidation, S-nitrosylation, and S-glutathionylation.

    “Although the canonical role for BCAT has traditionally been associated with transamination and glutamate regulation, it is important to note that it is also a redox-sensitive protein subject to oxidation (Conway et al. 2002), S-nitrosylation (Conway et al. 2004) and S-glutathionylation (Conway et al. 2008).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Conway et al. 2002

      Not checked in the free run.

    • cites Conway et al. 2004

      Not checked in the free run.

    • cites Conway et al. 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The glutamate/glutamine cycle is not 100% effective; during its transition some Glu is lost in astrocytes through metabolism, generating lactate or in the production of purines and glutathione.

    “Whilst the glutamate/glutamine cycle is an efficient method to regenerate Glu, this recycling is not 100% effective. During its transition some Glu is ‘lost’ in astrocytes through metabolism, generating lactate (Sonnelwald et al. 1993), or in the production of purines and glutathione (Shank et al. 1985).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Sonnelwald et al. 1993

      Not checked in the free run.

    • cites Shank et al. 1985

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Regulation of brain Glu is primarily governed through the Glu/glutamine cycle, where excess Glu remaining after excitation is taken up by astrocytes.

    “Regulation of brain Glu is thought to be primarily governed through the Glu/glutamine cycle, where excess Glu remaining after excitation is taken up by astrocytes (Fig. 2) (reviewed in Conway and Hutson 2016; Yudkoff 2017).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Conway and Hutson 2016

      Not checked in the free run.

    • cites Yudkoff 2017

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Glutamatergic neurotransmission decreases with age but is further perturbed in individuals with aMCI and AD, and correlates with cognitive measures.

    “Together, 1H MRS studies confirm that glutamatergic neurotransmission decreases as we age but is further perturbed in individuals with aMCI and AD, respectively and correlates with cognitive measures.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Wang et al. 2015a, b

      Not checked in the free run.

    • cites Antuono et al. 2001

      Not checked in the free run.

    • cites Riese et al. 2015

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment using memantine has improved cognition, behaviour and global function, but the degree of efficacy remains to be fully determined.

    “Treatment using memantine has improved cognition, behaviour, global function but the degree of efficacy remains to be fully determined (Kishi et al. 2017; Matsunga et al. 2015).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kishi et al. 2017

      Not checked in the free run.

    • cites Matsunga et al. 2015

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The authors propose that increased levels of endothelial BCATm would serve in a neuroprotective capacity.

    “Similar to BCATc, we propose that increased levels of endothelial BCATm would serve in a neuroprotective capacity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    BCAA regulate brain Glu and can impact associated cognitive function.

    “Collectively, these results support a role for BCAA in regulating brain Glu and can impact associated cognitive function.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: BCAA are important nutrient signals in regulating brain Glu.

  • May combine two claims.

    Premisecitation

    Following TBI, there is a combined metabolic response including Glu toxicity, secondary brain oedema, and increased cranial pressure.

    “Following TBI, there is combined metabolic response including Glu toxicity, secondary brain oedema and increased cranial pressure (Vuille-Dit-bille et al. 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Vuille-Dit-bille et al. 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    c.509G>A (p.Arg170Gln) was found in the patient's father, and c.790G>A (p.Glu264Lys) was found in his mother.

    “Interestingly, c.509G> A (p.Arg170Gln) was found in his father while c.790G>A (p.Glu264Lys) was found in his mother.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wang et al. 2015a, b

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    BCAA and aromatic amino acids are important sources of neurotransmitter synthesis.

    “As discussed the BCAA and aromatic amino acids are important sources of neurotransmitter synthesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sequencing analysis revealed two heterozygous mutations: c.509G>A (p.Arg170Gln) and c.790G>A (p.Glu264Lys).

    “Sequencing analysis revealed two heterogeneous mutations including: c.509G> A (p.Arg170Gln) and c.790G>A (p.Glu264Lys).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wang et al. 2015a, b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A 22-year-old male presented with MCI lasting longer than 6 years, headaches, and a blood profile of hypervalinaemia, hyperleucinemia, and isoleucinemia, aligned with a diagnosis of MSUD.

    “Wang et al. (2015a, b) first reported a case of a 22 year-old male who presented with MCI, lasting longer than 6 years, headaches and a striking blood profile of hypervalinaemia, hyperleucinemia and isoleucinemia, which aligned with a diagnosis of MSUD (Wang et al. 2015a, b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wang et al. 2015a, b

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The mechanisms underlying brain damage in these patients are not well established but are most likely related to increased BCAA levels similar to MSUD.

    “The mechanisms underlying the brain damage observed in these patients are not well established but will most likely be related to the increased BCAA levels similar to that reported for MSUD (Yudkoff 1997; Barschak et al. 2009; Funchal et al. 2006; Sgaravatti et al. 2003).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Yudkoff 1997 source

      Not checked in the free run.

    • cites Barschak et al. 2009

      Not checked in the free run.

    • cites Funchal et al. 2006

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    In this case, MSUD-linked mutations were not indicated and the patient did not present with the classical maple syrup urine smell.

