APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice

May combine two claims.

During epileptic seizures, the lactate concentration rises whereas the pyruvate concentration falls via LDH, resulting in decreased use of pyruvate in TCA cycle and oxidative phosphorylation.

“During epileptic seizures, the lactate concentration rises whereas the pyruvate concentration falls via LDH, resulting in decreased use of pyruvate in TCA cycle and oxidative phosphorylation (McDonald et al., 2018).”

• cites McDonald et al., 2018 sourceDisputed

  The “Changes in Glucose Transport and Glycolysis Between and After Seizures” section supports elevated lactate during seizures, but says that the cellular pyruvate pool increases, driving LDH to convert pyruvate to lactate—not that pyruvate concentration falls. The paper also suggests reduced pyruvate entry into the TCA cycle, but does not present it as a consequence of falling pyruvate concentration. Page numbers were not supplied in our copy. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

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

APOE4 is associated with age-dependent impairments in cerebral glucose metabolism independent of Aβ accumulation and reduces ATP production in mouse prefrontal cortex.

“APOE4 is associated with age-dependent impairments in cerebral glucose metabolism independent of Aβ accumulation (Jagust et al., 2012) and reduces ATP production in mouse prefrontal cortex (Fang et al., 2021).”

• cites Jagust et al., 2012 sourcePartly supported

  The Discussion (page unavailable) reports that APOE4 was associated with lower cerebral glucose metabolism in older adults after accounting for age, and that fibrillar Aβ did not explain the association. It does not establish an age-dependent APOE4 effect or independence from all forms of Aβ; the authors say soluble Aβ cannot be definitively excluded. The mouse ATP-production claim is attributed to Fang et al., not to this source. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Fang et al., 2021 sourcePartly supported

  The Results section on ATP supplementation reports lower prefrontal-cortex ATP concentrations in 18-month-old apoE4 mice and in 8-month-old apoE4 mice after stress, compared with age-matched apoE3 mice. This supports an ATP decline under those conditions, but the paper measures ATP levels rather than ATP production directly. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Seizures are a prevalent feature in Alzheimer's disease patients, with 10-22% displaying unprovoked seizures and 22-54% showing subclinical epileptic activity.

“seizures have emerged as a prevalent feature in AD patients, with 10-22% displaying unprovoked seizures and 22-54% showing subclinical epileptic activity (Vossel et al., 2017).”

• cites Vossel et al., 2017 sourcePartly supported

  The “Risk of seizures in Alzheimer’s disease” section reports unprovoked seizures in 10–22% of patients. The “Subclinical and interictal epileptiform activity” section reports varying estimates, including 42% in one monitored cohort, but does not give the claimed 22–54% range. Page numbers were not available in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

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

APOE4 increases pTau levels and promotes tau pathology in mice.

“APOE4 also increases pTau levels and promotes tau pathology in mice (Shi et al., 2017).”

• cites Shi et al., 2017 sourceSupported

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

The kainic acid model of status epilepticus preferentially arises from the hippocampus.

“Using a kainic acid (KA) model of status epilepticus (SE), which preferentially arises from the hippocampus (Rusina et al., 2021)”

• cites Rusina et al., 2021 sourcePartly supported

  The Administration Routes > Intrahippocampal and intra-amygdaloid injections section (page unavailable) says kainic acid induces status epilepticus after injection into either the hippocampus or the amygdala. It supports the use of a kainic-acid status-epilepticus model, but does not establish that status epilepticus preferentially originates in the hippocampus. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

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

APOE4 is the major genetic risk factor for sporadic Alzheimer's disease.

“APOE4, the major genetic risk factor for sporadic AD (Serrano-Pozo et al., 2021)”

• cites Serrano-Pozo et al., 2021 sourceSupported

Classified as probably not a substantial claim.

Terazosin has a proconvulsant effect via antagonizing α1-adrenergic receptor.

“Considering the proconvulsant effect of terazosin via antagonizing α1-adrenergic receptor (Chen et al., 2007; Perez and Doze, 2011)”

• cites Chen et al., 2007 sourceNot checked — no full text of the source
• cites Perez and Doze, 2011 sourcePartly supported

  The Neurophysiology section (‘α1A-ARs in epilepsy’; page unavailable) says α1-receptor activity can mediate anticonvulsant effects and that α1A-receptor knockout mice often have spontaneous seizures. It does not report that terazosin is proconvulsant or establish that terazosin causes seizures by antagonizing α1 receptors; a search for terazosin found no relevant passage. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

ATP hydrolysis is essential for Na+/K+-ATPase to transport 3 Na+ out of the cell and 2 K+ into the cell.

