Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice
Bibliographic
Year of Publication:
2021
Contact PI Name:
Eugenia Trushina
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
National Institute of Neurological Disorders and Stroke (NINDS)
National Cancer Institute (NCI)
Alzheimer's Drug Discovery Foundation (ADDF)
Alzheimer's Association
Minnesota Partnership for Biotechnology and Medical Genomics
Noaber Foundation
Robert P. and Arlene R. Kogod Family Foundation
Robert J. and Theresa W. Ryan Foundation
The Connor Group
Study Goal and Principal Findings:
Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership–AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.
Bibliographic Notes:
Full Author List: Andrea Stojakovic, Sergey Trushin, Anthony Sheu, Layla Khalili, Su-Youne Chang, Xing Li, Trace Christensen, Jeffrey L. Salisbury, Rachel E. Geroux, Benjamin Gateno, Padraig J. Flannery, Mrunal Dehankar, Cory C. Funk, Jordan Wilkins, Anna Stepanova, Tara O’Hagan, Alexander Galkin, Jarred Nesbitt, Xiujuan Zhu, Utkarsh Tripathi, Slobodan Macura, Tamar Tchkonia, Tamar Pirtskhalava, James L. Kirkland, Rachel A. Kudgus, Renee A. Schoon, Joel M. Reid, Yu Yamazaki, Takahisa Kanekiyo, Song Zhang, Emirhan Nemutlu, Petras Dzeja, Adam Jaspersen, Ye In Christopher Kwon, Michael K. Lee, Eugenia Trushina.
Therapeutic Agent
Therapeutic Information:
Therapeutic Notes:
CP2 competes with flavin mononucleotide for binding to the redox center of mitochondrial respiratory complex I (Zhang et al., 2015, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465115/).
Animal Model
Model Information:
Species:
Mouse
Model Type:
APPxPS1
Model Name:
PS/APP
Strain/Genetic Background:
Not Reported
Species:
Mouse
Model Type:
Non-transgenic
Model Name:
C57BL/6
Strain/Genetic Background:
C57BL/6J
Species:
Mouse
Model Type:
Non-transgenic
Model Name:
CD-1
Strain/Genetic Background:
CD-1
Experimental Design
Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest
Outcomes
Outcome Measured
Outcome Parameters
Behavioral
Exploratory Activity
Morris Water Maze
Novel Object Recognition Test (NORT)
Open Field Test
Spontaneous Activity
Motor Function
Hanging Bar Test
Locomotor Activity
Rotarod Test
Histopathology
Activated Astrocytes
Activated Microglia
beta Amyloid Deposits
beta Amyloid Load
Neuronal Loss
Biochemical
Brain-Buffer Soluble beta Amyloid Peptide 40
Brain-Buffer Soluble beta Amyloid Peptide 42
Brain-Guanidine Soluble beta Amyloid Peptide 40
Brain-Guanidine Soluble beta Amyloid Peptide 42
Mitochondrial Respiratory Complex I Activity
Mitochondrial Respiratory Complex II/Succinate Dehydrogenase (SDH) Activity
Mitochondrial Respiratory Complex III Activity
Mitochondrial Respiratory Complex IV Activity
Mitochondrial DNA (mtDNA)
Senescence-Associated beta-Galactosidase (SA-beta Gal) Activity
Brain-Fatty Acid Profile
Plasma-Fatty Acid Profile
Brain-Glucose
Malondialdehyde (MDA)
AMP-Activated Protein Kinase (AMPK)
phospho-AMP-Activated Protein Kinase (phospho-AMPK)
phospho-Acetyl-Coenzyme A Carboxylase (phospho-ACC)
Autophagosomal Marker LC3-I
Autophagosomal Marker LC3-II
Brain-Derived Neurotrophic Factor (BDNF)
Catalase (CAT)
Chemokine C-C Motif Ligand 2/Monocyte Chemoattractant Protein 1 (CCL2/MCP1)
Chemokine C-C Motif Ligand 3/Macrophage Inflammatory Protein 1 (CCL3/MIP1)
Chemokine C-C Motif Ligand 5 (CCL5)/Regulated on Activation Normal T Cell Expressed and Secreted (RANTES)
Chemokine C-X-C Motif Ligand 2/Macrophage Inflammatory Protein 2 (CXCL2/MIP2)
Chemokine C-X-C Motif Ligand 5 (CXCL5/LIX)
Chemokine C-X-C Motif Ligand 10/Interferon gamma-Induced Protein 10 (CXCL10/IP-10)
Eotaxin
