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A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer’s disease mouse model
- Source :
- Scientific Reports, Vol 8, Iss 1, Pp 1-15 (2018), Scientific reports, vol 8, iss 1, Scientific Reports
- Publication Year :
- 2018
- Publisher :
- Nature Publishing Group, 2018.
-
Abstract
- We describe here the results from the testing of a small molecule first-in-class apolipoprotein E4 (ApoE4)-targeted sirtuin1 (SirT1) enhancer, A03, that increases the levels of the neuroprotective enzyme SirT1 while not affecting levels of neurotoxic sirtuin 2 (SirT2) in vitro in ApoE4-transfected cells. A03 was identified by high-throughput screening (HTS) and found to be orally bioavailable and brain penetrant. In vivo, A03 treatment increased SirT1 levels in the hippocampus of 5XFAD-ApoE4 (E4FAD) Alzheimer’s disease (AD) model mice and elicited cognitive improvement while inducing no observed toxicity. We were able to resolve the enantiomers of A03 and show using in vitro models that the L-enantiomer was more potent than the corresponding D-enantiomer in increasing SirT1 levels. ApoE4 expression has been shown to decrease the level of the NAD-dependent deacetylase and major longevity determinant SirT1 in brain tissue and serum of AD patients as compared to normal controls. A deficiency in SirT1 level has been recently implicated in increased tau acetylation, a dominant post-translational modification and key pathological event in AD and tauopathies. Therefore, as a novel approach to therapeutic development for AD, we targeted identification of compounds that enhance and normalize brain SirT1 levels.
- Subjects :
- 0301 basic medicine
Aging
Apolipoprotein E4
Hippocampus
lcsh:Medicine
Neurodegenerative
Pharmacology
Alzheimer's Disease
Transgenic
Antiparkinson Agents
Mice
Sirtuin 2
0302 clinical medicine
Sirtuin 1
2.1 Biological and endogenous factors
Medicine
Aetiology
lcsh:Science
Tumor
Multidisciplinary
biology
3. Good health
5.1 Pharmaceuticals
Neurological
Sirtuin
Serotonin Uptake Inhibitors
lipids (amino acids, peptides, and proteins)
Development of treatments and therapeutic interventions
Selective Serotonin Reuptake Inhibitors
Transgene
Mice, Transgenic
SIRT2
Neuroprotection
Article
Cell Line
03 medical and health sciences
Alzheimer Disease
In vivo
Cell Line, Tumor
Acquired Cognitive Impairment
Animals
Animal
business.industry
lcsh:R
Neurosciences
Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)
In vitro
Brain Disorders
Disease Models, Animal
030104 developmental biology
Disease Models
biology.protein
Dementia
lcsh:Q
business
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 8
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....2d436e539995681da6b7c0dc4a3662c0
- Full Text :
- https://doi.org/10.1038/s41598-018-35687-8