Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease

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

33-50% of pyruvate entering astrocytic mitochondria is not used for ATP synthesis but rather for anaplerosis to replenish TCA intermediates.

“33 -50% of the pyruvate that enters astrocytic mitochondria is not used for ATP synthesis but rather anaplerosis to replenish TCA intermediates (Weber and Barros, 2015).”

• cites Weber and Barros, 2015 sourceSupported

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

Astrocytes are glucose's main consumers in the brain.

“Thus, astrocytes are glucose ' s main consumers in the brain (Bonvento and Bolanos, 2021; Weber and Barros, 2015).”

• cites Bonvento and Bolanos, 2021 sourcePartly supported

  The Concluding Remarks (page unavailable) say astrocytes are well suited to convert blood glucose into intermediates for neurons, and that glycolytic enzymes are more active in astrocytes than in neurons. But “Glucose breakdown: beyond ATP production” (page unavailable) says most glucose processed in astrocytes belongs to a particular fraction of brain glucose, not that astrocytes are the brain’s main consumers of glucose overall. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Weber and Barros, 2015 sourcePartly supported

  In “Energy Uptake, Storage, and Delivery” (page not available), the paper says astrocytes consume more glucose than neurons in cultured cells and tissue slices. That supports the comparison in those settings, but not the unqualified claim that astrocytes are the brain’s main glucose consumers. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Pyruvate is imported into mitochondria through the mitochondrial pyruvate carrier (MPC).

“Pyruvate, the end product of glycolysis, is imported into mitochondria through the mitochondrial pyruvate carrier (MPC) (Bricker et al., 2012; Herzig et al., 2012).”

• cites Bricker et al., 2012 sourceSupported
• cites Herzig et al., 2012 sourceNot checked — no full text of the source

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

Astrocyte alterations precede microglia reactivity in AD.

“In fact, based on the kinetics of appearance of reactivity markers, previous studies concluded that astrocyte alterations would precede microglia reactivity (Chun et al., 2018; Gordon et al., 2002; Tournier et al., 2020).”

• cites Chun et al., 2018 sourceSupported
• cites Gordon et al., 2002 sourceNot checked — no full text of the source
• cites Tournier et al., 2020 sourceSupported

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

A drop in brain glucose uptake is associated with cognitive decline and increased astrocyte reactivity.

“A drop in brain glucose uptake was reported to be associated with cognitive decline and increased astrocyte reactivity (Nam et al., 2021).”

• cites Nam et al., 2021 sourceSupported

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

Pharmacological inhibition of astrocytes in organotypic brain culture slices results in an increase in Aβ.

“Another study demonstrated that pharmacological inhibition of astrocytes in organotypic brain culture slices resulted in an increase in A β (Davis et al., 2021)”

• cites Davis et al., 2021 sourceSupported

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

The MPC is a heterodimer composed of two subunits MPC1 and MPC2.

“This transporter is a heterodimer composed of two subunits MPC1 and MPC2 (Tavoulari et al., 2019).”

• cites Tavoulari et al., 2019 sourcePartly supported

  The Results (Expression and purification of the yeast Mpc proteins) show that yeast Mpc1 and Mpc2 form a hetero-complex, but the paper selected Mpc1/Mpc3—not Mpc1/Mpc2—for direct determination of its dimeric state. The Discussion says the functional yeast carrier is a heterodimer and explicitly cautions that its results cannot safely establish the oligomeric state of mammalian MPCs. The unqualified claim therefore goes beyond what the paper establishes. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

Genetic inhibition of the MPC in glutamatergic neurons renders them hyperexcitable.

“Genetic inhibition of the MPC in glutamatergic neurons renders them hyperexcitable (De La Rossa et al., 2022).”

• cites De La Rossa et al., 2022 sourceSupported

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

Some TZD compounds are mild inhibitors of the mitochondrial pyruvate carrier (MPC).

“Interestingly, some of these compounds have been discovered to be mild inhibitors of the MPC (Tavoulari et al., 2022).”

• cites Tavoulari et al., 2022 sourceSupported

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

Aβ induces a decrease in glucose uptake by reducing the availability of GLUT1, which amplifies the decrease in glycolysis.

