Role of HDAC4 in pre- and post-synaptic protein SUMOylation imbalance in a mouse model of Alzheimer’s disease

Early dysfunction in Alzheimer's disease (AD) is characterized by abnormal synapse structure and function. We investigated the role of the class II member HDAC4, which controls synaptic plasticity and memory, as potential new modulator of synaptic function in AD. HDAC4 localization and function was assessed in hippocampal tissue from adult control (WT) and 3×Tg mice (AD) by confocal analyses, co-IP and biochemical fractioning. The effects of the overexpression of a cytoplasmic mutant form of HDAC4 (HDACSD) or the empty vector were analyzed in cultured hippocampal neurons or organotypic brain slices from WT and AD mice.In WT mice, HDAC4 was localized at synapses and interacted with synapsin I and several post-synaptic proteins, whereas in the AD mice it underwent nuclear import (synaptic HDAC4 in AD: 0.62±0.08 vs WT; nuclear HDAC4 in AD: 2.14±0.36 vs WT). Similar results were found in WT neuronal cultures treated with Ab or tau. Loss of synaptic HDAC4 in AD was associated with decreased HDAC4-mediated SUMO2/3ylation of synapsin I and PSD95. Overexpression of HDAC4SD in AD hippocampal neurons recovered synapsin I SUMO2/3ylation and its clustering and interaction with actin favoring the formation of a reserve pool. At the post-synaptic domain HDAC4SD recovered PSD95 SUMO2/3ylation, dendritic length and expression of synaptic proteins. Moreover, in AD organotypic hippocampal slices HDAC4SD rescued spine density and synaptic transmission. Our results suggest a new HDAC4 synaptic function based on SUMOylation of synaptic proteins that can improve AD pathology.PRIN2022-2022H4MHXE