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Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease

Bibliographic

Year of Publication:
2008
Contact PI Name:
Ottavio Arancio
Contact PI Affiliation:
Department of Pathology and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, New York, USA
Co-Authors:
Fabrizio Trinchese, Mauro Fa, Shumin Liu, Hong Zhang, Ariel Hidalgo, Stephen D. Schmidt, Hisako Yamaguchi, Narihiko Yoshii, Paul M. Mathews, Ralph A. Nixon
Primary Reference (PubMED ID):
Funding Source:
National Institute of Neurological Disorders and Stroke (NINDS)
Institute for the Study of Aging (ISOA)
Study Goal and Principal Findings:

Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. Calpains have been linked to the modulation of memory and are key to the pathogenesis of Alzheimer disease (AD). When abnormally activated, calpains can also initiate degradation of proteins essential for neuronal survival. Here was show that calpain inhibition through E64, a cysteine protease inhibitor, and the highly specific calpain inhibitor BDA-410 restored normal synaptic function both in hippocampal cultures and in hippocampal slices from the APP/PS1 mouse, an animal model of AD. Calpain inhibition also improved spatial-working memory and associative fear memory in APP/PS1 mice. These beneficial effects of the calpain inhibitors were associated with restoration of normal phosphorylation levels of the transcription factor CREB and involved redistribution of the synaptic protein synapsin I. Thus, calpain inhibition may prove useful in the alleviation of memory loss in AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
E64
Therapeutic Target:
Calpain 1
Therapy Type:
Small Molecule
Therapeutic Agent:
BDA-410
Therapeutic Target:
Calpain 1

Animal Model

Model Information:
Species:
Mouse
Model Type:
APPxPS1
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
Radial Arm Water Maze
Histopathology
Congophillic Amyloid Deposits
Dense-core/Compact Plaques
Biochemical
Spectrin
Polymerized Tubulin
CREB/phospho-CREB
Cell-beta Amyloid Peptide 42
Calpain Cleavage
Immunochemistry
Synapsin
Calpain
phospho-cAMP Response Element-Binding Protein (phospho-CREB)
Biomarker
Plasma-beta Amyloid Peptides
Electrophysiology
Basal Synaptic Transmission
Miniature Excitatory Postsynaptic Currents (mEPSCs)
Long Term Potentiation (LTP)
field Excitatory Postsynaptic Potential (fEPSP)
Pharmacodynamics
Target Engagement (Inhibition Spectrin Cleavage)