Evaluation of Class IIa Histone Deacetylases Expression and In Vivo Epigenetic Imaging in a Transgenic Mouse Model of Alzheimer’s Disease

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.

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Increased levels of Stress-inducible phosphoprotein-1 accelerates amyloid-β deposition in a mouse model of Alzheimer’s disease

Acta Neuropathologica Communications ◽

10.1186/s40478-020-01013-5 ◽

2020 ◽

Vol 8 (1) ◽

Author(s):

Rachel E. Lackie ◽

Jose Marques-Lopes ◽

Valeriy G. Ostapchenko ◽

Sarah Good ◽

Wing-Yiu Choy ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Protein Quality ◽

Amyloid Β ◽

Amyloid Burden ◽

C Elegans ◽

Model Of Alzheimer’S Disease

Abstract Molecular chaperones and co-chaperones, which are part of the protein quality control machinery, have been shown to regulate distinct aspects of Alzheimer’s Disease (AD) pathology in multiple ways. Notably, the co-chaperone STI1, which presents increased levels in AD, can protect mammalian neurons from amyloid-β toxicity in vitro and reduced STI1 levels worsen Aβ toxicity in C. elegans. However, whether increased STI1 levels can protect neurons in vivo remains unknown. We determined that overexpression of STI1 and/or Hsp90 protected C. elegans expressing Aβ(3–42) against Aβ-mediated paralysis. Mammalian neurons were also protected by elevated levels of endogenous STI1 in vitro, and this effect was mainly due to extracellular STI1. Surprisingly, in the 5xFAD mouse model of AD, by overexpressing STI1, we find increased amyloid burden, which amplifies neurotoxicity and worsens spatial memory deficits in these mutants. Increased levels of STI1 disturbed the expression of Aβ-regulating enzymes (BACE1 and MMP-2), suggesting potential mechanisms by which amyloid burden is increased in mice. Notably, we observed that STI1 accumulates in dense-core AD plaques in both 5xFAD mice and human brain tissue. Our findings suggest that elevated levels of STI1 contribute to Aβ accumulation, and that STI1 is deposited in AD plaques in mice and humans. We conclude that despite the protective effects of STI1 in C. elegans and in mammalian cultured neurons, in vivo, the predominant effect of elevated STI1 is deleterious in AD.

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Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-151046 ◽

2016 ◽

Vol 52 (1) ◽

pp. 223-242 ◽

Cited By ~ 9

Author(s):

Patricia R. Spilman ◽

Veronique Corset ◽

Olivia Gorostiza ◽

Karen S. Poksay ◽

Veronica Galvan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Amyloid Β ◽

Model Of Alzheimer’S Disease

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Cognition and memory function of Taraxacum coreanum in an in vivo amyloid-β-induced mouse model of Alzheimer’s disease

Archives of Biological Sciences ◽

10.2298/abs1404357l ◽

2014 ◽

Vol 66 (4) ◽

pp. 1357-1366 ◽

Cited By ~ 4

Author(s):

Ah Lee ◽

Noriko Yamabe ◽

Ki Kang ◽

Young Kim ◽

Sanghyun Lee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Memory Function ◽

Amyloid Β ◽

Model Of Alzheimer’S Disease ◽

Taraxacum Coreanum

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A rationally designed small molecule for identifying an in vivo link between metal–amyloid-β complexes and the pathogenesis of Alzheimer's disease

Chemical Science ◽

10.1039/c4sc03239j ◽

2015 ◽

Vol 6 (3) ◽

pp. 1879-1886 ◽

Cited By ~ 46

Author(s):

Michael W. Beck ◽

Shin Bi Oh ◽

Richard A. Kerr ◽

Hyuck Jin Lee ◽

So Hee Kim ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Small Molecule ◽

Amyloid Β ◽

Model Of Alzheimer’S Disease ◽

5Xfad Mouse ◽

Target Metal

An in vivo chemical tool designed to target metal−Aβ complexes and modulate their activity was applied to the 5XFAD mouse model of Alzheimer’s disease (AD) demonstrating the involvement of metal−Aβ in AD pathology.

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