“ATP hydrolysis is essential for Na+/K+-ATPase to transport 3 Na+ out of the cell and 2 K+ into the cell (Sun et al., 2022; Zhang et al., 2022).”

• cites Sun et al., 2022 sourceSupported
• cites Zhang et al., 2022 sourcePartly supported

  Section 2.1 identifies Na+/K+-ATPase as a sodium pump, section 2.2 describes its ATP-binding catalytic subunit, and section 2.3 says it modulates Na+ and K+ gradients. Our copy does not specify that it transports three Na+ out for every two K+ in, or explicitly link that transport cycle to ATP hydrolysis. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Terazosin activates PGK1 at much lower concentration, resulting in enhanced production of ATP and pyruvate.

“it also activates PGK1 at much lower concentration, resulting in enhanced productions of ATP and pyruvate (Fig. 4A) (Cai et al., 2019; Chen et al., 2015; Kokotos et al., 2024)”

• cites Cai et al., 2019 sourcePartly supported

  The Introduction states that terazosin activates PGK1 and prevented falls in ATP and pyruvate levels in MPTP-treated mice. The Discussion describes a concentration-dependent relationship with ATP levels, but gives no comparison establishing that PGK1 is activated at a much lower concentration. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Chen et al., 2015 sourceSupported
• cites Kokotos et al., 2024 sourcePartly supported

  The Introduction identifies terazosin as an off-target PGK1 activator, and Results (‘PGK1 expression accelerates local ATP production’) report improved nerve-terminal ATP production with terazosin. The copy does not establish activation at a ‘much lower concentration’ or show that terazosin enhances pyruvate production; it mentions pyruvate only as the end product of glycolysis. Page numbers were not available in the indexed passages. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

TZ-mediated activation of PGK1 inhibits synaptic vesicle recycling dysfunction at glutamatergic synapses induced by PARK20 mutation under hypometabolic condition.

“TZ-mediated activation of PGK1 has previously shown to inhibit synaptic vesicle recycling dysfunction at glutamatergic synapses induced by PARK20 mutation under hypometabolic condition (Kokotos et al., 2024)”

• cites Kokotos et al., 2024 sourcePartly supported

  The Results report that terazosin (TZ) improved synaptic endurance under low-glucose conditions, while PGK1 expression reversed the PARK20 synaptic vesicle recycling deficit. The PARK20 experiment used PGK1 expression, not TZ, and was conducted in 5 mM glucose; the paper does not report TZ rescuing PARK20 synapses under hypometabolic conditions. Page numbers were not provided in our copy. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Reducing hippocampal hyperexcitability is shown to stall cognitive decline and disease progression in mouse models of AD.

“In contrast, reducing hippocampal hyperexcitability is shown to stall cognitive decline and disease progression in mouse models of AD (Sanchez et al., 2012).”

• cites Sanchez et al., 2012 sourcePartly supported

  The paper reports that levetiracetam reduced abnormal spiking and reversed learning and memory deficits and hippocampal remodeling in hAPP mice (opening summary; page unavailable). It does not show that treatment stalled cognitive decline over time or halted disease progression. The Results report no reduction in amyloid levels or early deposition, and the Discussion describes prevention or treatment as a potential benefit requiring further study. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

A strong link between APOE4 and seizure risk has been well established.

“A strong link between APOE4 and seizure risk has been well established (Sen et al., 2018; Tai et al., 2023; Vossel et al., 2017)”

• cites Sen et al., 2018 sourceCould not verify

  The ‘Common risk factors for epilepsy and dementia’ section links APOE4 to greater amyloid deposition in an epilepsy cohort and to dementia risk, but does not establish an APOE4–seizure-risk association. Searches for APOE4 with seizure risk and for apolipoprotein E with epilepsy or seizures found no passage making that claim. Page numbers were not available in our copy. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites Tai et al., 2023 sourceCould not verify

  The Methods (Statistical Analysis) and Results (Sensitivity Analysis; page unavailable) use APOE e4 status to assess or control for dementia risk in people with epilepsy. Neither passage addresses whether APOE4 is associated with seizure risk. Searches for APOE e4 with seizure and epilepsy risk found no such finding in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites Vossel et al., 2017 sourcePartly supported

  The “Seizures in animal models of Alzheimer’s disease” section reports that apolipoprotein E4 contributes to hippocampal overexcitation in mice. That supports a possible mechanism related to seizures, but the paper does not establish a strong link between APOE4 and seizure risk, particularly in people. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

APOE4 induces hyperactivity in the hippocampal formation and decreases seizure threshold in aged APOE-targeted replacement mice.

