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Insulin reverses the high-fat diet-induced increase in brain Aβ and improves memory in an animal model of Alzheimer disease

BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2014
Contact PI Name:
Frederic Calon
Contact PI Affiliation:
Faculté de Pharmacie, Université Laval, Québec, Canada; Axe Neurosciences, Centre de Recherche du Centre Hospitalier de l’Université Laval, Québec, Canada
Co-Authors:
Milene Vandal, Phillip J. White, Cyntia Tremblay, Isabelle St-Amour, Geneviève Chevrier, Vincent Emond, Dominique Lefrançois, Jessica Virgili, Emmanuel Planel, Yves Giguere, Andre Marette
Primary Reference (PubMED ID):
25008180
Funding Source:
Alzheimer Society of Canada
Canada Foundation for Innovation
Canadian Institutes of Health Research (CIHR)
Fonds de Recherche du Québec Santé (FRQS)
Study Goal and Principal Findings:

The goal of this study was to investigate the interrelation between AD and diabetes using a high fat diet (HFD) in a mouse model of AD-like neuropathology (3xTg-AD).  The HFD massively increased brain beta amyloid pathology and worsened memory function in 3xTg-AD mice. A single acute injection of insulin in 3xTg-AD mice fed with HFD restored memory function and brought back soluble brain Abeta concentrations to control levels, while increasing plasma Abeta levels in plasma. These data reveal tight links between AD and peripheral metabolic defects and suggest that insulin signaling in the brain plays a key role in the production and clearance of Abeta from the brain to the blood. If replicable in humans, these findings highlight the potential of correcting insulin signaling defects as a promising therapeutic tool to modulate cerebral concentrations of Abeta and treat Abeta-related symptoms of AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Hormone
Therapeutic Agent:
Insulin
PubMed
PubChem
DrugBank
ClinicalTrials
Patents
Therapeutic Target:
Insulin Receptor
Open Targets
Pharos
Agora
Therapeutic Notes:
Insulin Receptor has been nominated as a potential target for AD. Nominated targets are obtained from several sources, including the National Institute on Aging's Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) consortium. Targets have been identified using computational analyses of high-dimensional genomic, proteomic and/or metabolomic data derived from human samples. See Agora link for more information.

Animal Model

Model Information:
Species:
Mouse
Model Type:
APPxPS1xTau
Model Name:
3xTg
ALZFORUM
Strain/Genetic Background:
C57BL6/129SvJ

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
Barnes Maze
Novel Object Recognition Test (NORT)
Open Field Test
Dark-Light Emergence Test
Histopathology
beta Amyloid Load
Biochemical
phospho-Tau
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Synaptic Proteins
Amyloid Precursor Protein (APP) Metabolites
Insulin Degrading Enzyme (IDE)
Low Density Lipoprotein Receptor-Related Protein 1 (LRP1)
Insulin Tolerance Test
Glucose Tolerance Test
Plasma-beta Amyloid Peptide 42
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)
A Disintegrin and Metalloproteinase Domain 10 (ADAM10)
Biomarker
Plasma-beta Amyloid Peptides
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