Interplay of Neuroinflammation and Tau Transport in a Microfluidic Primary Neural Cell Tri-Culture Model
Interplay of Neuroinflammation and Tau Transport in a Microfluidic Primary Neural Cell Tri-Culture Model
批准号:
10289580
负责人:
Erkin Seker
金额:
$7.14万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-04-01 至 2022-03-31
关键词:
AchievementAddressAdministrative SupplementAlzheimer&aposs DiseaseAmericanAmyloid beta-ProteinAnatomyAnti-Inflammatory AgentsApoptosisAstrocytesAwardAxonAxonal TransportBeta CellBiochemicalBiological AssayBrainBrain DiseasesBrain regionCessation of lifeChemicalsCollaborationsComplexDementiaDepositionDiffuseDisease ProgressionDistalElderlyEngineeringEnsureFluorescence MicroscopyFormulationFoundationsFutureGoalsHealthHistologicHumanHydrostatic PressureIn VitroInflammationInterneuronsLeadLiquid substanceMemory impairmentMethodologyMicrofabricationMicrofluidicsMicrogliaModelingMolecular ConformationMonitorMorphologyNerve DegenerationNeurogliaNeuronsPathogenesisPathogenicityPathologicPilot ProjectsPlayProtein ConformationProteinsProteomicsRattusResistanceRoleRouteSenile PlaquesSignal TransductionSynapsesTissuesTransfectionaxon growthcognitive functioncytokinehuman old age (65+)hyperphosphorylated tauin vivoinsightminiaturizeneuroinflammationneuron lossneutralizing antibodynovelrapid testingrelating to nervous systemresponsetau Proteinstau expressiontau mutationtau-1therapeutic evaluationuptake
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Alzheimer’s Disease (AD) is a progressive neurodegenerative brain disorder that impairs memory and cognitive
functions. It is the most common dementia among older adults over age 65 and it is estimated that more than
5.8 million Americans may have dementia caused by AD. While the pathogenesis of AD is unclear, abnormal
deposits of amyloid-β (Aβ) plaques and hyperphosphorylated tau proteins throughout the brain are thought to
play a role in neuroinflammation, synapse loss, and neuronal cell death. While Aβ appears to spread in a diffuse
manner, phosphorylated tau proteins are hypothesized to propagate between synaptically connected neurons.
Recent studies suggest that the presence of Aβ may increase the rate of propagation, potentially due to
neuroinflammatory effects. In addition, neuroinflammation may directly induce or exacerbate Aβ and tau
proteinopathies, thereby worsen neuroinflammation and leading to further loss of synapses and neurons,
creating a vicious cycle that likely promotes disease progression. However, the exact mechanisms that underlie
propagation phosphorylated tau and its interplay with neuroinflammation remain elusive. Distinguishing these
complex factors from each other in vivo, where numerous confounding signals exist, is extremely challenging.
There is, therefore, a need for new methodologies to bridge this gap for revealing the underlying mechanisms
by which transport of aberrant proteins and neuroinflammation accelerate the progression of AD.
In order to address this need, we will employ a microfluidic in vitro platform in combination with a novel tri-culture
(primary neuron, astrocyte, microglia) rat model of neuroinflammation that have been developed as part of the
PIs’ current R03 award. The microfluidic platform consists of two physically distinct culture chambers (e.g.,
primary and secondary), corresponding to proximal and distal anatomic regions interconnected by microchannels
that allow synaptic connectivity between the two cultures. The immediate goal of this administrative supplement
is to study the contribution of glial cells and inflammation to the transport of abnormal tau proteins. Specifically,
we will (i) determine the influence of Aβ and phosphorylated human tau (expressed by transfected neurons) on
neuroinflammation in the tri-culture model, and (ii) employ the microfluidic platform to decouple the influences of
Aβ addition itself and the Aβ-triggered neuroinflammation on tau propagation along the axonal tracts connecting
the two cultures maintained in the primary and secondary chambers. The pilot study described here is expected
to (i) identify the influence of pathogenic conformations Aβ added to the culture and/or human tau expression
by transfected neurons on neuroinflammation, (ii) decouple the influence of pathogenic Aβ itself or its
corresponding neuroinflammatory cytokine profile on propagation of pathogenic tau via axonal tracts, and (iii)
establish the foundation for future mechanistic studies of the interplay between neuroinflammation and axonal
transport of pathogenic tau in the context of Alzheimer’s Disease.
期刊论文(6)
专著(0)
科研奖励(0)
会议论文
DOI:
10.3390/biomedicines10092122
发表时间:
2022-08-29
期刊:
BIOMEDICINES
影响因子:
4.7
作者:
[Goshi, Noah, Kim, Hyehyun, Seker, Erkin]
通讯作者:
Seker, Erkin
DOI:
10.3390/bios13060601
发表时间:
2023-05-31
期刊:
Biosensors
影响因子:
--
作者:
[]
通讯作者:
DOI:
10.3390/nano11020498
发表时间:
2021-02-16
期刊:
Nanomaterials (Basel, Switzerland)
影响因子:
--
作者:
[Palanisamy B, Goshi N, Seker E]
通讯作者:
Seker E
Neuronal Contribution to the Propagation of Inflammation in the Central Nervous System
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批准号:10042405
-
项目类别:
-
资助金额:$14.48万
-
财政年份:2020
-
负责人:Erkin Seker
-
依托单位:
海外基金