“prior studies demonstrating that APOE4 induces hyperactivity in the hippocampal formation and decreases seizure threshold in aged mice using APOE-targeted replacement mice (Hunter et al., 2012; Lamoureux et al., 2021; Nuriel et al., 2017)”

• cites Hunter et al., 2012 sourceNot checked — no full text of the source
• cites Lamoureux et al., 2021Not matched

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

• cites Nuriel et al., 2017 sourcePartly supported

  The Introduction (page not given) reports increased activity in the hippocampal formation of aged APOE4-targeted replacement mice, especially the entorhinal cortex. The Discussion reports an age-associated seizure phenotype, but the paper does not establish a decreased seizure threshold; its Results found no significant difference between APOE3 and APOE4 mice in NMDA-evoked seizure-like discharges. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

May combine two claims.

Estrogen is synthesized in the hippocampus and increases intrinsic neuronal excitability and long-term potentiation in the hippocampus while decreasing inhibitory transmission.

“Synthesized in the hippocampus, estrogen is shown to increase intrinsic neuronal excitability and long-term potentiation in the hippocampus (Christian et al., 2020) while decreasing inhibitory transmission (Rudick and Woolley, 2001).”

• cites Christian et al., 2020 sourcePartly supported

  The hormonal-mechanisms section (page unavailable) says estradiol increases neuronal excitability and reports greater hippocampal excitability at estrous-cycle stages associated with higher estradiol. It also describes conversion of testosterone to estradiol in the brain, but does not establish synthesis specifically in the hippocampus or increased hippocampal long-term potentiation. The decrease in inhibitory transmission is attributed to a different citation in the citing sentence and is not judged here. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Rudick and Woolley, 2001 sourcePartly supported

  Rudick and Woolley support the part attached to their citation: the Abstract reports that estrogen transiently suppresses GABAₐ-mediated inhibition of CA1 pyramidal cells in adult female rats. The claim omits that this decrease is temporary; the Abstract and the section “Dynamic balance of excitatory and inhibitory synaptic input” report that inhibition later recovers and is enhanced relative to controls. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Individuals with MCI display increased hippocampal activity during memory tasks, which correlates with poor memory performance.

“Individuals with MCI display increased hippocampal activity during memory tasks, which correlates with poor memory performance (Dickerson et al., 2005).”

• cites Dickerson et al., 2005 sourcePartly supported

  The Results and Discussion (page unavailable) report greater hippocampal activation during a memory task in the MCI group than in older controls. They do not support a correlation with poor memory-task performance: the MCI group performed similarly to controls, and the Results found no significant activation–performance correlation within the MCI group. Across all subjects, greater activation correlated with better performance. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

APOE4 is associated with age-dependent decreases in GABA release, postsynaptic GABAergic response, and the density of hilar GABAergic interneurons in the hippocampus, all of which impairs inhibitory transmission.

“APOE4 is associated with age-dependent decreases in GABA release, postsynaptic GABAergic response, and the density of hilar GABAergic interneurons in the hippocampus, all of which impairs inhibitory transmission (Najm et al., 2019).”

• cites Najm et al., 2019 sourcePartly supported

  The Background section on GABAergic interneuron susceptibility reports an age- and tau-dependent decrease in hilar GABAergic interneurons in apoE4 knock-in mice. The section on inhibitory network dysfunction links interneuron loss to reduced inhibitory function. The cited paper does not report age-dependent decreases in GABA release or postsynaptic GABAergic response, so those parts of the claim are unsupported. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Na+/K+-ATPase α1 establishes and maintains electrochemical gradients of Na+ and K+ ions across the plasma membrane.

“the Na+/K+-ATPase α1 establishes and maintains electrochemical gradients of Na+ and K+ ions across the plasma membrane (Sun et al., 2022; Zhang et al., 2022)”

• cites Sun et al., 2022 sourceSupported
• cites Zhang et al., 2022 sourceSupported

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

Female APOE4 carriers have a higher risk of developing AD and show accelerated pTau accumulation and memory decline than male carriers.

“The female-specific effect of APOE4 and pTau in seizure severity is intriguing because female APOE4 carriers have a higher risk of developing AD and show accelerated pTau accumulation and memory decline than male carriers (Altmann et al., 2014; Coughlan et al., 2025).”

