Exosome biology in Alzheimer's disease and concussion.
阿尔茨海默病和脑震荡中的外泌体生物学。
基本信息
- 批准号:10317655
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-15 至 2021-10-02
- 项目状态:已结题
- 来源:
- 关键词:3xTg-AD mouseAcuteAdultAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAlzheimer&aposs disease related dementiaAlzheimer&aposs disease riskAlzheimer’s disease biomarkerAmericanAmyloidAssessment toolAstrocytesBiologicalBiological MarkersBiologyBloodBlood - brain barrier anatomyBlood specimenBrainBrain ConcussionBrain InjuriesBrain PathologyCellsClinicalCognitiveCognitive deficitsCohort StudiesDataDementiaDiagnosticDiseaseDrug TargetingElderlyEquilibriumExposure toFemaleFutureGeneticGenetic DiseasesGoalsGrantHealthHumanHuman ResourcesIce HockeyImpaired cognitionIn VitroInflammationInjectionsInjuryItalyLabelLacrosseLeadLongitudinal StudiesManufactured footballMeasurementMental DepressionMilitary PersonnelMolecularMusNeuraxisNeurodegenerative DisordersNeuronsNewborn InfantPathologicPathologyPreventive treatmentResearchResearch PersonnelRiskSeedsSportsStreamSurfaceTechnologyTestingTextTransgenesTransgenic MiceTraumaWild Type Mouseage relatedagedamyloid pathologybasebiomarker panelbrain healthcohortdementia riskdesigndisabilitydrug developmentepidemiology studyequilibration disorderexosomeexperimental studyextracellular vesiclesin vivomalemild traumatic brain injurymilitary servicemouse modelnanosizedneuropathologynormal agingnovelnovel markerprimary outcomeprion-likeprognosticprogramspupresponsesecondary outcometau Proteinstau aggregationtooluptake
项目摘要
ABSTRACT
Repeated concussions (mild Traumatic Brain Injury, mTBI), which are particularly prevalent in athletes and
military personnel, can lead to long-term brain health issues including dementia, depression, and other
psychiatric conditions. Recent studies suggest that mTBIs may give rise to increased risk for Alzheimer's disease
(AD) or other AD-related dementias (ADRDs), but there are few conclusive studies, and no reliable blood
biomarkers available as a predictive diagnostic tool. We are studying a unique cohort of NCAA Division I athletes
in high impact sports to develop a reliable blood biomarker assessment and examine biological mechanisms for
AD/ADRD risk after multiple mTBIs. To our knowledge, studies have not been conducted using neuron- or
astrocyte-derived exosomes (NDEs vs. ADEs) to detect Tau and amyloid pathology and seeding capacity from
those with sports-related brain injuries. The revised application now contains more specifics regarding the
existing cohort and the experiments proposed. The overall hypothesis of this project is that exosome
alterations after repeated mTBIs reflect and contribute to long-term risk for AD/ADRD. In Aim 1, we will
test the hypothesis that NDE and ADE biomarkers correlate with cognitive dysfunction following one or repeated
mTBIs in humans. Experiments in this Aim will validate exosomal biomarkers and distinguish between cargos
obtained from NDEs vs. ADEs. In Aim 2, we will test the hypothesis that age-dependent and genetics-driven
cognitive decline and brain pathology are accelerated following either repeated mTBIs or injection of TBI-derived
exosomes in mice. The relationship between a transgene leading to amyloid and Tau aggregation and added
trauma via repeated mTBIs will be examined. In Aim 3, we hypothesize that NDEs vs. ADEs from athletes with
multiple mTBIs can elicit differential responses in primary cortical neuronal cultures. We propose that NDEs
and/or ADEs from athletes with repeated mTBIs can propagate AD pathology to primary neuronal cultures.
Our interdisciplinary team has the unique potential to reveal molecular mechanisms involved in AD pathology
after mTBIs, using a unique cohort consisting of male and female Division I athletes including baseline and post-
concussion measurements. In the revised submission, we are proposing to use primary cultures from 3xTg-AD
or wildtype mouse pups, to connect the in vivo studies in Aim 2 with the in vitro studies in Aim 3. The major
goal of this research program is to develop sensitive biomarkers post-concussion that could predict future risk
for AD/ADRD and to reveal mechanisms for exosome propagation of brain pathology post-mTBI. The unique
value of this program is the interdisciplinary team, including both mouse models and human studies, the large
cohort of Division I athletes, and the long-term biomarker studies proposed. Based on the biological
mechanisms examined herein, and the wealth of preliminary data, we will be able to design better preventative
treatment options long-term for those with one or several mTBIs who are at risk of developing dementia.
摘要
项目成果
期刊论文数量(0)
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Ann-Charlotte Esther Granholm-Bentley其他文献
Ann-Charlotte Esther Granholm-Bentley的其他文献
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{{ truncateString('Ann-Charlotte Esther Granholm-Bentley', 18)}}的其他基金
Exosome biology in Alzheimer's disease and concussion
阿尔茨海默病和脑震荡中的外泌体生物学
- 批准号:
10468223 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Exosome biology in Alzheimer's disease and concussion
阿尔茨海默病和脑震荡中的外泌体生物学
- 批准号:
10577115 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Exosome biology in Alzheimer's disease and concussion
阿尔茨海默病和脑震荡中的外泌体生物学
- 批准号:
10614055 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Tau pathology in Down syndrome and Alzheimer's
唐氏综合症和阿尔茨海默病中的 Tau 蛋白病理学
- 批准号:
10596917 - 财政年份:2019
- 资助金额:
-- - 项目类别:
Biological Correlates of Alzheimer in Down Syndrome.
唐氏综合症中阿尔茨海默病的生物学相关性。
- 批准号:
9375943 - 财政年份:2017
- 资助金额:
-- - 项目类别:
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