Chloe Larson | The Rockefeller University (original) (raw)

Papers by Chloe Larson

Research paper thumbnail of Correction: Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease

Translational Psychiatry, Feb 4, 2019

The author's name was spelled incorrectly as "Masahir Okamoto". This has been updated to "Masahir... more The author's name was spelled incorrectly as "Masahir Okamoto". This has been updated to "Masahiro Okamoto" in the HTML and PDF of the article.

Research paper thumbnail of Chronic Intermittent Hypoxia Enhances Pathological Tau Seeding, Propagation, and Accumulation and Exacerbates Alzheimer-like Memory and Synaptic Plasticity Deficits and Molecular Signatures

Biological Psychiatry, 2021

BACKGROUND Obstructive sleep apnea, characterized by sleep fragmentation and chronic intermittent... more BACKGROUND Obstructive sleep apnea, characterized by sleep fragmentation and chronic intermittent hypoxia (CIH), is a risk factor for Alzheimer's disease (AD) progression. Recent epidemiological studies point to CIH as the best predictor of developing cognitive decline and AD in older adults with obstructive sleep apnea. However, the precise underlying mechanisms remain unknown. This study was undertaken to evaluate the effect of CIH on pathological human tau seeding, propagation, and accumulation; cognition; synaptic plasticity; neuronal network excitability; and gene expression profiles in a P301S human mutant tau mouse model of AD and related tauopathies. METHODS We exposed 4- to 4.5-month-old male P301S and wild-type mice to an 8-week CIH protocol (6-min cycle: 21% O2 to 8% O2 to 21% O2, 80 cycles per 8 hours during daytime) and assessed its effect on tau pathology and various AD-related phenotypic and molecular signatures. Age- and sex-matched P301S and wild-type mice were reared in normoxia (21% O2) as experimental controls. RESULTS CIH significantly enhanced pathological human tau seeding and spread across connected brain circuitry in P301S mice; it also increased phosphorylated tau load. CIH also exacerbated memory and synaptic plasticity deficits in P301S mice. However, CIH had no effect on seizure susceptibility and network hyperexcitability in these mice. Finally, CIH exacerbated AD-related pathogenic molecular signaling in P301S mice. CONCLUSIONS CIH-induced increase in pathologic human tau seeding and spread and exacerbation of other AD-related impairments provide new insights into the role of CIH and obstructive sleep apnea in AD pathogenesis.

Research paper thumbnail of Assessing the role of serotonergic receptors in cannabidiol's anticonvulsant efficacy

Epilepsy & Behavior, Aug 1, 2017

Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several ... more Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD's anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100 mg/kg) or vehicle 60 min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1 mg/kg), a 5HT1A antagonist, or saline vehicle injection 80 min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3 mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80 min prior to seizure testing. 85 mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30 min. Seizure behaviors were subsequently coded using a 5-point scale of severity. Across both experiments, subjects in the vehicle control groups exhibited high levels of seizure activity and mortality. In both experiments, CBD treatment significantly attenuated seizure activity. Pre-treatment with either WAY-100635 or MDL-100907 did not block CBD's anticonvulsant effect. WAY-100635 administration, by itself, also led to a significant attenuation of seizure activity. These results do not support the hypothesis that CBD attenuates seizure activity through activation of the 5HT1A or 5HT2A receptor. While this work further confirms the anticonvulsant efficacy of CBD and supports its application in the treatment of human seizure disorders, additional research on CBD's mechanism of action must be conducted.