• cites Altmann et al., 2014 sourcePartly supported

  The Discussion and Results (pages unavailable in our copy) report a stronger APOE4-related risk of clinical conversion to AD in women than in men. They do not establish accelerated pTau accumulation: the pTau difference was measured at study entry and did not remain significant after correction for multiple comparisons. The paper reports clinical conversion, not a direct comparison of rates of memory decline. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Coughlan et al., 2025 sourceNot checked — no full text of the source

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

Shuttling the lactate out of neurons via hydroxycarboxylic acid receptor 1 prevents seizures and reduces firing and glutamatergic transmission of hippocampal CA1 neurons.

“Shuttling the lactate out of neurons via hydroxycarboxylic acid receptor 1 prevents seizures and reduces firing and glutamatergic transmission of hippocampal CA1 neurons (Szklarczyk et al., 2023).”

• cites Szklarczyk et al., 2023 sourceCould not verify

  The paper’s Experiment-Level Confidence Scoring section discusses protein-association methods, not neuronal lactate transport or seizure outcomes. Searches for the cited sentence and for lactate, HCAR1, seizures, and hippocampal CA1 neurons found no passage in our copy addressing the claim. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

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

Out of three CNS catalytic α subunits of Na+/K+-ATPase, the α1 is expressed in both neurons and glia cells, whereas the α2 and α3 are mainly expressed in astrocytes and neurons, respectively.

“Out of three CNS catalytic α subunits of Na+/K+-ATPase, the α1 is expressed in both neurons and glia cells, whereas the α2 and α3 are mainly expressed in astrocytes and neurons, respectively (Sun et al., 2022; Zhang et al., 2022).”

• cites Sun et al., 2022 sourcePartly supported

  Table 1 in “Structure and Function of Na+-K+-ATPase in the CNS” identifies α1 in neurons and glial cells and α3 in neurons, as claimed. It lists α2 in both astrocytes and oligodendrocytes; it does not establish that α2 is mainly expressed in astrocytes. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Zhang et al., 2022 sourceSupported

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

Loss-of-function mutations in all three CNS α subunits cause epilepsy.

“Loss-of-function mutations in all three CNS α subunits cause epilepsy (Zhang et al., 2022)”

• cites Zhang et al., 2022 sourcePartly supported

  Section 2.2 (page unavailable) says α2 mutations can cause epilepsy, and the References list links ATP1A3 (α3) mutations with early-life epilepsy. But section 2.2 describes α1 mutations as fatal, not as causing epilepsy, and the copy does not establish that the epilepsy-associated mutations in all three isoforms are loss-of-function. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

Reducing tau expression can suppress seizures in a mouse model of epilepsy.

“while reducing tau expression can suppress seizures in a mouse model of epilepsy (Holth et al., 2013)”

• cites Holth et al., 2013 sourceSupported

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

Cerebral glucose hypometabolism occurs in both the early stage of AD and epilepsy.

“Importantly, cerebral glucose hypometabolism occurs in both the early stage of AD (Christian et al., 2020; Yamazaki et al., 2019) and epilepsy (McDonald et al., 2018; Patel, 2018).”

• cites Christian et al., 2020 sourceCould not verify

  Christian et al. is cited for the early-stage Alzheimer disease (AD) portion of the sentence, not the epilepsy portion. The paper’s Cognitive and Learning Deficits section discusses AD risk, and its Focal Seizures discussion mentions hypometabolism in temporal lobe epilepsy, but neither passage addresses cerebral glucose hypometabolism in early-stage AD (searched: Alzheimer disease, glucose metabolism, hypometabolism). (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites Yamazaki et al., 2019 sourceSupported
• cites McDonald et al., 2018 sourceSupported

Classified as probably not a substantial claim.

Reduced Na+/K+-ATPase activity has been reported in the epileptic human cortices and animal models of epilepsy.

“Reduced Na+/K+-ATPase activity has been reported in the epileptic human cortices and animal models of epilepsy (Sun et al., 2022).”

• cites Sun et al., 2022 sourceSupported

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

Hippocampal hyperexcitability is a key feature of early AD and contributes to cognitive decline throughout disease progression.

“Hippocampal hyperexcitability is a key feature of early AD and contributes to cognitive decline throughout disease progression (Targa Dias Anastacio et al., 2022).”

• cites Targa Dias Anastacio et al., 2022 sourcePartly supported

  The Abstract and “Evidence of neuronal network hyperactivity from human studies” describe hippocampal hyperactivity in early AD. The “Is hyperexcitability neuroprotective or neurodegenerative?” section links increased activity to AD pathology and cognitive deficits, but the Abstract says hyperactivity progresses to hypoactivity in later stages; the source does not establish that hippocampal hyperexcitability contributes to decline throughout progression. Page numbers were not provided in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

APOE4 exacerbates tau pathology in PS19 mice.

