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Morphological and functional consequ...

Kopeikina, Katherine Julia.

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Morphological and functional consequences of pathological changes in tau: Are aggregated or soluble forms of tau detrimental to neurons?

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Morphological and functional consequences of pathological changes in tau: Are aggregated or soluble forms of tau detrimental to neurons?/
作者:	Kopeikina, Katherine Julia.
面頁冊數:	175 p.
附註:	Source: Dissertation Abstracts International, Volume: 74-07(E), Section: B.
Contained By:	Dissertation Abstracts International74-07B(E).
標題:	Biology, Neurobiology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3536997
ISBN:	9781267959775

Morphological and functional consequences of pathological changes in tau: Are aggregated or soluble forms of tau detrimental to neurons?
Kopeikina, Katherine Julia.

Morphological and functional consequences of pathological changes in tau: Are aggregated or soluble forms of tau detrimental to neurons? - 175 p.

Source: Dissertation Abstracts International, Volume: 74-07(E), Section: B.

Thesis (Ph.D.)--Boston University, 2013.

Tau is a microtubule-associated protein. In Alzheimer's Disease (AD), the intracellular accumulation of fibrillar tau, or neurofibrillary tangles (NFT), has been considered a cause of neuronal death. However, recent evidence challenges this idea. Other forms of tau, such as soluble misfolded, hyperphosphorylated, and mislocalized forms, are now implicated as toxic. The basic question addressed in this study is: which form of tau, soluble or aggregated, is more detrimental to neuronal structure and function? A mouse model (rTg4510) that over-expresses human mutant tau and develops NFT was used for all experiments. These animals harbor a doxycycline-regulatable transgene that serves as an 'off-switch' for tau over-expression, that can be applied after formation of NFT, providing the opportunity to dissociate soluble tau and NFT. Tau over-expression in cell culture has been shown to impair localization and trafficking of organelles. We tested the hypothesis that changes in mitochondrial distribution occur secondary to pathological changes in tau, that only occur in vivo. Array tomography, a high-resolution imaging technique, was used to demonstrate that mitochondrial distribution is disrupted in rTg4510 neurons but can recover following suppression of soluble tau, though NFT persist. As mitochondria are crucial for calcium buffering, the second set of studies tested the hypothesis that tau over-expression leads to calcium dysregulation in the rTg4510 mouse brain. In-vivo imaging of a FRET-based ratiometric calcium indicator showed generalized elevation of resting calcium levels in dendrites and axons of rTg4510 mice with a fraction of these exhibiting calcium overload. This calcium dysregulation recovers following suppression of soluble tau over-expression, even in the continued presence of NFT, suggesting soluble tau as detrimental. Since normal synaptic function requires the presence of mitochondria and regulation of intracellular calcium levels, we tested the hypothesis that tau over-expression results in synapse loss in rTg4510 mice. Array tomography indicated maintenance of overall synapse density though cortical atrophy is known to occur in these animals, while in-vivo imaging showed loss of linear dendritic spine density, altogether suggesting synapse loss commensurate with volume loss in these mice. Taken together these studies support soluble forms of pathological tau in disruption of neuronal structure and function.

ISBN: 9781267959775Subjects--Topical Terms:

1681328
Biology, Neurobiology.

Morphological and functional consequences of pathological changes in tau: Are aggregated or soluble forms of tau detrimental to neurons?
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