Research paper thumbnail of Chronic intermittent hypoxia enhances tau seeding and propagation and exacerbates Alzheimer’s‐like memory and synaptic plasticity deficits and molecular signatures

Alzheimer's & Dementia, 2020

Obstructive sleep apnea (OSA), characterized by sleep fragmentation and chronic intermittent hypo... more Obstructive sleep apnea (OSA), characterized by sleep fragmentation and chronic intermittent hypoxia (CIH), is a risk factor for Alzheimer’s disease (AD) development and progression. Recent epidemiological studies point to CIH as the best predictor of developing cognitive decline and AD in elderly with OSA. However, the precise underlying mechanism(s) remain unknown. Tau pathology, a major neuropathological hallmark of the disease, is known to be correlated with cognitive impairment in AD. Further, increase in tau pathology has been linked to CIH suggesting that CIH may mediate AD risk through tau pathology. The present study was undertaken to evaluate the effect of CIH on human tau seeding and propagation, and to further investigate the effects of CIH on cognition, synaptic plasticity, neuronal network excitability, and gene expression profiles in a human mutant tau mouse model of AD and related tauopathies (P301S mice).

Research paper thumbnail of Neuronal Network Excitability in Alzheimer’s Disease: The Puzzle of Similar versus Divergent Roles of Amyloid β and Tau

eneuro

initial ideas related to the discussion and perspectives presented in manuscript were generated a... more initial ideas related to the discussion and perspectives presented in manuscript were generated and a part of this review was written. The authors would like to acknowledge the support from the Neuronal network excitability in Alzheimer's disease: The puzzle of similar versus divergent roles of amyloid β and tau

Research paper thumbnail of Assessing the role of serotonergic receptors in cannabidiol's anticonvulsant efficacy

Epilepsy & Behavior, 2017

Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several ... more Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD's anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100mg/kg) or vehicle 60min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1mg/kg), a 5HT1A antagonist, or saline vehicle injection 80min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80min prior to seizure testing. 85mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30min. Seizure behaviors were subsequently c...

Research paper thumbnail of Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease

Alzheimer’s disease (AD) represents a major healthcare burden with no effective treatment. The gl... more Alzheimer’s disease (AD) represents a major healthcare burden with no effective treatment. The glutamate modulator, riluzole, was shown to reverse many AD-related gene expression changes and improve cognition in aged rats. However, riluzole’s effect on amyloid beta (Aβ) pathology, a major histopathological hallmark of AD, remains unclear. 5XFAD transgenic mice, which harbor amyloid β precursor protein (APP) and presenilin mutations and exhibit early Aβ accumulation, were treated with riluzole from 1 to 6 months of age. Riluzole significantly enhanced cognition and reduced Aβ42, Aβ40, Aβ oligomers levels, and Aβ plaque load in 5XFAD mice. RNA-Sequencing showed that riluzole reversed many gene expression changes observed in the hippocampus of 5XFAD mice, predominantly in expression of canonical gene markers for microglia, specifically disease-associated microglia (DAM), as well as neurons and astrocytes. Central to the cognitive improvements observed, riluzole reversed alterations in ...

Research paper thumbnail of Chronic Intermittent Hypoxia Enhances Pathological Tau Seeding, Propagation, and Accumulation and Exacerbates Alzheimer-like Memory and Synaptic Plasticity Deficits and Molecular Signatures

Research paper thumbnail of Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer’s molecular signatures

Proceedings of the National Academy of Sciences

The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain e... more The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer’s disease (AD) patients’ brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with...

Research paper thumbnail of Correction: Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease

Translational Psychiatry, Feb 4, 2019

The author's name was spelled incorrectly as "Masahir Okamoto". This has been updated to "Masahir... more The author's name was spelled incorrectly as "Masahir Okamoto". This has been updated to "Masahiro Okamoto" in the HTML and PDF of the article.

Research paper thumbnail of Correction: Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease

Translational Psychiatry, Feb 4, 2019

The author's name was spelled incorrectly as "Masahir Okamoto". This has been updated to "Masahir... more The author's name was spelled incorrectly as "Masahir Okamoto". This has been updated to "Masahiro Okamoto" in the HTML and PDF of the article.

