Proteomics Evidence of the Role of TDMQ20 in the Cholinergic System and Synaptic Transmission in a Mouse Model of Alzheimer's Disease.

The interaction between copper ions and amyloid peptide Aβ has been reported to be involved in Alzheimer's disease (AD) pathology. Based on copper coordination biochemistry, we designed specific copper chelators [tetradentate monoquinolines (TDMQs)] in order to regulate copper homeostasis in the AD brain and inhibit the deleterious oxidative stress catalyzed by copper-Aβ complexes. We previously reported that TDMQ20, a highly selective copper chelator selected as a drug candidate, was able to extract copper from the Cu-Aβ1-16 complex and restore cognitive and behavioral deficits in AD mouse models. For a better understanding of the mechanism of action of TDMQ20, we decided to investigate the change of profile of proteins expressed in 5xFAD mice after an oral treatment of TDMQ20 (dose = 10 mg/kg, once every two days for 3 months, in total 45 times). Clioquinol (CQ), a non-specific chelator, has been used as a comparator. Here, we report the proteomic alterations in the cortex of 5xFAD mice using iTRAQ (isobaric tags for relative and absolute quantification) proteomics technology. The results indicated that 178 differentially expressed proteins (DEPs) have been identified in the AD mouse group with respect to wild type (WT) animals (AD/WT). After treatment by TDMQ20, 35 DEPs were found common in AD/WT and TDMQ20/AD groups in an opposite change manner (up- or down-regulated, respectively). In addition, among the 35 DEPs mentioned above, 10 common target proteins have been identified in AD/WT, TDMQ20/AD, and CQ/AD groups, among which 3 target proteins were successfully validated by western blot analysis. In particular, the expression levels of ChAT and CHRM4 are significantly increased upon TDMQ20 treatment with respect to 5xFAD mice, while CQ did not significantly change the expression of these proteins. Our study suggests the involvement of the copper chelator TDMQ20 on the cholinergic system, a feature that may explain the improved cognitive and behavioral performance in AD mice upon oral treatment of TDMQ20.

[1]  Elisabeth Mahase.  Aducanumab: European agency rejects Alzheimer’s drug over efficacy and safety concerns , 2021, BMJ.

[2]  C. Masters,et al.  The Amyloid-β Pathway in Alzheimer’s Disease , 2021, Molecular Psychiatry.

[3]  Sang Ryong Kim,et al.  Linking Oxidative Stress and Proteinopathy in Alzheimer’s Disease , 2021, Antioxidants.

[4]  David T. Jones,et al.  Alzheimer disease , 2021, Nature Reviews Disease Primers.

[5]  A. Atri,et al.  Aducanumab produced a clinically meaningful benefit in association with amyloid lowering , 2021, Alzheimer's Research & Therapy.

[6]  B. Meunier,et al.  TDMQ20, a Specific Copper Chelator, Reduces Memory Impairments in Alzheimer's Disease Mouse Models. , 2020, ACS chemical neuroscience.

[7]  Jian Ding,et al.  Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression , 2019, Cell Research.

[8]  M. Nguyen,et al.  Metal Ions in Alzheimer's Disease: A Key Role or Not? , 2019, Accounts of chemical research.

[9]  Javed Iqbal,et al.  Proteomics Study of Peripheral Blood Mononuclear Cells (PBMCs) in Autistic Children , 2019, Front. Cell. Neurosci..

[10]  Shijun Lu,et al.  HSPC159 promotes proliferation and metastasis by inducing epithelial‐mesenchymal transition and activating the PI3K/Akt pathway in breast cancer , 2018, Cancer science.

[11]  C. Hureau,et al.  N4 -Tetradentate Chelators Efficiently Regulate Copper Homeostasis and Prevent ROS Production Induced by Copper-Amyloid-β1-16. , 2018, Chemistry.

[12]  M. Mesulam,et al.  The cholinergic system in the pathophysiology and treatment of Alzheimer's disease. , 2018, Brain : a journal of neurology.

