Effect of Trichostatin A on Gelsolin Levels, Proteolysis of Amyloid Precursor Protein, and Amyloid Beta-Protein Load in the Brain of Transgenic Mouse Model of Alzheimer's Disease

Author(s): Wenzhong Yang, Abha Chauhan, Jerzy Wegiel, Izabela Kuchna, Feng Gu, Ved Chauhan

Journal Name: Current Alzheimer Research

Volume 11 , Issue 10 , 2014

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In vivo and in vitro studies have shown that gelsolin is an anti-amyloidogenic protein. Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, promotes the expression of gelsolin. Fibrillized amyoid beta-protein (Aβ) is a key constituent of amyloid plaques in the brains of patients with Alzheimer’s disease (AD). We studied the effects of TSA on the levels of gelsolin; amyloid precursor protein (APP); proteolytic enzymes (γ-secretase and β-secretase) responsible for the production of Aβ; Aβ-cleaving enzymes, i.e., neprilysin (NEP) and insulin-degrading enzyme (IDE); and amyloid load in the double transgenic (Tg) APPswe/PS1δE9 mouse model of AD. Intraperitoneal injection of TSA for two months (9–11 months of age) resulted in decreased activity of HDAC, and increased levels of gelsolin in the hippocampus and cortex of the brain in AD Tg mice as compared to vehicle-treated mice. TSA also increased the levels of γ-secretase and β-secretase activity in the brain. However, TSA did not show any effect on the activities or the expression levels of NEP and IDE in the brain. Furthermore, TSA treatment of AD Tg mice showed no change in the amyloid load (percent of examined area occupied by amyloid plaques) in the hippocampus and cortex, suggesting that TSA treatment did not result in the reduction of amyloid load. Interestingly, TSA prevented the formation of new amyloid deposits but increased the size of existing plaques. TSA treatment did not cause any apoptosis in the brain. These results suggest that TSA increases gelsolin expression in the brain, but the pleiotropic effects of TSA negate the anti-amyloidogenic effect of gelsolin in AD Tg mice.

Keywords: Alzheimer's disease, amyloid plaques, gelsolin, histone deacetylase, insulin-degrading enzyme, neprilysin, secretases, transgenic mice, trichostatin A.

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Article Details

Year: 2014
Published on: 28 November, 2014
Page: [1002 - 1011]
Pages: 10
DOI: 10.2174/1567205011666141107125531
Price: $65

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