BACE1 RNAi restores the composition of phosphatidylethanolamine-derivates related to memory improvement in aged 3xTg-AD mice

BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2016
Contact PI Name:
Gloria P. Cardona-Gómez
Contact PI Affiliation:
Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, Sede de Investigación Universitaria, University of Antioquia, Medellín, Colombia
Co-Authors:
Javier G. Villamil-Ortiz, Alvaro Barrera-Ocampo, Diego Piedrahita, Claudia M. Velásquez-Rodríguez, Julian D. Arias-Londoño
Primary Reference (PubMED ID):
27891075
Funding Source:
National Science Foundation (NSF)
University of Antioquia
Study Goal and Principal Findings:

β-amyloid (Aβ) is produced by the β-secretase 1 (BACE1)-mediated enzymatic cleavage of the amyloid precursor protein through the amyloidogenic pathway, making BACE1 a therapeutic target against Alzheimer’s disease (AD). Alterations in lipid metabolism are a risk factor for AD by an unknown mechanism. The objective of this study was to determine the effect of RNA interference against BACE1 (shBACEmiR) on the phospholipid profile in hippocampal CA1 area in aged 3xTg-AD mice after 6 and 12 months of treatment compared to aged PS1KI mice. The shBACEmiR treatment induced cognitive function recovery and restored mainly the fatty acid composition of lysophosphatidylethanolamine and etherphosphatidylethanolamine, reduced the cPLA2’s phosphorylation, down-regulated the levels of arachidonic acid and COX2 in the hippocampi of 3xTg-AD mice. Together, our findings suggest, for the first time, that BACE1 silencing restores phospholipids composition which could favor the recovery of cellular homeostasis and cognitive function in the hippocampus of triple transgenic AD mice.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - RNA
Therapeutic Agent:
shBACEmiR
PubMed
Patents
Therapeutic Target:
BACE1
Open Targets
Pharos
Agora

Animal Model

Model Information:
Species:
Mouse
Model Type:
APPxPS1xTau
Model Name:
3xTg
ALZFORUM
Strain/Genetic Background:
Not Reported
Species:
Mouse
Model Type:
PS1
Model Name:
PSEN1(M146V) Knock-In
ALZFORUM
Strain/Genetic Background:
Not Reported

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
Morris Water Maze
Biochemical
Brain-Lipid Profile
Brain-Fatty Acid Profile
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)
Cyclooxygenase 2 (COX 2)
Phospholipase A2 (PLA2)
Spectroscopy
Mass Spectrometry
Omics
Lipidomics
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Source URL: http://alzped.nia.nih.gov/bace1-rnai-restores