“In turn, A β , in a vicious circle, induces a decrease in glucose uptake, notably by reducing the availability of GLUT1, the plasma membrane transporter of glucose, which amplifies the decrease in glycolysis (Hendrix et al., 2021; Tarczyluk et al., 2015)”

• cites Hendrix et al., 2021 sourcePartly supported

  The Results report reduced glucose uptake in Aβ42-tg mouse brains and less GLUT1 at the plasma membrane of Aβ-treated astrocytes. The paper links impaired GLUT1 localization to reduced cerebral glucose utilization, but does not report that this amplifies a decrease in glycolysis. Page numbers are not available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Tarczyluk et al., 2015 sourcePartly supported

  The Results section (‘Glucose Uptake Is Decreased After Treatment with Amyloid Beta’; page unavailable) reports reduced glucose uptake after Aβ treatment. The Discussion suggests inhibition of glycolysis, but proposes that this leads to glucose accumulation and reduced uptake—not that reduced uptake amplifies glycolytic inhibition. Our copy does not identify reduced GLUT1 availability as the mechanism. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Pharmacological inhibition of the MPC is neuroprotective and stimulates long-term potentiation and cognition.

“pharmacological inhibition of the MPC is neuroprotective and stimulates long-term potentiation and cognition (Mansour et al., 2021; Zhong et al., 2023)”

• cites Mansour et al., 2021 sourceNot checked — no full text of the source
• cites Zhong et al., 2023 sourcePartly supported

  The Discussion reports some support for a protective effect against dementia, and the Conclusions report improved cognitive function, with PPAR-γ agonists. The paper does not establish that these effects result from pharmacological inhibition of the MPC, or report stimulation of long-term potentiation; searches for MPC inhibition and long-term potentiation found no relevant passage. Page numbers were not available in our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

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

GFAP knockout results in an increase in Aβ load, implicating GFAP as required for astrocyte activation in response to AD pathology.

“It has been demonstrated that GFAP knockout results in an increase in A β load, thereby implicating the filament protein that is required for astrocyte activation in the response to AD pathology (Kraft et al., 2013).”

• cites Kraft et al., 2013 sourcePartly supported

  The Abstract reports increased plaque load in APP/PS1 mice after deletion of both Gfap and Vim, not Gfap alone. The Discussion states that deleting either gene individually still allows astrocyte activation under pathological conditions, so the paper does not establish that GFAP alone is required for that response. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

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

Genetic or pharmacological inhibition of the MPC in the brain affects diverse brain activities.

“Genetic or pharmacological inhibition of the MPC in the brain has been shown to affect diverse brain activities (Buchanan and Taylor, 2020; Zangari et al., 2020).”

• cites Buchanan and Taylor, 2020 sourceSupported
• cites Zangari et al., 2020 sourcePartly supported

  Section 4.1 reports several effects of pharmacological MPC inhibition relevant to the brain, including neuronal protection and increased glucose uptake in affected brain regions. It does not establish comparable effects from genetic inhibition in the brain; instead, it calls for neuron- or glia-specific genetic studies to confirm the drug findings. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Pioglitazone reduces amyloid load in an ApoE and/or IDE-dependent process, neurofibrillary tangle formation, and cognitive decline in 3xTgAD mice.

“Pioglitazone, which belongs to the TZD class of compounds, has been shown to reduce the amyloid load in an ApoE and/ or IDE-dependent process, neurofibrillary tangle formation and decline in cognitive function in 3xTgAD mice (Mandrekar-Colucci et al., 2012; Mansour et al., 2021; Searcy et al., 2012; Zhong et al., 2023).”

• cites Mandrekar-Colucci et al., 2012 sourcePartly supported

  The Results sections on Aβ clearance and behavioral deficits report reduced amyloid burden and improved memory after pioglitazone treatment, but the mice studied were APP/PS1, not 3xTgAD (Materials and Methods, Animals; page unavailable). The paper demonstrates ApoE-dependent soluble Aβ degradation in cultured cells; it does not establish that the reduction in mouse amyloid burden depends on ApoE or IDE, or report reduced neurofibrillary tangle formation. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites Mansour et al., 2021 sourceNot checked — no full text of the source
• cites Searcy et al., 2012 sourcePartly supported

  The Results sections on CA1 Aβ staining and phosphorylated-tau-positive neurons report reduced Aβ staining and fewer phosphorylated-tau-positive cells after pioglitazone treatment in 3×Tg-AD mice; the Abstract reports improved learning. These findings do not directly establish reduced neurofibrillary tangle formation. The Discussion section on amyloid processing says the authors found no supporting evidence for a change in IDE expression and does not establish an ApoE- or IDE-dependent mechanism. Page numbers were not available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Glucose hypometabolism could be responsible for decreased ATP levels in the brain as observed, a drop in cognitive performances, and an upregulation of the main pathological markers in Alzheimer's disease.

