Studies On Contribution Of Astrocytes To Neuron Death In Alzheimer’s Disease
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Studies On Contribution Of Astrocytes To Neuron Death In
Alzheimer’s Disease
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| Creator |
Saha, Pampa
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| Subject |
Cell Biology & Physiology
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| Description |
Astrocyte activation is one of the crucial characteristics of several neurodegenerative disorders including Alzheimer’s disease (AD). In AD, amyloid-β (Aβ) which is considered to be main causative factor for neuronal death, activates astrocytes. Astrocyte activation has both beneficial and detrimental effect on neuron health. But, neither the pathway through which astrocytes are being affected by Aβ nor the molecular mechanisms by which activated astrocytes are affecting neuron health has been deciphered. The endeavour of this thesis was first to characterise astrocyte activation upon Aβ exposure and identify the molecular mechanisms of astrocyte activation evoked by Aβ oligomer. Secondly our aim was to check how exactly astrocyte activation influence neuron health in a cell culture model of AD.
We found that a lower concentration (1.5μM) of Aβ oligomer causes astrocytes to proliferate and change their morphology whereas higher dose (4μM) of Aβ rather induces astrocyte cell death. Astrocyte cell death upon high Aβ concentration, then found to be mediated through FoxO3a/Bim/Caspase3 signal axis whereas a couple of MAPK pathways have been found to be involved in low Aβ dose. Interestingly we found a strong correlation between activation of both p38k and JNK/c-Jun pathways and Aβ induced astrocyte cell proliferation. Only p38K pathway was found to be involved in morphological changes of astrocytes due to Aβ.
Next in order to identify the role of astrocytes on neuron in AD condition we performed an investigation on the secretion profile of activated astrocytes. Tissue inhibitor of matrixmetalloproteinase-1 (Timp-1) which is a MMP inhibitor, has been found to be increased in Astrocyte conditioned medium (ACM) upon Aβ. AD brain contains high level of Timp-1 but its precise role on neurons remains to be elusive. Here we are demonstrating that Timp-1 is significantly neuroprotective against Aβ as recombinant Timp-1 rescued both cortical and hippocampal neurons but deprivation of timp-1 from ACM fails to protect neurons from Aβ. In addition the arborisations of neurons were poor particularly with the astrocytes in which timp-1 was knocked down in culture condition. Finally we found, Timp-1 restores Akt survival signal in neurons even in the presence of Aβ and thus can protect them.
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| Date |
2016-09-23
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| Type |
Thesis
NonPeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2577/1/01_THESIS___PAMPA_SAHA.pdf
Saha, Pampa (2016) Studies On Contribution Of Astrocytes To Neuron Death In Alzheimer’s Disease. PhD thesis, C U. |
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| Relation |
http://www.eprints.iicb.res.in/2577/
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