The role of mTORC1 activation in seizure-induced exacerbation of Alzheimer's disease

Gourmaud, Sarah; Stewart, David A.; Irwin, David J.; Roberts, Nicholas L S; Barbour, Aaron J.; Eberwine, Grace; O’Brien, William T.; Vassar, Robert; Talos, Delia M.; Jensen, Frances E.

doi:10.1093/brain/awab268

Cited by 25 publications

(60 citation statements)

References 101 publications

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“…However, the connection between mTOR overactivity and AMPA receptor potentiation [ 13 ] allows us to consider the perspective of toning down the deleterious activity of AMPA receptors within the piriform cortex by suppressing mTOR. This is in line with data showing that seizures may be considered “mTORpathies,” and mTOR overexpression may foster the onset of SE [ 14 - 16 ]. The protein complex mTOR was previously defined as the “mammalian target of rapamycin,” and it is now defined as a “mechanistic target of rapamycin.” This occurs in two structurally and functionally distinct complexes, mTORC1 and mTORC2.…”

Section: Introductionsupporting

confidence: 89%

Perspective on mTOR-dependent Protection in Status Epilepticus

Biagioni

Celli

Giorgi

et al. 2022

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Background: The piriform cortex known as area tempestas owns a high propensity to trigger limbic epileptic seizures. Recent studies on human patients indicate that a resection containing the piriform cortex produces a marked improvement in patients suffering from intractable limbic seizures. This calls for looking back pharmacological and anatomical data on area tempestas. Within the piriform cortex status epilepticus can be induced by impairing desensitization of AMPA receptors. The mechanistic target of rapamycin complex1 (mTORC1) is a promising candidate. Objective : The present perspective joins the novel role of the piriform cortex with recent evidence on the modulation of AMPA receptors under the influence of mTORC1. This is based on recent evidence and preliminary data, which lead to formulate an interaction between mTORC1 and AMPA receptors to mitigate the onset of long-lasting, self-sustaining, neurotoxic status epilepticus. Methods: The perspective grounds its method on recent literature along with the actual experimental procedure to elicit status epilepticus from the piriform cortex and the method to administer the mTORC1 inhibitor rapamycin to mitigate seizure expression and brain damage. Results: The available and present perspective converge to show that rapamycin may disrupt the seizure circuitry initiated in the piriform cortex to mitigate seizure duration, severity, and brain damage. Conclusions : The perspective offered by this manuscript provides a novel scenario to understand refractory epilepsy and self-sustaining status epilepticus. This is expected to provide a beneficial outcome in patients suffering from temporal lobe epilepsy.

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Section: Introductionsupporting

confidence: 89%

Perspective on mTOR-dependent Protection in Status Epilepticus

Biagioni

Celli

Giorgi

et al. 2022

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“…We and others have demonstrated bidirectional interactions with AD and epilepsy sharing similar pathology and convergence upon common underlying cellular mechanisms. Human temporal lobe epilepsy brain tissue shows increased Aβ plaques and increased hyperphosphorylated tau (pTau) (Gourmaud et al 2020; Thom et al 2011; Tai et al 2016) and the accumulation of these neuropathological proteins in AD animal models are associated with elevated neuronal hyperexcitability and seizure susceptibility (Palop and Mucke 2009; Westmark et al 2008; DeVos et al 2013; Johnson, Ho, et al 2020; Chang et al 2021; Gourmaud et al 2022). Indeed, development of late-onset epilepsy substantially increases dementia risk and accelerates the rate of cognitive decline (Johnson, Krauss, Kucharska-Newton, et al 2020; Johnson, Krauss, Walker, et al 2020; Kawakami et al 2018; Keret et al 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Considering these data and that rapamycin and other rapalogs are approved by the United States Food and Drug Administration for other indications, mTORC1 is a promising target for therapeutic intervention for patients with AD and co-morbid epilepsy. In a recent study, we found that AD patients with a history of seizure display elevated tau and Aβ pathology, associated with increased mTORC1 activity (Gourmaud et al 2022). In addition, we observed that the induction of seizures in the five times familial AD (5XFAD) mice exacerbates Aβ pathology and cognitive deficits, and that these changes are reversible with chronic low-dose rapamycin treatment.…”

Section: Introductionmentioning

confidence: 99%

“…We hypothesized that markers of E:I balance, including GABA A Rs, Cl - cotransporters, NMDARs, and AMPARs may be dysregulated in AD and that these alterations and cognitive deficits may be exacerbated by seizures. Here, using tissue from the same human subjects (Gourmaud et al 2022), we measured markers of E:I imbalance in AD temporal neocortex from patients with and without known seizure history and examined their cognitive and functional scores. In parallel studies, we examined the 5XFAD mouse model for the same markers of neuronal excitability at prodromal and intermediate stages, and in response to pentylenetetrazol (PTZ)-induced seizures.…”

Section: Introductionmentioning

confidence: 99%

“…In parallel studies, we examined the 5XFAD mouse model for the same markers of neuronal excitability at prodromal and intermediate stages, and in response to pentylenetetrazol (PTZ)-induced seizures. Finally, given that we found meaningful protective effects on pathology and cognition with rapamycin (Gourmaud et al 2022), we also utilized the tissue from this cohort of animals to further examine whether these therapeutic benefits extend to markers of E:I balance. Overall, we found that seizures significantly contribute to E:I imbalance in human AD and the 5XFAD mouse model, with markers of E:I imbalance correlated with AD severity and pathology and memory deficits in 5XFAD mice.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Excitatory: inhibitory imbalance in Alzheimer’s disease is exacerbated by seizures with attenuation after rapamycin treatment in 5XFAD mice