“This glucose hypometabolism could be responsible for decreased ATP levels in the brain (Rossi et al., 2020) as we observed in our study, a drop in cognitive performances (El Hayek et al., 2019) and an upregulation of the main pathological markers in AD (Fu et al., 2015; Liu et al., 2004).”

• cites Rossi et al., 2020 sourcePartly supported

  The Abstract and In Brief report reduced mitochondrial ATP synthesis in Alzheimer’s disease cell models, supporting a link between impaired energy metabolism and ATP production. The Discussion says these models did not show reduced glycolysis and only speculates that reduced glucose uptake might worsen the defect in patients’ brains; it does not demonstrate that brain glucose hypometabolism caused decreased ATP levels. The cognitive-performance and pathological-marker claims are cited to other papers, not Rossi et al. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites El Hayek et al., 2019 sourcePartly supported

  The section “Lactate enhances learning and memory formation” reports that lactate-treated mice performed better on spatial learning and memory tests, supporting a link between a metabolic factor and cognitive performance. It does not test whether glucose hypometabolism causes cognitive decline. The ATP and Alzheimer’s-marker claims are attached to other citations, not El Hayek et al.; page numbers were unavailable in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Fu et al., 2015Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

Blocking astrocyte reactivity has positive effects on AD pathology.

“On the other hand, blocking astrocyte reactivity has demonstrated positive effects on pathology (Ceyzeriat et al., 2018; Reichenbach et al., 2019).”

• cites Ceyzeriat et al., 2018 sourceSupported
• cites Reichenbach et al., 2019 sourceSupported

May combine two claims.

The number of double-strand breaks was higher in 3xTgAD (p<0.001) and 3xTgAD.MPC1 GFAP (p<0.01) mice compared to WT mice.

“The number of double-strand breaks was higher in 3xTgAD ( p &lt; 0.001) and 3xTgAD.MPC1 GFAP (p &lt; 0.01) mice in comparison to WT mice”

May combine two claims.

Mice with MPC inhibition express less GFAP and less Aβ.

“Our results indicate that mice with an MPC inhibition express less GFAP but also less A β”

May combine two claims.

ATP synthesis capacity was reduced in 3xTgAD mice (p<0.05) but not in 3xTgAD.MPC1 GFAP mice.

“A reduction in ATP synthesis capacity was observed in 3xTgAD mice (Fig. 7 A, p &lt; 0.05) but not in 3xTgAD.MPC1 GFAP mice”

May combine two claims.

Only a slight decrease of sAPPβ in the guanidine-soluble fraction was observed, without a shift in favor of the non-amyloidogenic pathway.

“as only a slight decrease of sAPP β in the Gua-soluble fraction was observed without a shift in favor of the non-amyloidogenic pathway”

May combine two claims.

GFAP signal intensity was significantly increased in 3xTgAD mice and normalized in 3xTgAD.MPC1 GFAP mice (p<0.05 vs 3xTgAD and p>0.05 vs WT).

“the GFAP signal intensity was significantly increased in 3xTgAD mice (Fig. 6 I-L) and this effect was normalized in 3xTgAD.MPC1 GFAP mice (p &lt; 0.05 vs 3xTgAD and p &gt; 0.05 vs WT, one-way ANOVA: F 2,9 = 8.96; p = 0.0072).”

May combine two claims.

MPC1 is no longer expressed in astrocytes in the KO model compared to WT, whereas it is clearly visible in neurons.

“MPC1 is no longer expressed in astrocytes in the KO model as compared to WT, whereas it is clearly visible in neurons.”

Classified as probably not a substantial claim. May combine two claims.

In astrocytes, about 60% of pyruvate is converted into lactate by lactate dehydrogenase, which restricts the amount of pyruvate oxidized within mitochondria.

“in astrocytes, ~60% pyruvate is converted into lactate by the lactate dehydrogenase, which restricts the amount of pyruvate oxidized within mitochondria (Iglesias et al., 2017).”

• cites Iglesias et al., 2017 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Intracellular Aβ has previously been associated with cognitive decline.

“However, intracellular A β has previously been associated with cognitive decline (Billings et al., 2005)”

• cites Billings et al., 2005 sourceNot checked — no full text of the source

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

Blocking glycolysis amplifies the effects of Aβ on human astrocytes in terms of GFAP reactivity, Aβ accumulation and apoptosis.

“Blocking glycolysis amplifies the effects of A β on human astrocytes in terms of GFAP reactivity, A β accumulation and apoptosis (Fu et al., 2015).”

