title: A multifunctional therapeutic approach to disease modification in multiple familial mouse models and a novel sporadic model of Alzheimer's disease.
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.
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Sue H
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Lawren
authors.initials: L
authors.lastname: VandeVrede
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Qin
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.|Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Manel
authors.initials: M
authors.lastname: Ben Aissa
authors.affiliation: Department of Psychiatry, Neuropsychiatric Institute, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: John
authors.initials: J
authors.lastname: Larson
authors.affiliation: Department of Pathology, The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Teich
authors.affiliation: Department of Pathology, The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.affiliation: Department of Biomedical & Molecular Sciences, Faculty of Health Sciences, Queen's University, Kingston, ON, Canada.
authors.forename: Yohan
authors.initials: Y
authors.lastname: D'Souza
authors.affiliation: Department of Biomedical & Molecular Sciences, Faculty of Health Sciences, Queen's University, Kingston, ON, Canada.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Elharram
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Koster
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Leon M
authors.initials: LM
authors.lastname: Tai
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: LaDu
authors.affiliation: Department of Biomedical & Molecular Sciences, Faculty of Health Sciences, Queen's University, Kingston, ON, Canada.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Bennett
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA. thatcher@uic.edu.
authors.forename: Gregory R J
authors.initials: GR
authors.lastname: Thatcher
mesh_terms: D000544:Alzheimer Disease / Q000628:therapy*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000378:metabolism*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism; D008568:Memory / Q000502:physiology*; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins
keywords: AD mouse models; Aldh2 −/− mice; Alzheimer’s disease modifying approach; CMZ; CREB activation; Mixed pathology dementia; NMZ; NO/cGMP signaling; Neuroprotection