Barbour

Gourmaud

et al. 2023

Preprint

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Increasing evidence indicates a bidirectional relationship between epilepsy and Alzheimer’s disease (AD) with 22% of AD patients additionally suffering from seizures, which may be a targetable component of disease progression. Since epileptogenesis is associated with changes in excitatory: inhibitory (E:I) balance, we examined postmortem AD brain tissue from patients with and without seizure history and five times familial AD (5XFAD) mice for changes in several markers of E:I balance, including the inhibitory GABAAreceptor, the chloride cotransporters, sodium potassium chloride cotransporter 1 (NKCC1) and potassium chloride cotransporter 2 (KCC2), and the excitatory NMDA and AMPA type glutamate receptors. We hypothesized that seizure history in AD patients would be associated with greater E:I imbalances, and that such changes would also be observed in the 5XFAD mice following pentylenetetrazol (PTZ) kindling. We found that seizures in AD patients were associated with alterations in NKCC1 and KCC2 expression, indicative of depolarizing GABA, and exacerbated cognitive deficits. Seizures also significantly contributed to E:I imbalance in the 5XFAD mouse model, as similar changes in NKCC1 and KCC2 expression were found in PTZ treated 5XFAD mice, along with altered AMPA receptor protein expression indicative of calcium permeable-AMPA receptors. In addition, we found that chronic treatment with the mTOR inhibitor rapamycin at doses we have previously shown to attenuate seizure-inducedβ-amyloid pathology and cognitive deficits in 5XFAD mice, can mitigate the dysregulation of markers of E:I balance in this model. These data suggest that mTOR activation plays a role in modifying the E:I imbalance and network hyperexcitability in AD and that the FDA-approved mTOR inhibitors such as rapamycin may have potential for therapy in AD patients with a seizure history.

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Posttraumatic Epilepsy and Dementia Risk

Schneider,

Law,

Gottesman

et al. 2024

JAMA Neurol

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ImportanceAlthough both head injury and epilepsy are associated with long-term dementia risk, posttraumatic epilepsy (PTE) has only been evaluated in association with short-term cognitive outcomes.ObjectiveTo investigate associations of PTE with dementia risk.Design, Setting, and ParticipantsThe Atherosclerosis Risk in Communities (ARIC) study initially enrolled participants from 1987 to 1989 and this prospective cohort study uses data through December 31, 2019, with a median follow-up of 25 years. Data were analyzed between March 14, 2023, and January 2, 2024. The study took place in 4 US communities in Minnesota, Maryland, North Carolina, and Mississippi. Of 15 792 ARIC study participants initially enrolled, 2061 were ineligible and 1173 were excluded for missing data, resulting in 12 558 included participants.ExposuresHead injury was defined by self-report and International Classification of Diseases (ICD) diagnostic codes. Seizure/epilepsy was defined using ICD codes. PTE was defined as a diagnosis of seizure/epilepsy occurring more than 7 days after head injury. Head injury, seizure/epilepsy, and PTE were analyzed as time-varying exposures.Main Outcomes and MeasuresDementia was defined using cognitive assessments, informant interviews, and ICD and death certificate codes. Adjusted Cox and Fine and Gray proportional hazards models were used to estimate dementia risk.ResultsParticipants had a mean (SD) age of 54.3 (5.8) years at baseline, 57.7% were female, 28.2% were of self-reported Black race, 14.4% were ultimately categorized as having head injury, 5.1% as having seizure/epilepsy, and 1.2% as having PTE. Over a median follow-up of 25 (25th to 75th percentile, 17-30) years, 19.9% developed dementia. In fully adjusted models, compared with no head injury and no seizure/epilepsy, PTE was associated with 4.56 (95% CI, 4.49-5.95) times the risk of dementia, while seizure/epilepsy was associated with 2.61 (95% CI, 2.21-3.07) times the risk and head injury with 1.63 (95% CI, 1.47-1.80) times the risk. The risk of dementia associated with PTE was significantly higher than the risk associated with head injury alone and with nontraumatic seizure/epilepsy alone. Results were slightly attenuated in models accounting for the competing risks of mortality and stroke, but patterns of association remained similar. In secondary analyses, the increased dementia risk associated with PTE occurring after first vs second head injury and after mild vs moderate/severe injury was similar.Conclusions and RelevanceIn this community-based cohort, there was an increased risk of dementia associated with PTE that was significantly higher than the risk associated with head injury or seizure/epilepsy alone. These findings provide evidence that PTE is associated with long-term outcomes and supports both the prevention of head injuries via public health measures and further research into the underlying mechanisms and the risk factors for the development of PTE, so that efforts can also be focused on the prevention of PTE after a head injury.

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The role of mTORC1 activation in seizure-induced exacerbation of Alzheimer's disease

Cited by 25 publications

References 101 publications

Perspective on mTOR-dependent Protection in Status Epilepticus

Perspective on mTOR-dependent Protection in Status Epilepticus

Excitatory: inhibitory imbalance in Alzheimer’s disease is exacerbated by seizures with attenuation after rapamycin treatment in 5XFAD mice

Posttraumatic Epilepsy and Dementia Risk

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