Abstract
Epigenetic regulation by histone deacetylase (HDAC) is associated with synaptic plasticity and memory formation, and its aberrant expression has been linked to cognitive disorders, including Alzheimer’s disease (AD). This study aimed to investigate the role of class IIa HDAC expression in AD and monitor it in vivo using a novel radiotracer, 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]TFAHA). A human neural cell culture model with familial AD (FAD) mutations was established and used for in vitro assays. Positron emission tomography (PET) imaging with [18F]TFAHA was performed in a 3xTg AD mouse model for in vivo evaluation. The results showed a significant increase in HDAC4 expression in response to amyloid-β (Aβ) deposition in the cell model. Moreover, treatment with an HDAC4 selective inhibitor significantly upregulated the expression of neuronal memory-/synaptic plasticity-related genes. In [18F]TFAHA-PET imaging, whole brain or regional uptake was significantly higher in 3xTg AD mice compared with WT mice at 8 and 11 months of age. Our study demonstrated a correlation between class IIa HDACs and Aβs, the therapeutic benefit of a selective inhibitor, and the potential of using [18F]TFAHA as an epigenetic radiotracer for AD, which might facilitate the development of AD-related neuroimaging approaches and therapies.
Highlights
The characteristics of Alzheimer’s disease (AD) include abnormal deposition of amyloid-β (Aβ) plaques, synaptic degeneration, and neuronal loss [1,2]
Almost of all pan-inhibitor treatments can upregulate GLUR2, ments can upregulate GLUR2, which encodes the subunit protein of the AMPA receptor: which encodes the subunit protein of the AMPA receptor: we used this gene as we used this gene as a positive control. These results demonstrated that HDAC4 a positive control. These results demonstrated that HDAC4 inhibition upregulated the inhibition upregulated the expression of target genes, suggesting the HDAC4 restored expression of target genes, suggesting the HDAC4 restored AD-associated gene expression
Our results showed that certain HDAC4 target genes involved in synaptic plasticity in familial AD (FAD) cells were upregulated after treatment with TasQ (Figure 3)
Summary
The characteristics of Alzheimer’s disease (AD) include abnormal deposition of amyloid-β (Aβ) plaques, synaptic degeneration, and neuronal loss [1,2]. An increasing number of studies indicate that impaired learning and deterioration of memory are associated with abnormal epigenetic modifications [5,6,7]. The widespread downregulation in gene expression is affected by post-translational histone modifications in which histone deacetylases (HDACs), histone acetyltransferases (HATs), histone methyltransferases (HMTs), and various DNA demethylases participate [8]. Among all HDAC family members, class I HDACs (HDAC1, 2, 3, and 8) are known to be ubiquitously expressed in different cell types and contain a deacetylase domain that can remove an acetyl group from other proteins efficiently. Class IIa HDACs (HDAC 4, 5, 7, and 9) have tissue-specific expression, primarily in the heart, skeletal muscle, and brain, and exhibit very low intrinsic deacetylase activity [9,10].
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