7,8-Dihydroxyflavone, a Small Molecule TrkB Agonist, Improves Spatial Memory and Increases Thin Spine Density in a Mouse Model of Alzheimer Disease-Like Neuronal Loss

Citation metadata

From: PLoS ONE(Vol. 9, Issue 3)
Publisher: Public Library of Science
Document Type: Article
Length: 5,984 words
Lexile Measure: 1600L

Document controls

Main content

Article Preview :

Author(s): Nicholas A. Castello 1,2, Michael H. Nguyen 1,2, Jenny D. Tran 1,2, David Cheng 1,2, Kim N. Green 1,2, Frank M. LaFerla 1,2,*

Introduction

The interaction between brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, TrkB, initiates downstream signaling that is critical for plasticity and memory [1]-[4]. Recent studies have highlighted the potential of targeting BDNF/TrkB signaling for the treatment of neurodegenerative diseases such as Alzheimer disease (AD) [5]-[8]. Such work has demonstrated that TrkB activation improves cognition, and this improvement is associated with increased synapse density. Furthermore, the effects of TrkB activation on cognition are typically independent of any effect on A[beta] or tau pathology [5], [6]. While promising, the efficacy of BDNF/TrkB-based therapies has yet to be demonstrated in a mouse model with severe neuronal and synaptic loss, such as occurs in AD [9], [10].

The loss of neurons is a prominent and early feature of AD, and this loss correlates with cognitive deficits more closely than amyloid load [9], [11], [12]. The hippocampal formation is particularly vulnerable, and in the late stages of the disease loss of neurons in the CA1 and layer II of the entorhinal cortex reaches 80-90% [13]. Even in mild AD, there is already a loss of over half of neurons in CA1 and layer II of the entorhinal cortex [10]. Patients can have significant plaque and tangle pathology without detectable cognitive impairment, and only once substantial neuronal loss develops do patients begin to show signs of dementia [10]. Since significant synaptic and neuronal loss has already occurred by the time symptoms manifest and AD is diagnosed, it may be useful to promote the restoration of lost synapses by targeting signaling pathways such as BDNF/TrkB.

Since BDNF has poor blood-brain barrier penetration and a short half life [14], TrkB has typically been targeted by locally upregulating BDNF through viral overexpression or direct protein infusion [6], [7], [15]. While these methods have provided a convincing proof of principle, other delivery methods should be developed to make clinical translation more feasible. Specific small molecule TrkB agonists have been recently developed that can be administered systemically and initiate TrkB activation with equal potency to BDNF [16], [17]. Treatment with these drugs has the benefit of being far less invasive than viral or recombinant protein delivery, and allows the chronic targeting of multiple affected brain regions.

One recently identified TrkB agonist, 7,8-dihydroxyflavone (DHF), has shown promising protective effects in mouse models of aging, Parkinson disease, and AD [8], [17]-[19]. In the current study, we investigate whether 7,8-DHF treatment can also reverse functional deficits related to severe neuronal loss using CaM/Tet-DTA mice. The CaM/Tet-DTA model harbors a tetracycline-inducible transgene system that selectively kills neurons of the hippocampus and cortex, and produces behavioral deficits in cognitive domains subserved by these regions [20]-[22]. The pattern and degree of neuronal loss in this model emulates that found in AD [9], [13], [23]-[25]. Furthermore, for the current study we modified the CaM/Tet-DT A model to carry a Thy1-GFP-M transgene,...

Source Citation

Source Citation   

Gale Document Number: GALE|A478772639