Research paper thumbnail of Chronic Intermittent Hypoxia Enhances Pathological Tau Seeding, Propagation, and Accumulation and Exacerbates Alzheimer-like Memory and Synaptic Plasticity Deficits and Molecular Signatures

Biological Psychiatry, 2021

BACKGROUND Obstructive sleep apnea, characterized by sleep fragmentation and chronic intermittent... more BACKGROUND Obstructive sleep apnea, characterized by sleep fragmentation and chronic intermittent hypoxia (CIH), is a risk factor for Alzheimer's disease (AD) progression. Recent epidemiological studies point to CIH as the best predictor of developing cognitive decline and AD in older adults with obstructive sleep apnea. However, the precise underlying mechanisms remain unknown. This study was undertaken to evaluate the effect of CIH on pathological human tau seeding, propagation, and accumulation; cognition; synaptic plasticity; neuronal network excitability; and gene expression profiles in a P301S human mutant tau mouse model of AD and related tauopathies. METHODS We exposed 4- to 4.5-month-old male P301S and wild-type mice to an 8-week CIH protocol (6-min cycle: 21% O2 to 8% O2 to 21% O2, 80 cycles per 8 hours during daytime) and assessed its effect on tau pathology and various AD-related phenotypic and molecular signatures. Age- and sex-matched P301S and wild-type mice were reared in normoxia (21% O2) as experimental controls. RESULTS CIH significantly enhanced pathological human tau seeding and spread across connected brain circuitry in P301S mice; it also increased phosphorylated tau load. CIH also exacerbated memory and synaptic plasticity deficits in P301S mice. However, CIH had no effect on seizure susceptibility and network hyperexcitability in these mice. Finally, CIH exacerbated AD-related pathogenic molecular signaling in P301S mice. CONCLUSIONS CIH-induced increase in pathologic human tau seeding and spread and exacerbation of other AD-related impairments provide new insights into the role of CIH and obstructive sleep apnea in AD pathogenesis.

Research paper thumbnail of Assessing the role of serotonergic receptors in cannabidiol's anticonvulsant efficacy

Epilepsy & Behavior, Aug 1, 2017

Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several ... more Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD's anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100 mg/kg) or vehicle 60 min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1 mg/kg), a 5HT1A antagonist, or saline vehicle injection 80 min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3 mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80 min prior to seizure testing. 85 mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30 min. Seizure behaviors were subsequently coded using a 5-point scale of severity. Across both experiments, subjects in the vehicle control groups exhibited high levels of seizure activity and mortality. In both experiments, CBD treatment significantly attenuated seizure activity. Pre-treatment with either WAY-100635 or MDL-100907 did not block CBD's anticonvulsant effect. WAY-100635 administration, by itself, also led to a significant attenuation of seizure activity. These results do not support the hypothesis that CBD attenuates seizure activity through activation of the 5HT1A or 5HT2A receptor. While this work further confirms the anticonvulsant efficacy of CBD and supports its application in the treatment of human seizure disorders, additional research on CBD's mechanism of action must be conducted.

Research paper thumbnail of Chronic intermittent hypoxia enhances tau seeding and propagation and exacerbates Alzheimer’s‐like memory and synaptic plasticity deficits and molecular signatures

Alzheimer's & Dementia, 2020

Obstructive sleep apnea (OSA), characterized by sleep fragmentation and chronic intermittent hypo... more Obstructive sleep apnea (OSA), characterized by sleep fragmentation and chronic intermittent hypoxia (CIH), is a risk factor for Alzheimer’s disease (AD) development and progression. Recent epidemiological studies point to CIH as the best predictor of developing cognitive decline and AD in elderly with OSA. However, the precise underlying mechanism(s) remain unknown. Tau pathology, a major neuropathological hallmark of the disease, is known to be correlated with cognitive impairment in AD. Further, increase in tau pathology has been linked to CIH suggesting that CIH may mediate AD risk through tau pathology. The present study was undertaken to evaluate the effect of CIH on human tau seeding and propagation, and to further investigate the effects of CIH on cognition, synaptic plasticity, neuronal network excitability, and gene expression profiles in a human mutant tau mouse model of AD and related tauopathies (P301S mice).