[13]  Javed Iqbal,et al.  Effect of Sodium Selenate on Hippocampal Proteome of 3×Tg-AD Mice-Exploring the Antioxidant Dogma of Selenium against Alzheimer's Disease. , 2018, ACS chemical neuroscience.

[14]  M. Nguyen,et al.  Preparation of Tetradentate Copper Chelators as Potential Anti‐Alzheimer Agents , 2018, ChemMedChem.

[15]  K. P. Kepp.  Alzheimer’s disease: How metal ions define β-amyloid function , 2017 .

[16]  M. Nguyen,et al.  Structures of the Copper and Zinc Complexes of PBT2, a Chelating Agent Evaluated as Potential Drug for Neurodegenerative Diseases , 2017 .

[17]  K. Schlett,et al.  Ras and Rab interactor 1 controls neuronal plasticity by coordinating dendritic filopodial motility and AMPA receptor turnover , 2017, Molecular biology of the cell.

[18]  M. Ananth,et al.  Basal Forebrain Cholinergic Circuits and Signaling in Cognition and Cognitive Decline , 2016, Neuron.

[19]  K. Föhr,et al.  Enlarged dendritic spines and pronounced neophobia in mice lacking the PSD protein RICH2 , 2016, Molecular Brain.

[20]  M. Nguyen,et al.  Transfer of Copper from an Amyloid to a Natural Copper-Carrier Peptide with a Specific Mediating Ligand. , 2015, Chemistry.

[21]  M. Nguyen,et al.  Regulation of copper and iron homeostasis by metal chelators: a possible chemotherapy for Alzheimer's disease. , 2015, Accounts of chemical research.

[22]  A. Bush,et al.  Biological metals and metal-targeting compounds in major neurodegenerative diseases. , 2014, Chemical Society reviews.

[23]  J. Cummings,et al.  Alzheimer’s disease drug-development pipeline: few candidates, frequent failures , 2014, Alzheimer's Research & Therapy.

[24]  J. Garrido,et al.  Hsp90 activity is necessary to acquire a proper neuronal polarization. , 2014, Biochimica et biophysica acta.

[25]  D. Holtzman,et al.  Efficacy and toxicity of clioquinol treatment and A-beta42 inoculation in the APP/PSI mouse model of Alzheimer's disease. , 2013, Current Alzheimer research.

[26]  J. Lassalle,et al.  Copper Chelator Induced Efficient Episodic Memory Recovery in a Non-Transgenic Alzheimer’s Mouse Model , 2012, PloS one.

[27]  H. Ramshaw,et al.  Neurodevelopmental and neuropsychiatric behaviour defects arise from 14-3-3ζ deficiency , 2012, Molecular Psychiatry.

[28]  Suzanna Lewis,et al.  Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium , 2011, Briefings Bioinform..

[29]  A. Godzik,et al.  S-Nitrosylation of Drp1 Mediates β-Amyloid-Related Mitochondrial Fission and Neuronal Injury , 2009, Science.

[30]  P. Faller,et al.  Redox Chemistry of Copper–Amyloid‐β: The Generation of Hydroxyl Radical in the Presence of Ascorbate is Linked to Redox‐Potentials and Aggregation State , 2007, Chembiochem : a European journal of chemical biology.

[31]  G. Waeber,et al.  Complexin I regulates glucose-induced secretion in pancreatic β-cells , 2004, Journal of Cell Science.

[32]  E. Giacobini,et al.  Cholinergic function and Alzheimer's disease , 2003, International journal of geriatric psychiatry.

[33]  R. Mcquade,et al.  Distribution of muscarinic receptor subtypes in rat brain from postnatal to old age. , 1996, Brain research. Developmental brain research.

[34]  Y. Agid,et al.  Decreased choline acetyltransferase mRNA expression in the nucleus basalis of Meynert in Alzheimer disease: an in situ hybridization study. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[35]  J. Coyle,et al.  Alzheimer disease: Evidence for selective loss of cholinergic neurons in the nucleus basalis , 1981, Annals of neurology.

[36]  D M Bowen,et al.  Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. , 1976, Brain : a journal of neurology.