HDAC6 modulates the cognitive behavioral function and hippocampal tissue pathological changes of APP/PS1 transgenic...

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Alzheimer's disease (AD) is characterized by amyloid-beta oligomers (Aβo) and hyperphosphorylated Tau (p-Tau).
• Histone deacetylase 6 (HDAC6) and heat shock protein 90 (HSP90)-heat shock transcription factor 1 (HSF1) pathway involvement in AD pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the role of HDAC6 in modulating the HSP90-HSF1 pathway.
• To determine the effects of HDAC6 and HSP90-HSF1 on Aβo and p-Tau levels.
• To assess the impact on cognitive behavior in an AD mouse model.

Main Methods:

• Utilized APP/PS1 transgenic mice and HT22 neuronal cells.
• Administered HDAC6 inhibitors/agonists and HSP90 inhibitors.
• Assessed cognitive function using the Morris water maze test.
• Analyzed protein and mRNA levels via Western blot, immunohistochemistry, immunofluorescence, and qRT-PCR.

Main Results:

• In APP/PS1 mice, elevated HDAC6, Aβo, and p-Tau correlated with decreased HSP90 and HSF1.
• HDAC6 inhibition improved cognitive function, reduced Aβo and p-Tau, and increased HSP90/HSF1.
• HSP90 modulation in HT22 cells affected HSF1, Aβo, p-Tau, and cell viability.

Conclusions:

• HDAC6 inhibition ameliorates AD pathology and cognitive deficits in mice.
• The HSP90-HSF1 pathway is a key regulator influenced by HDAC6.
• Targeting HDAC6 may offer a therapeutic strategy for Alzheimer's disease by modulating the HSP90-HSF1 pathway.