Abstract
BackgroundClinical 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.ResultsNMZ 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.ConclusionsThe 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.
Highlights
Clinical failures singularly targeting amyloid-β pathology indicate a critical need for alternative Alzheimer’s disease (AD) therapeutic strategies
In APP/PS1 mice, 4-methyl-5-(2(nitrooxy)ethyl)thiazol-3-ium chloride (NMZ) restores cognition and lowers amyloid-β peptide (Aβ) NMZ was first tested in APP/PS1 double transgenic mice that manifest aberrant accumulation of human Aβ driven by familial AD (FAD) mutations in APP695K670N/M671Land PS1M146L
Adding tau pathology in older 3 × Tg mice and hAPOE4 in E4FAD mice did not blunt the efficacy of NMZ, which was demonstrated in a novel mouse model of sporadic AD
Summary
Clinical failures singularly targeting amyloid-β pathology indicate a critical need for alternative Alzheimer’s disease (AD) therapeutic strategies. Of AD cases, >96 % are multifactorial in origin, and importantly, hallmark AD pathology is often accompanied by other neuropathologic changes. Not unexpectedly, in this substantial population with AD neuropathology, the correlation of Aβ histopathology with cognitive decline is poor [3, 4]; providing one possible contributor to the failure of at least eight therapeutics in late stage clinical trials singularly targeting Aβ [5, 6]. While not dismissing a role for Aβ in AD pathogenesis, cogent arguments have been made that a new strategy is needed towards an effective pharmacotherapeutic response [7,8,9,10]
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