Title: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
Volume: 11
Issue: 10
Author(s): Wenzhong Yang, Abha Chauhan, Jerzy Wegiel, Izabela Kuchna, Feng Gu and Ved Chauhan
Affiliation:
关键词:
阿尔茨海默病，淀粉样蛋白斑块，凝溶胶蛋白，组蛋白去乙酰化酶，胰岛素降解酶，脑啡肽酶，分泌酶，转基因大鼠，曲古抑菌素A
摘要: 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.