“Previous studies have demonstrated that APOE4 exacerbates tau pathology in PS19 mice (Shi et al., 2017)”

• cites Shi et al., 2017 sourceSupported

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

APOE4 is associated with cortical ATP decline and age-dependent impairments in cerebral glucose uptake and metabolism independent of Aβ accumulation.

“APOE4 is previously shown to be associated with cortical ATP decline (Fang et al., 2021) and age-dependent impairments in cerebral glucose uptake and metabolism independent of Aβ accumulation (Jagust et al., 2012).”

• cites Fang et al., 2021 sourceSupported
• cites Jagust et al., 2012 sourcePartly supported

  The Results report that APOE4 carriers and older participants had lower cerebral glucose metabolism, and the Discussion says the APOE4 association was not explained by fibrillar Aβ detected with florbetapir. The paper reports separate effects of age and APOE4, not an age-dependent APOE4 effect, and it does not establish independence from all Aβ accumulation: the Discussion says soluble Aβ could not be definitively excluded. Jagust et al. measured glucose metabolism with FDG-PET, not glucose uptake as a separate outcome. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

TZ-mediated activation of PGK1 attenuates neuronal death in multiple animal models of Parkinson's disease.

“and attenuates neuronal death in multiple animal models of Parkinson’s disease (Cai et al., 2019; Chen et al., 2015; Simmering et al., 2021).”

• cites Cai et al., 2019 sourceSupported
• cites Chen et al., 2015 sourcePartly supported

  The Results sections report that terazosin activates Pgk1 and that it reduced infarct volume in a rat stroke model, suggesting protection of neural cells. They do not report Parkinson’s disease models, let alone reduced neuronal death in multiple such models. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Simmering et al., 2021 sourceSupported

Classified as probably not a substantial claim.

Na+/K+-ATPase maintains Na+ and K+ gradient across the plasma membrane that is essential for neuronal RMP and excitability.

“Na+/K+-ATPase maintains Na+ and K+ gradient across the plasma membrane that is essential for neuronal RMP and excitability (Sun et al., 2022; Zhang et al., 2022).”

• cites Sun et al., 2022 sourceSupported
• cites Zhang et al., 2022 sourceSupported

May combine two claims. The quote only partly states this claim.

Terazosin treatment decreases kainic acid-induced seizure severity and seizure-induced death in E4 but not E3 mice.

“pharmacologically stimulating PGK1 with terazosin increased hippocampal ATP levels and decreased seizure severity in APOE4 but not APOE3 mice”

• Also stated in: § APOE4 decreases hippocampal levels of two glycolytic enzymes and ATP, whereas enhancing glycolysis suppresses APOE4-associated increase in seizure severity. · plain

  “TZ treatment reduced seizure severity within 30 min post KA injection in E4 mice, and this effect persisted through the 2-h duration (Fig. 4E, Supplementary Fig. 4A-B).”

• Also stated in: § APOE4 decreases hippocampal levels of two glycolytic enzymes and ATP, whereas enhancing glycolysis suppresses APOE4-associated increase in seizure severity. · plain

  “TZ treatment decreased the % of mice developing SE by 20% and completely abolished seizure-induced death from 100% to 0% in E4 mice (Fig. 4H-I, Supplementary Fig. 4E-F).”

• AssumptionRests on an assumption: The genetic background difference between E4 (mixed C57BL/6 and SJL) and E3 (congenic C57BL/6J) mice does not confound the observed differences in seizure susceptibility.
• AssumptionRests on an assumption: Terazosin's anti-seizure effects in E4 mice are mediated by PGK1 activation rather than its α1-adrenergic receptor antagonism.
• AssumptionRests on an assumption: The kainic acid model of status epilepticus in mice is a valid model for APOE4-associated seizure susceptibility in Alzheimer's disease.

May combine two claims. The quote only partly states this claim.

Co-treatment with terazosin and sodium oxamate further decreases seizure severity and increases hippocampal ATP levels in E4 mice compared to terazosin alone.

“co-application of lactate dehydrogenase inhibitor sodium oxamate to prevent the conversion of pyruvate to lactate further enhanced hippocampal ATP levels and suppressed seizure severity in APOE4 mice”

• Also stated in: § APOE4 decreases hippocampal levels of two glycolytic enzymes and ATP, whereas enhancing glycolysis suppresses APOE4-associated increase in seizure severity. · plain

  “Compared to TZ treatment alone, TZ/OXO treatment decreased seizure severity at 20-60 min post KA injections and cumulative seizure scores (Fig. 4E-F), prolonged the latency to stage 3 seizures in E4 mice of both sexes (Fig. 4G), and reduced % SE by 15% without altering % Death (Fig. 4H-I, Supplementary Fig. 4).”

