Apicidin attenuates memory deficits by reducing the Aβ load in APP/PS1 mice

• Published in: CNS neuroscience & therapeutics Vol. 29; no. 5; pp. 1300 - 1311
• Main Authors: Luo, Biao, Chen, Jian, Zhou, Gui‐Feng, Xie, Xiao‐Yong, Tang, Jing, Wen, Qi‐Xin, Song, Li, Xie, Shi‐Qi, Long, Yan, Chen, Guo‐Jun, Hu, Xiao‐Tong
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.05.2023; John Wiley and Sons Inc
• Subjects: ADAM10; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Animals; apicidin; Dementia; Disease Models, Animal; Enzyme-linked immunosorbent assay; Epigenetics; Fear conditioning; Histone deacetylase; histone deacetylase inhibitor; Laboratory animals; Memory; Memory Disorders - drug therapy; Memory Disorders - etiology; Memory Disorders - metabolism; Mice; Mice, Transgenic; Neurodegenerative diseases; Original; Phosphorylation; phosphorylation tau; Presenilin 1; Presenilin-1 - genetics; Presenilin-1 - metabolism; Proteins; Proteolysis; Secretase; Software; Spatial Memory; Tau protein; Western blotting; ADAM10; phosphorylation tau; apicidin; Alzheimer's disease; histone deacetylase inhibitor
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.14102

Aims Amyloid beta (Aβ) is an important pathological feature of Alzheimer's disease (AD). A disintegrin and metalloproteinase 10 (ADAM10) can reduce the production of toxic Aβ by activating the nonamyloidogenic pathway of amyloid precursor protein (APP). We previously found that apicidin, which is a histone deacetylase (HDAC) inhibitor, can promote the expression of ADAM10 and reduce the production of Aβ in vitro. This study was designed to determine the potential of apicidin treatment to reverse learning and memory impairments in an AD mouse model and the possible correlation of these effects with ADAM10. Methods Nine‐month‐old APP/PS1 mice and C57 mice received intraperitoneal injections of apicidin or vehicle for 2 months. At 11 months of age, we evaluated the memory performance of mice with Morris water maze (MWM) and context fear conditioning tests. The Aβ levels were assessed in mouse brain using the immunohistochemical method and ELISA. The expression of corresponding protein involved in proteolytic processing of APP and the phosphorylation of tau were assessed by Western blotting. Results Apicidin reversed the deficits of spatial reference memory and contextual fear memory, attenuated the formation of Aβ‐enriched plaques, and decreased the levels of soluble and insoluble Aβ40/42 in APP/PS1 mice. Moreover, apicidin significantly increased the expression of ADAM10, improved the level of sAPPα, and reduced the production of sAPPβ, but did not affect the levels of phosphorylated tau in APP/PS1 mice. Conclusion Apicidin significantly improves the AD symptoms of APP/PS1 mice by regulating the expression of ADAM10, which may contribute to decreasing the levels of Aβ rather than decreasing the phosphorylation of tau. Apicidin improves cognitive deficits in APP/PS1 mice by promoting ADAM10 expression. The α‐site cleavage of APP by ADAM10 generates more sAPPα relative to sAPPβ, leading to the decreased Aβ burden, which contributes to the reversal of memory deficits in AD. The present work highlights the crucial role of histone deacetylase inhibitors in alleviating AD‐like pathology and supports that ADAM10 could serve as a disease‐modifying and therapeutic target.