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The Role of Histone Deacetylase 3 (H...

Janczura, Karolina J.

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The Role of Histone Deacetylase 3 (HDAC3) in Alzheimer's Disease (AD)-Related Pathologies In Vitro and in the Triple Transgenic AD Mouse Model.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Role of Histone Deacetylase 3 (HDAC3) in Alzheimer's Disease (AD)-Related Pathologies In Vitro and in the Triple Transgenic AD Mouse Model./
Author:	Janczura, Karolina J.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	140 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-12, Section: B.
Contained By:	Dissertations Abstracts International80-12B.
Subject:	Neurosciences. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13885116
ISBN:	9781392230893

The Role of Histone Deacetylase 3 (HDAC3) in Alzheimer's Disease (AD)-Related Pathologies In Vitro and in the Triple Transgenic AD Mouse Model.
Janczura, Karolina J.

The Role of Histone Deacetylase 3 (HDAC3) in Alzheimer's Disease (AD)-Related Pathologies In Vitro and in the Triple Transgenic AD Mouse Model. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 140 p.

Source: Dissertations Abstracts International, Volume: 80-12, Section: B.

Thesis (Ph.D.)--University of Miami, 2019.

This item must not be sold to any third party vendors.

Alzheimer's disease (AD) is the leading cause of age-related dementia. Neuropathological hallmarks of AD include brain deposition of β-amyloid (Aβ) plaques and accumulation of both hyperphosphorylated and acetylated tau. Here, we demonstrate that HDAC3 is a negative regulator of AD pathophysiology. RGFP-966, a brain-penetrant and selective HDAC3 inhibitor, or HDAC3 knockdown increases BDNF expression, increases histone H3 and H4 acetylation, decreases tau phosphorylation and tau acetylation at disease-associated sites, reduces β-secretase cleavage of the amyloid precursor protein (APP) and decreases Aβ1-42 accumulation in HEK-293 cells over-expressing APP with the double Swedish mutation (HEK/APPsw). In the triple transgenic AD mouse model (3xTg-AD), repeated administration of 3 and 10 mg/kg of RGFP-966 reverses pathological tau phosphorylation at Thr181, Ser202 and Ser396, increases levels of the Aβ degrading enzyme Neprilysin in the plasma, decreases Aβ1-42 protein levels in the brain and periphery and improves spatial learning and memory. Lastly, we show that HDAC3 activity, Aβ1-42 accumulation and pathological tau acetylation and phosphorylation decrease in response to RGFP-966 in neurons derived from induced pluripotent stem cells (iPSCs) obtained from APOEε4-carrying AD patients. These data indicate that HDAC3 plays an important regulatory role in the expression and regulation of proteins associated with AD pathophysiology, supporting the notion that HDAC3 may be a disease-modifying therapeutic target.

ISBN: 9781392230893Subjects--Topical Terms:

588700
Neurosciences.

The Role of Histone Deacetylase 3 (HDAC3) in Alzheimer's Disease (AD)-Related Pathologies In Vitro and in the Triple Transgenic AD Mouse Model.
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100 1 $a Janczura, Karolina J. $3 3434280
245 1 4 $a The Role of Histone Deacetylase 3 (HDAC3) in Alzheimer's Disease (AD)-Related Pathologies In Vitro and in the Triple Transgenic AD Mouse Model.
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500 $a Publisher info.: Dissertation/Thesis.
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502 $a Thesis (Ph.D.)--University of Miami, 2019.
506 $a This item must not be sold to any third party vendors.
520 $a Alzheimer's disease (AD) is the leading cause of age-related dementia. Neuropathological hallmarks of AD include brain deposition of β-amyloid (Aβ) plaques and accumulation of both hyperphosphorylated and acetylated tau. Here, we demonstrate that HDAC3 is a negative regulator of AD pathophysiology. RGFP-966, a brain-penetrant and selective HDAC3 inhibitor, or HDAC3 knockdown increases BDNF expression, increases histone H3 and H4 acetylation, decreases tau phosphorylation and tau acetylation at disease-associated sites, reduces β-secretase cleavage of the amyloid precursor protein (APP) and decreases Aβ1-42 accumulation in HEK-293 cells over-expressing APP with the double Swedish mutation (HEK/APPsw). In the triple transgenic AD mouse model (3xTg-AD), repeated administration of 3 and 10 mg/kg of RGFP-966 reverses pathological tau phosphorylation at Thr181, Ser202 and Ser396, increases levels of the Aβ degrading enzyme Neprilysin in the plasma, decreases Aβ1-42 protein levels in the brain and periphery and improves spatial learning and memory. Lastly, we show that HDAC3 activity, Aβ1-42 accumulation and pathological tau acetylation and phosphorylation decrease in response to RGFP-966 in neurons derived from induced pluripotent stem cells (iPSCs) obtained from APOEε4-carrying AD patients. These data indicate that HDAC3 plays an important regulatory role in the expression and regulation of proteins associated with AD pathophysiology, supporting the notion that HDAC3 may be a disease-modifying therapeutic target.
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