• Also stated in: § APOE4 decreases hippocampal levels of two glycolytic enzymes and ATP, whereas enhancing glycolysis suppresses APOE4-associated increase in seizure severity. · plain

  “TZ/OXO co-treatment significantly enhanced hippocampal ATP levels in KA-injected E4 mice compared to saline treatment, completely restoring to similar levels as those of KA-injected E3 mice that received saline (Fig. 4J).”

• AssumptionRests on an assumption: The genetic background difference between E4 (mixed C57BL/6 and SJL) and E3 (congenic C57BL/6J) mice does not confound the observed differences in seizure susceptibility.
• AssumptionRests on an assumption: Terazosin's anti-seizure effects in E4 mice are mediated by PGK1 activation rather than its α1-adrenergic receptor antagonism.
• AssumptionRests on an assumption: Hippocampal tissue ATP levels measured by the ATP assay kit reflect neuronal ATP available for Na+/K+-ATPase function.

May combine two claims.

Pharmacological inhibition of Na+/K+-ATPase with ouabain depolarizes resting membrane potential and increases hippocampal neuronal network activity, including spontaneous firing, Ca2+ transient frequency, and synchronous Ca2+ dynamics.

“While inhibition of Na+/K+- ATPase increased hippocampal neuronal activity”

• Also stated in: § APOE4 decreases hippocampal expression of Na+/K+-ATPase α1 which affects hippocampal neuronal network activity. · plain

  “Ouabain application depolarized the RMP (Fig. 3F-G) and induced spontaneous firing of action potentials in hippocampal pyramidal cells (Fig. 3F, Supplementary Fig. 2).”

• Also stated in: § APOE4 decreases hippocampal expression of Na+/K+-ATPase α1 which affects hippocampal neuronal network activity. · hedged

  “Ouabain treatment also enhanced temporal clustering of Ca2+ peaks in neuronal soma and dendrites compared to the baseline prior to treatment (Fig. 3H), resulting in significant increases in Ca2+ transient frequency (Fig. 3I) and synchronous Ca2+ dynamics (Fig. 3J), indicating network-wide hippocampal neuronal hyperexcitability induced by reduction of Na+/K+-ATPase α1 activity.”

May combine two claims.

Terazosin treatment increases hippocampal ATP levels in kainic acid-injected E4 mice, but this increase is not statistically different from saline-treated E3 or E4 mice, and does not alter ATP in E3 mice.

“pharmacologically stimulating PGK1 with terazosin increased hippocampal ATP levels”

• Also stated in: § APOE4 decreases hippocampal levels of two glycolytic enzymes and ATP, whereas enhancing glycolysis suppresses APOE4-associated increase in seizure severity. · hedged

  “TZ treatment increased hippocampal ATP levels in KA-injected E4 mice, however, this trend was not statistically different from either saline-treated E3 or E4 mice (Fig. 4J), suggesting a partial rescue.”

• Also stated in: § APOE4 decreases hippocampal levels of two glycolytic enzymes and ATP, whereas enhancing glycolysis suppresses APOE4-associated increase in seizure severity. · plain

  “In KA-injected E3 mice, neither TZ or TZ/OXO application altered hippocampal ATP levels compared to saline application (Fig. 4K).”

• AssumptionRests on an assumption: The genetic background difference between E4 (mixed C57BL/6 and SJL) and E3 (congenic C57BL/6J) mice does not confound the observed differences in seizure susceptibility.
• AssumptionRests on an assumption: Terazosin's anti-seizure effects in E4 mice are mediated by PGK1 activation rather than its α1-adrenergic receptor antagonism.
• AssumptionRests on an assumption: Hippocampal tissue ATP levels measured by the ATP assay kit reflect neuronal ATP available for Na+/K+-ATPase function.

May combine two claims.

In human APOE4 targeted replacement (E4) mice, kainic acid-induced seizure severity and seizure-induced death are increased at 5.5-7 months but not 2-3 months of age compared to APOE3 (E3) mice.

“We discovered that human APOE4 targeted replacement mice showed increased seizure severity and seizure-induced death at 5.5-7 but not 2-3 months of age compared to APOE3 mice using the kainic acid model of status epilepticus which preferentially arises from the hippocampus.”

