A Class I HDAC Inhibitor BG45 Alleviates Cognitive Impairment through the CaMKII/ITPKA/Ca²⁺ Signaling Pathway

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Alzheimer's disease (AD) poses a significant global health challenge with no effective clinical treatments currently available.
• Investigating novel therapeutic targets is crucial for developing effective AD interventions.
• Histone deacetylase inhibitors (HDACIs) are emerging as potential therapeutic agents for neurodegenerative disorders.

Purpose of the Study:

• To investigate the effect of the class I histone deacetylase inhibitor (HDACI) BG45 on synapse-related proteins in Alzheimer's disease (AD) models.
• To evaluate the therapeutic potential of BG45 in improving cognitive function and alleviating AD pathology in vivo.
• To elucidate the molecular mechanisms underlying BG45's effects on synaptic plasticity and neuronal function.

Main Methods:

• Primary neurons from APP/PS1 transgenic mice were used for in vitro studies.
• In vivo studies involved treating APPswe/PS1dE9 (APP/PS1) transgenic mice with BG45.
• Behavioral testing, proteomic analysis, and molecular pathway verification were employed.

Main Results:

• BG45 upregulated synaptotagmin-1 (SYT-1) and neurofilament light chain (NF-L) in primary neurons.
• BG45 treatment improved learning and memory in APP/PS1 mice.
• BG45 alleviated dendritic spine damage, reduced amyloid-beta (Aβ) deposition, and increased synapse-related proteins in the prefrontal cortex.
• Proteomic analysis revealed alterations in energy metabolism and calmodulin regulation pathways.
• The CaMKII/ITPKA/Ca²⁺ pathway was implicated in BG45's effects.

Conclusions:

• Class I HDACI BG45 demonstrates potential as a therapeutic agent for early Alzheimer's disease treatment.
• BG45 positively impacts synaptic function, cognitive performance, and AD pathology.
• Further research into the CaMKII/ITPKA/Ca²⁺ pathway could reveal novel therapeutic strategies for AD.