Research paper thumbnail of Neuronal Network Excitability in Alzheimer’s Disease: The Puzzle of Similar versus Divergent Roles of Amyloid β and Tau

eneuro

initial ideas related to the discussion and perspectives presented in manuscript were generated a... more initial ideas related to the discussion and perspectives presented in manuscript were generated and a part of this review was written. The authors would like to acknowledge the support from the Neuronal network excitability in Alzheimer's disease: The puzzle of similar versus divergent roles of amyloid β and tau

Research paper thumbnail of Assessing the role of serotonergic receptors in cannabidiol's anticonvulsant efficacy

Epilepsy & Behavior, 2017

Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several ... more Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD's anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100mg/kg) or vehicle 60min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1mg/kg), a 5HT1A antagonist, or saline vehicle injection 80min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80min prior to seizure testing. 85mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30min. Seizure behaviors were subsequently c...

Research paper thumbnail of Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease

Alzheimer’s disease (AD) represents a major healthcare burden with no effective treatment. The gl... more Alzheimer’s disease (AD) represents a major healthcare burden with no effective treatment. The glutamate modulator, riluzole, was shown to reverse many AD-related gene expression changes and improve cognition in aged rats. However, riluzole’s effect on amyloid beta (Aβ) pathology, a major histopathological hallmark of AD, remains unclear. 5XFAD transgenic mice, which harbor amyloid β precursor protein (APP) and presenilin mutations and exhibit early Aβ accumulation, were treated with riluzole from 1 to 6 months of age. Riluzole significantly enhanced cognition and reduced Aβ42, Aβ40, Aβ oligomers levels, and Aβ plaque load in 5XFAD mice. RNA-Sequencing showed that riluzole reversed many gene expression changes observed in the hippocampus of 5XFAD mice, predominantly in expression of canonical gene markers for microglia, specifically disease-associated microglia (DAM), as well as neurons and astrocytes. Central to the cognitive improvements observed, riluzole reversed alterations in ...

Research paper thumbnail of Chronic Intermittent Hypoxia Enhances Pathological Tau Seeding, Propagation, and Accumulation and Exacerbates Alzheimer-like Memory and Synaptic Plasticity Deficits and Molecular Signatures

Research paper thumbnail of Divergent roles of astrocytic versus neuronal EAAT2 deficiency on cognition and overlap with aging and Alzheimer’s molecular signatures

Proceedings of the National Academy of Sciences

The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain e... more The excitatory amino acid transporter 2 (EAAT2) is the major glutamate transporter in the brain expressed predominantly in astrocytes and at low levels in neurons and axonal terminals. EAAT2 expression is reduced in aging and sporadic Alzheimer’s disease (AD) patients’ brains. The role EAAT2 plays in cognitive aging and its associated mechanisms remains largely unknown. Here, we show that conditional deletion of astrocytic and neuronal EAAT2 results in age-related cognitive deficits. Astrocytic, but not neuronal EAAT2, deletion leads to early deficits in short-term memory and in spatial reference learning and long-term memory. Neuronal EAAT2 loss results in late-onset spatial reference long-term memory deficit. Neuronal EAAT2 deletion leads to dysregulation of the kynurenine pathway, and astrocytic EAAT2 deficiency results in dysfunction of innate and adaptive immune pathways, which correlate with cognitive decline. Astrocytic EAAT2 deficiency also shows transcriptomic overlaps with...

Research paper thumbnail of Correction: Riluzole reduces amyloid beta pathology, improves memory, and restores gene expression changes in a transgenic mouse model of early-onset Alzheimer’s disease

Translational Psychiatry, Feb 4, 2019

The author's name was spelled incorrectly as "Masahir Okamoto". This has been updated to "Masahir... more The author's name was spelled incorrectly as "Masahir Okamoto". This has been updated to "Masahiro Okamoto" in the HTML and PDF of the article.