• cites Fu et al., 2015Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

All experimental procedures were approved by the Ethics Committee for Animal Experimentation of the Canton of Geneva, Switzerland.

“All experimental procedures were approved by the Ethics Committee for Animal Experimentation of the Canton of Geneva, Switzerland.”

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

Inhibition of the MPC in GFAP-expressing cells stimulates neurogenesis in the dentate gyrus.

“Recently, inhibition of the MPC in GFAP-expressing cells specifically was reported to stimulate neurogenesis in the dentate gyrus (Petrelli et al., 2023a).”

• cites Petrelli et al., 2023aNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

tdTomato-GFAP expressing cells include astrocytes throughout the brain and radial glial cells in the SVZ and dentate gyrus.

“tdTomato-GFAP expressing cells include astrocytes (all brain) and radial glial cells in the SVZ and dentate gyrus.”

Classified as probably not a substantial claim.

The hippocampus of 3xTgAD mice displays hypometabolism.

“The hippocampus of 3xTgAD mice also displays this hypometabolism (Le Douce et al., 2020).”

• cites Le Douce et al., 2020Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

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

In the 3xTgAD model, there is reduced glucose uptake by reactive astrocytes, which leads to a decrease in lactate release.

“In 3xTgAD model, there is a reduced glucose uptake by reactive astrocytes, which leads to a decrease in lactate release.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The absence of amyloid and phospho-Tau in WT animals was previously validated.

“The absence of amyloid and phospho-Tau in WT animals was previously validated (data not shown).”

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

The lack of cognitive and neurodegenerative measures in our study could limit the clinical interpretations of our findings.

“In addition, the lack of cognitive and neurodegenerative measures in our study could limit the clinical interpretations of our findings”

May combine two claims.

In 3xTgAD.MPC1 GFAP mice, there is a reduction in amyloid and Tau deposition as well as an increase in amyloid phagocytosis by astrocytes.

“we observed a reduction in amyloid and Tau deposition as well as an increase in amyloid phagocytosis by astrocytes.”

• AssumptionThe authors state this as an assumption: Increased Aβ phagocytosis by astrocytes in vitro can explain the reduced amyloid deposits in MPC1-deficient mice in vivo.

May combine two claims.

MPC inhibition reduces both astrocytic cell reactivity and the drop in overall ATP levels.

“In addition, MPC inhibition reduces both astrocytic cell reactivity and drop in overall ATP levels.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based). May combine two claims.

The use of very early therapies could cut this chain of events and have positive effects on the progression of AD.

“Thus, the use of very early therapies could cut this chain of events and have positive effects on the progression of AD.”

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

All analyses were performed by experimenters blind to the genotype.

“All analyses were performed by experimenters blind to the genotype.”

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

It was not possible to directly measure lactate in our studies.

“Unfortunately, it was not possible to directly measure lactate in our studies”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

In physiological conditions, astrocytes take up glucose from the blood, convert it to pyruvate, some of which is internalized by mitochondria through the MPC dimer, but most of which is converted to lactate for neuron consumption.

“In physiological conditions, astrocytes uptake glucose from the blood, convert it to pyruvate, some of it is internalized by the mitochondria through the MPC dimer but most of it is converted to lactate for neuron consumption.”

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

This may indicate a better cognitive maintenance in mice lacking astrocytic MPC activity.

“which may indicate a better cognitive maintenance in mice lacking astrocytic MPC activity.”

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

Thiazolidinediones tested in AD patients reestablish glucose regulation, reduce inflammation and Aβ peptide accumulation, and increase cerebral blood flow.

“Recently the insulin sensitizers thiazolidinediones (TZD), primarily developed to treat diabetes, have been tested in AD patients and reported to reestablish glucose regulation but also reduce inflammation and A β peptide accumulation as well as increase cerebral blood flow (Sato et al., 2011).”

• cites Sato et al., 2011 sourceNot checked — no full text of the source

May combine two claims.

3xTgAD mice exhibit both amyloid and phospho-Tau accumulation.

“3xTgAD mice, a well-described AD model exhibiting both amyloid and phospho-Tau accumulation (Oddo et al., 2003b)”

• cites Oddo et al., 2003bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

Inhibition of astrocytic MPC could also be relevant to other degenerative neuropathologies where hypometabolism is observed.

“and could also be relevant to other degenerative neuropathologies where hypometabolism is observed.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

It has been widely demonstrated in Alzheimer's disease that glycolysis is downregulated and that this change precedes cognitive dysfunction by decades.

“It has been widely demonstrated in AD that glycolysis is downregulated and that this change precedes cognitive dysfunction by decades.”