A multifunctional therapeutic approach to disease modification in multiple familial mouse models and a novel sporadic model of Alzheimer's disease


BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2016
Contact PI Name:
Gregory R.J. Thatcher
Contact PI Affiliation:
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA
Co-Authors:
Jia Luo, Sue H. Lee, Lawren VandeVrede, Zhihui Qin, Manel Ben Aissa, John Larson, Andrew F. Teich, Ottavio Arancio, Yohan D’Souza, Ahmed Elharram, Kevin Koster, Leon M. Tai, Mary Jo LaDu, Brian M. Bennett
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Alzheimer's Drug Discovery Foundation (ADDF)
Institute for the Study of Aging (ISOA)
National Center for Advancing Translational Sciences (NCATS)
Study Goal and Principal Findings:

In this study the authors retooled a clinical drug with known neuroprotective and anti-inflammatory activity to activate CREB, and validated this novel multifunctional drug, NMZ, in 4 different mouse models of AD. NMZ was tested in three mouse models of familial AD and one model of sporadic AD. In 3 × Tg hippocampal slices, NMZ restored LTP. In vivo, memory was improved with NMZ in all animal models with robust cognitive deficits. NMZ treatment lowered neurotoxic forms of Aβ in both APP/PS1 and 3 × Tg transgenic mice while also restoring neuronal plasticity biomarkers in the 3 × Tg mice. In EFAD mice, incorporation of the major genetic AD risk factor, hAPOE4, did not mute the beneficial drug effects. In a novel sporadic mouse model that manifests AD-like pathology caused by accelerated oxidative stress in the absence of any familial AD mutation, oral administration of NMZ attenuated hallmark AD pathology and restored biomarkers of synaptic and neuronal function.The multifunctional approach, embodied by NMZ, was successful in mouse models of AD incorporating Aβ pathology (APP/PS1), tau pathology (3xTg), and APOE4, the major human genetic risk factor for AD (EFAD). The efficacy observed in a novel model of sporadic AD (Aldh2−/− ) demonstrates that the therapeutic approach is not limited to rare, familial AD genetic mutations. The multifunctional drug, NMZ, was not designed directly to target Aβ and tau pathology; however, the attenuation of this hallmark pathology suggests the approach to be a highly promising, disease-modifying strategy for AD and mixed pathology dementia.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
4-methyl-5-(2-(nitrooxy) ethyl) thiazol-3-ium chloride (NMZ)
Therapeutic Target:
Multi Target
Therapeutic Notes:
Luo J, Lee SH, VandeVrede L, Qin Z, Piyankarage S, Tavassoli E, Asghodom RT, Aissa MB, Fa M, Arancio O, et al. Re-engineering a neuroprotective, clinical drug as a procognitive agent with high in vivo potency and with GABAA potentiating activity for use in dementia. BMC Neurosci. 2015;16:67; Qin Z, Luo J, VandeVrede L, Tavassoli E, Fa M, Teich AF, Arancio O, Thatcher GR. Design and synthesis of neuroprotective methylthiazoles and modification as NO-chimeras for neurodegenerative therapy. J Med Chem. 2012;55:6784–801.

Animal Model

Model Information:
Species:
Mouse
Model Type:
APPxPS1xTau
Strain/Genetic Background:
129/SvJ x C57BL/6
Species:
Mouse
Model Type:
APPxPS1
Strain/Genetic Background:
Not Reported
Species:
Mouse
Model Type:
APPxPS1xApoE4
Strain/Genetic Background:
Not Reported
Species:
Mouse
Model Type:
Non-transgenic
Strain/Genetic Background:
C57BL/6

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest
Experiment Notes

Study Balanced for Sex: Studies using 3xTg and APPx PS1 mice were balanced for sex. The studies using the E4FAD mice exclusively used males and therefore were not balanced for sex. Sex was not reported for studies using the Aldh2−/− mice.

Outcomes

Outcome Measured
Outcome Parameters
Behavioral
Radial Arm Water Maze
Y Maze
Novel Object Recognition Test (NORT)
Biochemical
Brain-beta Amyloid Peptide 42
phospho-Tau
Tumor Necrosis Factor alpha (TNF alpha)
cAMP Response Element-Binding Protein (CREB)
GABA Levels
Brain-Derived Neurotrophic Factor (BDNF)
Brain-Buffer Insoluble beta Amyloid Peptide 42
Brain-Buffer Soluble beta Amyloid Peptide 42
Acetylcholine Levels
Brain-beta Amyloid Oligomers
Caspase Activation
phospho-cAMP Response Element-Binding Protein (phospho-CREB)
Total Tau Protein
Lipid Peroxidation
Synaptic Proteins
Immunochemistry
Tau Protein
Activated Microglia
phospho-Tau
Electrophysiology
Long Term Potentiation (LTP)
field Excitatory Postsynaptic Potential (fEPSP)
Microscopy
Cell Survival
Stereology
Pharmacodynamics
Target Engagement (Activation cAMP Response Element-Binding Protein)

Source URL: http://alzped.nia.nih.gov/multifunctional-therapeutic