Department of Engineering, Istituto di Analisi dei Sistemi ed Informatica 'Antonio Ruberti', National Research Council, Rome, Italy.
Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
Neuropathol Appl Neurobiol. 2023 Feb;49(1):e12861. doi: 10.1111/nan.12861. Epub 2022 Nov 15.
Early dysfunction in Alzheimer's disease (AD) is characterised by alterations of synapse structure and function leading to dysmorphic neurites, decreased spine density, impaired synaptic plasticity and cognitive deficits. The class II member HDAC4, which recently emerged as a crucial factor in shaping synaptic plasticity and memory, was found to be altered in AD. We investigated how the modulation of HDAC4 may contribute to counteracting AD pathogenesis.
Using a cytoplasmic HDAC4 mutant (HDAC4 ), we studied the recovery of synaptic function in hippocampal tissue and primary neurons from the triple-transgenic mouse model of AD (3×Tg-AD).
Here, we report that in wild-type mice, HDAC4 is localised at synapses and interacts with postsynaptic proteins, whereas in the 3×Tg-AD, it undergoes nuclear import, reducing its interaction with synaptic proteins. Of note, HDAC4 delocalisation was induced by both amyloid-β and tau accumulation. Overexpression of the HDAC4 mutant in CA1 pyramidal neurons of organotypic hippocampal slices obtained from 3×Tg-AD mice increased dendritic length and promoted the enrichment of N-cadherin, GluA1, PSD95 and CaMKII proteins at the synaptic level compared with AD neurons transfected with the empty vector. Moreover, HDAC4 overexpression recovered the level of SUMO2/3ylation of PSD95 in AD hippocampal tissue, and in AD organotypic hippocampal slices, the HDAC4 rescued spine density and synaptic transmission.
These results highlight a new role of cytoplasmic HDAC4 in providing a structural and enzymatic regulation of postsynaptic proteins. Our findings suggest that controlling HDAC4 localisation may represent a promising strategy to rescue synaptic function in AD, potentially leading to memory improvement.
阿尔茨海默病（AD）早期功能障碍的特征是突触结构和功能的改变，导致神经突形态异常、棘突密度降低、突触可塑性受损和认知功能障碍。最近发现 II 类组蛋白去乙酰化酶 4（HDAC4）是调节突触可塑性和记忆的关键因素，其在 AD 中发生改变。我们研究了 HDAC4 的调节如何有助于对抗 AD 的发病机制。
使用细胞质 HDAC4 突变体（HDAC4），我们研究了 AD 三转基因小鼠模型（3×Tg-AD）海马组织和原代神经元中突触功能的恢复情况。
在这里，我们报告在野生型小鼠中，HDAC4 定位于突触并与突触后蛋白相互作用，而在 3×Tg-AD 中，它发生核内易位，减少与突触蛋白的相互作用。值得注意的是，HDAC4 易位是由淀粉样蛋白-β和 tau 积累诱导的。在从 3×Tg-AD 小鼠获得的器官型海马切片的 CA1 锥体神经元中过表达 HDAC4 突变体，与转染空载体的 AD 神经元相比，增加了树突长度，并促进了 N-钙黏蛋白、GluA1、PSD95 和 CaMKII 蛋白在突触水平的富集。此外，HDAC4 过表达恢复了 AD 海马组织中 PSD95 的 SUMO2/3 化水平，在 AD 器官型海马切片中，HDAC4 挽救了棘突密度和突触传递。
这些结果突出了细胞质 HDAC4 在提供突触后蛋白的结构和酶调节方面的新作用。我们的研究结果表明，控制 HDAC4 的定位可能是挽救 AD 中突触功能的一种有前途的策略，可能导致记忆改善。
