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

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.

Presynaptic proteins complexin-I and complexin-II differentially influence cognitive function in early and late stages of Alzheimer’s disease

“…The results reported here provide some support for the relevance of treatment strategies in animal models of Alzheimer’s disease directed at increasing inhibitory tone [13, 26, 27, 51]. Limited evidence suggests pharmacotherapies directly targeting components of the presynaptic molecular machinery such as levetiracetam (which interacts with the vesicular protein SV2) may be of benefit in Alzheimer’s disease through modulating inhibitory tone [16, 28, 30, 39, 52].…”

EFAD transgenic mice as a human APOE relevant preclinical model of Alzheimerʼns disease

“…APP processing: APP by Western blot (66). Neurotrophic factors: BDNF and pCREB proteins by Western blot (70,193). Neuroinflammatory cytokines: TNF-, IL1- mRNA by qPCR (72,106).…”

2‐(4‐methyl‐thiazol‐5‐yl) ethyl nitrate maleate‐potentiated GABAA receptor response in hippocampal neurons

“…CMZ as an neuroprotective agent showed a potential therapeutic effect on neuronal injury by regulating excitatory and/or inhibitory neurotransmission balance in neurodegenerative diseases, which acts as the GABA A receptor positive allosteric modulator . As one of the CMZ derivatives, NMZ also exhibited neuroprotective effect, and it was reported to modify the symptoms and condition of AD in several animal models …”

“…In vivo, NMZ has been shown to reverse the cognitive impairment induced by many chemical lesions and to improve the learning and memory in rats with cognitive deficits in the cholinergic systems of the basal forebrain and in APP/PS1 mice . NMZ‐treated 3 × Tg mice exhibited long‐term potentiation (LTP) improvement via NO/cGMP, cognitive deficits reversing . NMZ belongs to a series of NO‐releasing hybrid agents and it is believed to be a novel therapeutic compound to treat Alzheimer's disease (AD).…”