    “Mutations linked with MSUD were not indicated nor did the patient present with the classical smell of maple syrup from his urine.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In untreated MSUD, infants present with neurological dysfunction, seizures, and infant death.

    “In untreated cases, infants present with symptoms including neurological dysfunction, seizures and infant death (Chuang et al. 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chuang et al. 2006

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Excitotoxicity plays a role in AD pathology, underpinned by the approval of memantine to treat moderate to severe confusion related to AD.

    “Clinically, a role for excitotoxicity in AD pathology is underpinned by the approval of memantine to treat moderate to severe confusion related to AD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Memantine does not cure AD but can improve memory, awareness, and the ability to carry out day-to-day activities.
    • Rests on an assumption: Memantine only targets the NMDA receptor; it reduces excitotoxicity but does not address other aspects of brain glutamate regulation.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MSUD is clinically characterised by an accumulation of BCAAs and their respective α-keto-acid derivatives that are severely toxic to cells.

    “The autosomal recessive congenital disease, MSUD, is clinically characterised by an accumulation of both BCAAs and their respective α-keto-acid derivatives that are severely toxic to cells (Dancis et al. 1960; Menkes 1959).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Dancis et al. 1960

      Not checked in the free run.

    • cites Menkes 1959

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After TBI, plasma BCAAs significantly decrease, whereas aromatic amino acids (phenylalanine, tryptophan, tyrosine) increase.

    “Interestingly, studies have reported a significant decrease in the plasma BCAAs, whereas the aromatic amino acids (phenylalanine, tryptophan and tyrosine) were increased (Vuille-Dit-bille et al. 2012; Jeter et al. 2013).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Vuille-Dit-bille et al. 2012

      Not checked in the free run.

    • cites Jeter et al. 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In MSUD, leucine concentrations are usually the highest among the increased BCAAs, but in this case valine was the highest.

    “Whilst leucine concentrations are usually the highest among the BCAA that are increased in MSUD, valine was shown to be the highest in this case.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wang et al. 2015a, b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In patients with TBI, BCAA supplementation improved cognition and in some cases improved recovery from a vegetative or minimally conscious state.

    “In patients with TBI, it was demonstrated that supplementation with BCAA improved cognition and has in some cases improved recovery from a vegetative or minimally conscious state (Aquilani et al. 2008a, 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Aquilani et al. 2008a, 2008

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Decreased transamination would impact Glu regeneration, potentially explaining the MCI presentation.

    “Decreased transamination would also impact Glu regeneration potentially explaining the MCI presentation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Treatment through vitamin B supplementation (BCAT2), BCAA restriction (MSUD), or supplementation (TBI) has improved cognitive outcome.

    “Treatment through Vitamin B supplementation (BCAT2), BCAA restriction (MSUD), or supplementation (TBI) has improved cognitive outcome.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Patients with these BCAT2 mutations had raised plasma BCAA with wide-ranging cognitive challenges.

    “The authors reported similar biochemical profiles i.e. raised plasma BCAA with wide-ranging cognitive challenges.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Knerr et al. 2019

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Mutations in BCAT2 and the BCKD complex result in blood profiles showing BCAAs or BCAA and α-keto acids accumulation, respectively.

    “Moreover, mutations in key metabolic enzymes specific to BCAA metabolism, such as BCAT2 and the BCKD complex, result in blood profiles that show BCAAs or BCAA and α-keto acids accumulation, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    If BCAA levels decrease, uptake of aromatic amino acids exceeds that of BCAAs, increasing the synthesis of serotonin and dopamine.

    “Should the levels of the BCAA decrease then uptake of the aromatic amino acids would exceed that of BCAAs, increasing the synthesis of serotonin and dopamine (Fernstrom and Fernstrom 2007; Scarna et al. 2005).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Fernstrom and Fernstrom 2007 source

      Not checked in the free run.

    • cites Scarna et al. 2005

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These patients had low-normal BCKAs, undetectable l-allo-isoleucine, and absence of acute encephalopathy even with exceptionally high BCAA levels.

    “Other distinguishable features from MSUD such as low‐normal BCKAs with undetectable l‐allo‐isoleucine and absence of acute encephalopathy even with exceptionally high BCAA levels were evident.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Knerr et al. 2019

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Five classifications of MSUD have been identified based on residual BCKD activity, age of onset, and serum leucine concentration.

    “Five classifications of MSUD have been identified (varying from severe classic forms to mild variant types with an additional thiamine responsive form) based on the residual BCKD activity, the age of onset and the concentration of leucine in serum (Chuang and Chuang 2000).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chuang and Chuang 2000

      Not checked in the free run.

43 of 43

  • The paper relies on this without support.

    There is little insight into how glutamate is regulated more broadly in the brain and the influence of anaplerotic pathways.

    “Much work has focussed on the post-synaptic response with little insight into how glutamate is regulated more broadly in the brain and the influence of anaplerotic pathways that finely tune these mechanisms.”