• Also stated in: § INTRODUCTION · plain

  “we found that E4 mice displayed increased seizure severity and seizure-induced death at 5.5-7 but not 2-3 months of age compared to E3 mice, irrespective of sex.”

• Also stated in: § APOE4 increases seizure severity in mice by 5 months of age compared to APOE3 in the kainic acid model of status epilepticus. · plain

  “both male and female E4 mice at 5.5-7 months of age succumbed to SE within 40 min post injection, resulting in greater cumulative seizure scores compared to E3 mice”

• AssumptionRests on an assumption: The genetic background difference between E4 (mixed C57BL/6 and SJL) and E3 (congenic C57BL/6J) mice does not confound the observed differences in seizure susceptibility.
• AssumptionRests on an assumption: The kainic acid model of status epilepticus in mice is a valid model for APOE4-associated seizure susceptibility in Alzheimer's disease.

May combine two claims.

In E3 mice, TZ/OXO treatment decreases seizure severity and cumulative scores and increases latency to stage 3 seizures compared to TZ alone, but does not affect the percentage developing status epilepticus or death.

“In E3 mice, TZ/OXO treatment significantly decreased seizure severity at 30-40 min post-KA injection (Fig. 4E) and cumulative seizure scores (Fig. 4F) and increased the latency to stage 3 seizures (Fig. 4G) but did not affect % SE and % Death compared to TZ application alone (Fig. 4H-I).”

• AssumptionRests on an assumption: The genetic background difference between E4 (mixed C57BL/6 and SJL) and E3 (congenic C57BL/6J) mice does not confound the observed differences in seizure susceptibility.
• AssumptionRests on an assumption: Terazosin's anti-seizure effects in E4 mice are mediated by PGK1 activation rather than its α1-adrenergic receptor antagonism.
• AssumptionRests on an assumption: Hippocampal tissue ATP levels measured by the ATP assay kit reflect neuronal ATP available for Na+/K+-ATPase function.

May combine two claims.

At 5.5-7 months of age, E4 mice displayed significantly higher cumulative seizure scores and % SE, resulting in 100% seizure-induced mortality in response to KA compared to E3 mice.

“At 5.5-7 months of age, E4 mice displayed significantly higher cumulative seizure scores and % SE, resulting in 100% seizure-induced mortality in response to KA compared to E3 mice (Fig. 1).”

May combine two claims.

Treatment with TZ alone or together with OXO restores hippocampal ATP levels and suppresses KA-induced seizures in E4 mice.

“However, we show that treatment with TZ alone or together with OXO restores hippocampal ATP levels and suppresses KA-induced seizures in E4 mice (Fig. 4)”

May combine two claims.

TZ/OXO application prolonged the latency to stage-3 seizures and potently suppressed seizure severity and mortality in female E4/PS mice.

“The TZ/OXO application prolonged the latency to stage-3 seizures and potently suppressed seizure severity and mortality in female E4/PS mice (Fig. 5G-L).”

May combine two claims.

TZ application does not significantly alter hippocampal ATP level and seizure severity in E3 mice.

“Importantly, TZ application does not significantly alter hippocampal ATP level and seizure severity in E3 mice (Fig. 4D-I)”

May combine two claims.

The presence of APOE4 increases seizure severity in female but not male PS19 mice.

“However, we discover that the presence of APOE4 increases seizure severity in female but not male PS19 mice (Fig. 5B-F).”

May combine two claims.

PS19 transgenic mice express human tau with the P301S mutation and display neurofibrillary tangles at 6 months of age followed by progressive hippocampal and cortical atrophy at 9-12 months of age.

“we employed the PS19 transgenic mice which express the human tau protein containing the P301S mutation associated with frontotemporal dementia (FTD) and display NFTs at 6 months of age followed by progressive hippocampal and cortical atrophy at 9-12 months of age (Yoshiyama et al., 2007).”

• cites Yoshiyama et al., 2007 sourceNot checked — no full text of the source

May combine two claims.

APOE4 increases seizure susceptibility in PS19 mice in a sex-specific manner, with effects observed in females.

“These results together indicate that APOE4 increases seizure susceptibility in PS19 mice in a sex-specific manner.”

• Also stated in: § INTRODUCTION · plain

  “revealing a novel finding that APOE4 increases seizure propensity in sex-dependent manner in the presence of pTau burden.”

• AssumptionRests on an assumption: The genetic background difference between E4 (mixed C57BL/6 and SJL) and E3 (congenic C57BL/6J) mice does not confound the observed differences in seizure susceptibility.
• AssumptionRests on an assumption: The kainic acid model of status epilepticus in mice is a valid model for APOE4-associated seizure susceptibility in Alzheimer's disease.

