7,8-Dihydroxyflavone, a small-molecule TrkB agonist, reverses memory deficits and BACE1 elevation in a mouse model of Alzheimer’s disease


BIBLIOGRAPHIC THERAPEUTIC AGENT ANIMAL MODEL EXPERIMENTAL DESIGN OUTCOMES

Bibliographic

Year of Publication:
2012
Contact PI Name:
Masuo Ohno
Contact PI Affiliation:
Center for Dementia Research, Nathan Kline Institute, Orangeburg, New York, USA
Co-Authors:
Latha Devi
Primary Reference (PubMED ID):
Funding Source:
Alzheimer's Association
American Health Assistance Foundation
Study Goal and Principal Findings:

In this study the authors performed a preclinical evaluation of the TrkB agonist 7,8-DHF in the 5xFAD  mouse model of AD. Results showed that 7,8-DHF rescued memory deficits of Tg mice in the spontaneous alternation Y-maze task. In addition, 7,8-DHF restored deficient TrkB signaling inTg mice without affecting endogenous BDNF levels. Treatment Tg mice with 7,8-DHF also  blocked BACE1 elevations and lowered levels of the beta-secretase cleaved C-terminal fragment of amyloid precursor protein (C99), Abeta 40, and Abeta 42 in brain Treatment of non-transgenic mice with 7,8-DHF was associated with  decreased BACE1 expression, suggesting that BDNF-TrkB signaling is also important for down regulating baseline levels of BACE1. Together, the findings suggest that TrkB activation with a 7,8-DHF can ameliorate AD-associated memory deficits, which may be, at least in part, attributable to reductions in BACE1 expression and beta-amyloidogenesis.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
7,8-dihydroxyflavone (7,8-DHF)
Therapeutic Target:
Tyrosine Receptor Kinase B (TrkB)

Animal Model

Model Information:
Species:
Mouse
Model Type:
APPxPS1
Strain/Genetic Background:
C57BL6/ SJL
Species:
Mouse
Model Type:
Non-transgenic
Strain/Genetic Background:
C57BL6/ SJL

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
Y Maze
Biochemical
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
phospho-Tyrosine Receptor Kinase B (phospho-TrKB)
Amyloid Precursor Protein (APP) Metabolites
Amyloid Precursor Protein (APP)
beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1)
Brain-Derived Neurotrophic Factor (BDNF)
Immunochemistry
phospho-Tyrosine Receptor Kinase B (phospho-TrKB)
Pharmacodynamics
Target Engagement (Activation Tyrosine Receptor Kinase B)

Source URL: http://alzped.nia.nih.gov/78-dihydroxyflavone-small