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Early BDNF treatment ameliorates cell loss in the entorhinal cortex of APP transgenic mice


Year of Publication:
Contact PI Name:
Mark H. Tuszynski
Contact PI Affiliation:
Department of Neurosciences, University of California, San Diego, La Jolla, California, USA
Alan H. Nagahara, Michael Mateling, Imre Kovacs, Ling Wang, Simone Eggert, Edward Rockenstein, Edward H. Koo, Eliezer Masliah
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
Alzheimer's Association
United States Department of Veterans Affairs (VA)
State of California
Shiley Foundation
Study Goal and Principal Findings:

Brain-derived neurotrophic factor (BDNF) improves molecular, cellular, and behavioral measures of neural dysfunction in genetic models of Alzheimer’s disease. However, BDNF treatment after disease onset has not been reported to improve neuronal survival in these models. This study evaluated prevention of neuronal loss with early life BDNF treatment in mutant mice expressingtwo amyloid precursor protein (APP) mutations associated with early-onsetfamilial Alzheimer’s disease. APP transgenic mice underwent lentiviral BDNF gene delivery into the entorhinal cortices at age 2 months and were examined 5 months later. BDNF-treated mice exhibited significant improvements in hippocampal-dependent contextual fear conditioning compared with control treated APP mice (p 0.05). Stereological analysis of entorhinal cortical cell number demonstrated 20% reductions in neuronal number in layers II-VI of the entorhinal cortex in untreated APP mutant mice compared with wild-type mice (p0.0001), and significant amelioration of cell loss by BDNF (p 0.001). Moreover, BDNF gene delivery improved synaptophysin immunoreactivity in the entorhinal cortex and, through anterograde BDNF transport, in the hippocampus (p 0.01). Notably, BDNF did not affect amyloid plaque numbers, indicating that direct amyloid reduction is not necessary to achieve significant neuroprotective benefits in mutant amyloid models of Alzheimer’s disease. 

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Gene
Therapeutic Agent:
Brain-Derived Neurotrophic Factor (BDNF)
Therapeutic Target:
Tyrosine Receptor Kinase B (TrkB)
Therapeutic Notes:
Tyrosine Receptor Kinase B (TrkB) 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:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:

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
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


Outcome Measured
Outcome Parameters
Fear Conditioning Response
Brain-Derived Neurotrophic Factor (BDNF)
Brain-beta Amyloid Deposits
Brain-Derived Neurotrophic Factor (BDNF)
Neuronal Cell Number
BDNF Concentration-Brain