Keratinocyte Chemoattractant/Growth-Regulated Oncogene (KC/GRO)
Glycogen Synthase Kinase 3 beta (GSK3 beta)
phospho-Glycogen Synthase Kinase 3 beta (phospho-GSK3 beta)
Granulocyte Colony-Stimulating Factor (G-CSF)
Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)
Macrophage Colony-Stimulating Factor (M-CSF)
Glucose Transporter 3 (GLUT3)
Glucose Transporter 4 (GLUT4)
Heme Oxygenase 1 (HO1)
Inhibitor of kappa B (IkB)
Insulin-Like Growth Factor 1 (IGF1)
Insulin-Like Growth Factor 1 Receptor (IGF1R)
phospho-Insulin-Like Growth Factor 1 Receptor (phospho-IGF1R)
Interferon (IFN) gamma
Interleukin 1 alpha (IL-1 alpha)
Interleukin 1 beta (IL-1 beta)
Interleukin 2 (IL-2)
Interleukin 3 (IL-3)
Interleukin 4 (IL-4)
Interleukin 5 (IL-5)
Interleukin 6 (IL-6)
Interleukin 7 (IL-7)
Interleukin 9 (IL-9)
Interleukin 12p40 (IL-12p40)
Interleukin 12p70 (IL-12p70)
Interleukin 13 (IL-13)
Interleukin 17 (IL-17)
Interleukin 15 (IL-15)
Lysosomal Associated Membrane Protein 1 (LAMP1)
Mitochondrial Transcription Factor A (Tfam)
Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)
Peroxisome Proliferator-Activated Receptor-gamma Coactivator 1 alpha (PGC-1 alpha)
phospho-Beclin 1
phospho-Nuclear Factor kappa B (phospho-NFkB)
phospho-Unc-51 Like Autophagy Activating Kinase 1 (phospho-ULK1)
Pyruvate Dehydrogenase E1 alpha (PDH E1 alpha)
phospho-Pyruvate Dehydrogenase E1 alpha (phospho-PDHE1 alpha)
Postsynaptic Density Protein 95 (PSD95)
Sirtuin 3 (Sirt3)
Superoxide Dismutase (SOD)
Synaptophysin
Transcription Factor EB (TFEB)
Tumor Necrosis Factor alpha (TNF alpha)
Vascular Endothelial Growth Factor (VEGF)
Immunochemistry
Brain-beta Amyloid Deposits
Glial Fibrillary Acidic Protein (GFAP)
Ionized Calcium Binding Adaptor Molecule 1 (Iba1)
Tyrosine Hydroxylase (TH)
Microscopy
Stereology
Axon Length
Neuronal Density
Neuronal Fiber Density
Cell Count
Cell Volume
Electron Microscopy
Dendritic Spine Density
Dendritic Spine Morphology
Dendritic Spine Number
Synaptic Density
Synaptic Morphology
Mitochondria Count
Mitochondria Length
Mitochondria Morphology
Spectroscopy
Liquid Chromatography with Tandem Mass Spectrometry (LC/MS/MS)
Nuclear Magnetic Resonance Spectroscopy
Imaging
Dual-Energy X-Ray Absorptiometry (DEXA)
[18F]FDG-PET
Electrophysiology
Input/Output (I/O) Curve
field Excitatory Postsynaptic Potential (fEPSP)
Long Term Potentiation (LTP)
Paired-Pulse Facilitation (PPF)
Pharmacokinetics
Area Under the Curve (AUC)
Cmax
Clearance (L/h/kg)
Drug Concentration-Brain
Drug Concentration-Plasma
Oral Bioavailability (F%)
t1/2 (Elimination Half-Life)
Tmax
Pharmacodynamics
Target Engagement (Inhibition Mitochondrial Respiratory Complex I)
Target Engagement (Activation AMP-Activated Protein Kinase)
Toxicology
Body Weight
Body Fat
Grooming Behavior
General Activity
Motor Function
Food Intake
Water Consumption
Glucose Tolerance Test
Insulin Tolerance Test
Pharmacology
Binding Affinity
Cerep Profile
Target Selectivity
Omics
Cytokine Array Analysis
Gene Expression Profile-Alzheimer's-Related Genes
Lipidomics
Metabolomics
Whole Transcriptome Analysis
Physiology
Indirect Calorimetry
Outcomes Notes:
Toxicology and Physiology measures were monitored using the Comprehensive Laboratory Animal Monitoring System (CLAMS). The CLAMS allows automated, non-invasive, and simultaneous monitoring of horizontal and vertical activity, feeding and drinking, oxygen consumption, CO2 production and energy expenditure (or, indirect calorimetry) of an individual mouse. Additionally, DasGupta et al 2017, Indirect Calorimetry: from Bench to Bedside (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477450/) provides a concise review of indirect calorimetric measurements.