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01.12.2016 | Research article | Ausgabe 1/2016 Open Access

Molecular Neurodegeneration 1/2016

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

Zeitschrift:
Molecular Neurodegeneration > Ausgabe 1/2016
Autoren:
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, Gregory R. J. Thatcher
Wichtige Hinweise
An erratum to this article can be found at http://​dx.​doi.​org/​10.​1186/​s13024-016-0104-5.

Competing interests

GRJT and BMB are inventors on patents associated with NMZ.

Authors’ contributions

JL designed and directed experiments in primary cultures, immunoassays in APP/PS1 mice and behavioral and other studies in 3xTg and E4FAD mice and helped in drafting and revising the manuscript. SHL carried out experiments in E4FAD mice and drafted and revised the manuscript. LV conducted and interpreted LTP studies in 3xTg mice, assisted with studies in 3xTg and APP/PS1 mice and contributed to drafting the manuscript. ZQ prepared and characterized drugs and contributed to the manuscript draft. MBA generated Fig. 1, assisted with data interpretation and drafted and revised the manuscript. JL assisted with design and interpretation of 3xTg LTP experiments and helped draft the manuscript. OA and AFT designed, directed, and interpreted APP/PS1 mouse behavioral studies and helped draft the manuscript. BMB designed and directed all studies on Aldh2 −/− mice and drafted and revised the manuscript. YD and AE equally participated in conducting experiments on Aldh2 −/− mice and contributing to drafting the manuscript. MJL designed experiments on E4FAD mice and drafted and revised the manuscript. LMT and KK assisted with experiments on E4FAD mice and helped in drafting the manuscript. GRJT designed NMZ and conceived and coordinated the overall project, manuscript preparation and revision. All authors have read and approved the final manuscript.

Abstract

Background

Clinical failures singularly targeting amyloid-β pathology indicate a critical need for alternative Alzheimer’s disease (AD) therapeutic strategies. The mixed pathology reported in a large population of AD patients demands a multifunctional drug approach. Since activation of cAMP response element binding protein (CREB) plays a crucial role in synaptic strengthening and memory formation, we 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.

Results

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.

Conclusions

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.
Literatur
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