May combine two claims.

Terazosin has potent anti-seizure effects, supporting the possibility of repurposing this anti-hypertension drug to mitigate seizure comorbidity in Alzheimer's disease.

“Our results also demonstrate potent anti-seizure effects of terazosin, supporting the possibility of repurposing this anti-hypertension drug to mitigate seizure comorbidity in AD.”

• AssumptionRests on an assumption: Terazosin's anti-seizure effects in E4 mice are mediated by PGK1 activation rather than its α1-adrenergic receptor antagonism.

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

In response to ATP decline, ATP-sensitive potassium channels get activated to induce membrane hyperpolarization, thereby reducing neuronal excitability, glutamate release, and glutamate-induced excitotoxicity.

“In response to ATP decline, ATP-sensitive potassium channels get activated to induce membrane hyperpolarization, thereby reducing neuronal excitability, glutamate release, and glutamate-induced excitotoxicity (Lv et al., 2022).”

• cites Lv et al., 2022Not 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).

Testosterone may provide protection from APOE4-induced increase in seizure severity.

“Alternatively, the lack of APOE4 effect in male PS19 mice (Fig. 5B-F) suggest that testosterone may provide protection from APOE4-induced increase in seizure severity.”

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

TZ is expected to increase seizure severity or at least have no effect.

“TZ is expected to increase seizure severity or at least have no effect.”

May combine two claims.

Lower testosterone is linked to higher phosphorylated tau especially in APOE4 carriers, while testosterone reduces tau phosphorylation via the PI3K-Akt-GSK3β pathway in mice.

“Lower testosterone is linked to higher phosphorylated tau especially in APOE4 carriers, while testosterone is shown to reduce tau phosphorylation via the PI3K-Akt-GSK3β pathway in mice (Yao et al., 2022).”

• cites Yao et al., 2022Not 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). May combine two claims.

TZ is an α1-adrenergic receptor antagonist used to treat hypertension and benign prostatic hyperplasia.

“TZ is an α1-adrenergic receptor antagonist used to treat hypertension and benign prostatic hyperplasia (Wilt et al., 2002).”

• cites Wilt et al., 2002 sourceNot checked — no full text of the source

May combine two claims.

The E4 mice are on a hybrid background of C57BL/6J and SJL whereas the E3 mice are congenic on the C57BL/6J strain.

“One limitation of this study is that the E4 mice are on a hybrid background of C57BL/6J and SJL whereas the E3 mice are congenic on the C57BL/6J strain, which is widely reported to be resistant to seizures (Ferraro et al., 1995).”

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

Pathological accumulation of Aβ enhances seizure susceptibility and network hyperexcitability by blocking glial uptake of glutamate while enhancing neuronal firing, glutamate release, extrasynaptic NMDA receptor activity, and intracellular Ca2+ concentration.

“Pathological accumulation of Aβ also enhances seizure susceptibility and network hyperexcitability by blocking glial uptake of glutamate while enhancing neuronal firing, glutamate release, extrasynaptic NMDA receptor activity, and intracellular Ca2+ concentration (Stargardt et al., 2015).”

• cites Stargardt et al., 2015 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

Inhibition of Na+/K+-ATPase with ouabain induces seizures.

“and their inhibition with ouabain induces seizures (Baldy-Moulinier et al., 1973; Petsche et al., 1973).”

• cites Baldy-Moulinier et al., 1973Not matched

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

• cites Petsche et al., 1973 sourceNot checked — no full text of the source

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

Women display faster cognitive deterioration and greater hippocampal atrophy than men after diagnosis of MCI although Aβ levels were similar between the sexes.

“Women also display faster cognitive deterioration and greater hippocampal atrophy than men after diagnosis of MCI although Aβ levels were similar between the sexes (Ferretti et al., 2018).”

• cites Ferretti et al., 2018 sourceNot checked — no full text of the source

May combine two claims.

The aromatization of testosterone through 5α-reduction yields neurosteroids such as 3α-androstanediol which is a potent positive allosteric modulator of GABAA receptors and can enhance GABAergic inhibition.

“Furthermore, the aromatization of testosterone through 5α-reduction yields neurosteroids such as 3α-androstanediol which is potent positive allosteric modulator of GABAA receptors and can thereby enhance GABAergic inhibition (Reddy, 2004a; Reddy, 2004b).”

• cites Reddy, 2004aNot matched

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

• cites Reddy, 2004bNot matched

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