2,4-Diacetylphloroglucinol Reduces Beta-Amyloid Production and Secretion by Regulating ADAM10 and Intracellular Trafficking in Cellular and Animal Models of Alzheimer's Disease

초록

There is currently no effective treatment against Alzheimer's disease (AD), although many strategies have been applied to reduce beta-amyloid (A beta) levels. Here, we investigated 2,4-diacetylphloroglucinol (DAPG) effects on A beta levels and mechanisms of action. DAPG was the most effective phloroglucinol derivative for reducing A beta levels, without being toxic, in various models including HEK293 cells overexpressing Swedish mutant amyloid precursor protein (APP) (293sw), primary astrocytes isolated from APPsw/PS1dE9 transgenic mice, and after intrahippocampal injection of DAPG in APPsw/PS1dE9 transgenic mice. DAPG-mediated A beta reduction was associated with increased soluble APP alpha (sAPP alpha) levels mediated by a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) but not ADAM17. ADAM10 inhibition in DAPG-treated cells prevented the effects on sAPP alpha but only partly on intracellular and secreted A beta. To identify regulators of sAPP alpha and A beta secretion, various inhibitors of intracellular trafficking were administered with DAPG. Brefeldin A (BFA) reversed DAPG-mediated changes in A beta secretion in 293sw cells, whereas golgicide A (GCA) and BFA were effective in primary astrocytes, indicating a cell type-specific regulation of the trafficking. Moreover, GCA or BFA effects on sAPP alpha, but not A beta, levels in primary astrocytes resembled those of ADAM10 inhibition, indicating at least partly independent trafficking pathways for sAPP alpha and A beta. In conclusion, DAPG might be a promising drug candidate against AD regulating ADAM10 and intracellular trafficking, but optimizing DAPG ability to cross the BBB will be needed.

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