  • The paper relies on this without support.

    The number of plaques generated does not always reflect disease severity.

    “Whilst defective amyloid precursor protein (APP) processing and Aβ aggregation more than likely contribute to AD pathology the number of plaques generated do not always reflect disease severity, indicating that other factors, such as genetics and environmental cues, have a role in disease progression.”

  • The paper relies on this without support.

    Confirmation of AD can only be given at autopsy when morphological and histological examinations have been validated.

    “Confirmation of AD can only be given at autopsy when morphological and histological examinations have been validated.”

  • The paper relies on this without support.

    The aetiology of AD is not well understood.

    “The aetiology of AD is not well understood, but is often characterised as early-onset familial AD (less than 65 years of age) and late onset AD (greater than 65 years of age) (Tellechea et al. 2018; Wattmo and Wallin 2017).”

  • The paper relies on this without support.

    The redox switch is unique to these aminotransferases.

    “This redox switch is unique to these aminotransferases and has been shown to be important in regulating metabolite shuttling between the BCKD complex and GDH (Islam et al. 2007).”

  • The paper relies on this without support.

    Neuronal damage due to prolonged high brain BCAA concentrations was reported using MRS imaging.

    “Neuronal damage due to prolonged high brain BCAA concentrations was reported using MRS imaging.”

  • The paper relies on this without support.

    BCAAs and aromatic amino acids utilise the same transporters to access the brain.

    “The BCAAs and aromatic amino acids utilise the same transporters to access the brain.”

  • The paper relies on this without support.

    BCAA are important nutrient signals in regulating brain Glu.

    “As the BCAA are important nutrient signals in regulating brain Glu, a decrease would signal a reduction in brain repair and dysregulation of glutamate metabolism.”

  • The paper relies on this without support.

    Memantine does not cure AD but can improve memory, awareness, and the ability to carry out day-to-day activities.

    “Although it does not cure AD it can improve memory, awareness and the ability to carry out day-to-day activities.”

  • The paper relies on this without support.

    Memantine only targets the NMDA receptor; it reduces excitotoxicity but does not address other aspects of brain glutamate regulation.

    “However, this medication only targets the NMDA receptor, which although reduces excitotoxicity, it does not address other aspects of brain glutamate regulation.”

  • The paper relies on this without support.

    Excess or limiting dietary BCAAs cause neurological dysfunction, reducing cognitive function.

    “Excess or limiting dietary BCAAs cause neurological dysfunction, reducing cognitive function.”
11 of 11

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The glutamatergic hypothesis posits that dysregulation of glutamate plays a critical role in the pathogenesis of AD.

    “The glutamatergic hypothesis posits that dysregulation of glutamate, the main excitatory neurotransmitter in the central nervous system, plays a critical role in the pathogenesis of AD.”

    From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [10]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Memantine is called both an agonist and an antagonist

    Minor

    The abstract calls memantine a glutamate receptor agonist, while Table 1 identifies it as an NMDA receptor antagonist. These describe opposite actions at the receptor.

  • Figure 3 conflicts with the stated product of glutamate dehydrogenase

    Minor

    The Figure 3 caption says glutamate dehydrogenase generates glutamine. The main text instead says that enzyme converts glutamate to α-KG and NH4+, and attributes glutamine production to glutamine synthetase.

  • Memantine treatment stage differs between the table and conclusion

    Minor

    Table 1 lists memantine alone for mild AD, whereas the conclusion describes its approval for moderate to severe confusion related to AD.

  • BCATm staining is both excluded from and depicted in the medulla

    Minor

    The text identifies the medulla as an exception to observed BCATm staining, but Figure 4 is labelled as medulla BCATm staining and describes vessel staining there.

4 of 4

Cites

Flagged first, then by citations

2 of the 144 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Conway, M. E.
Affiliations
University of the West of England (GB)
Corresponding author
Conway, Myra E.
ORCID
Conway, Myra E.
Venue
Biogerontology
Publisher
Springer Science and Business Media LLC
Published
2020-02-11
Volume
21
Issue
3
Pages
257-274
ISSN
  • 1389-5729 (ISSN-L)
  • 1573-6768
DOI
10.1007/s10522-020-09860-4
PMC
PMC7196085
OpenAlex
W3006557860
Semantic Scholar
2de59f037abfd087bc036e020b3a584e8c7402c4
Cited by
180
References
144
Citations by year
2026: 18 · 2025: 28 · 2024: 37 · 2023: 24 · 2022: 41 · 2021: 22 · 2020: 9 · 2019: 1
FWCI
3.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Biogerontology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords
Alzheimer's disease, glutamatergic system, glutamate metabolism, amyloid-beta, astrocytes, glutamate uptake, anaplerotic pathway, branched-chain amino acids, branched-chain amino acid aminotransferase, BCAA supplementation, memantine, glutamate receptor agonists, neurodegeneration, cognitive decline
MeSH terms
Alzheimer Disease, Astrocytes, Humans, Amyloid beta-Peptides, Neurodegenerative Diseases, Endothelial Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review