Publication Date

2019-05-13

Availability

Open access

Embargo Period

2019-05-13

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Molecular and Cellular Pharmacology (Medicine)

Date of Defense

2019-04-04

First Committee Member

Grace Zhai

Second Committee Member

Vladlen Slepak

Third Committee Member

Lluis Morey

Fourth Committee Member

Claes Wahlestedt

Fifth Committee Member

Gavin Rumbaugh

Abstract

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 theAlzheimer’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.

Keywords

Epigenetics; HDAC; Alzheimer's Disease; Amyloid; Tau

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