Abstract
Augmenting BDNF/TrkB signaling has been demonstrated to be a promising strategy for reversing cognitive deficits in preclinical models of Alzheimer disease (AD). Although these studies highlight the potential of targeting BDNF/TrkB signaling, this strategy has not yet been tested in a model that develops the disease features that are most closely associated with cognitive decline in AD: severe synaptic and neuronal loss. In the present study, we investigated the impact of 7,8-dihydroxyflavone (DHF), a TrkB agonist, in CaM/Tet-DTA mice, an inducible model of severe neuronal loss in the hippocampus and cortex. Systemic 7,8-DHF treatment significantly improved spatial memory in lesioned mice, as measured by water maze. Analysis of GFP-labeled neurons in CaM/Tet-DTA mice revealed that 7,8-DHF induced a significant and selective increase in the density of thin spines in CA1 of lesioned mice, without affecting mushroom or stubby spines. These findings suggest chronic upregulation of TrkB signaling with 7,8-DHF may be an effective and practical strategy for improving function in AD, even after substantial neuronal loss has occurred.
Highlights
The interaction between brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, TrkB, initiates downstream signaling that is critical for plasticity and memory [1,2,3,4]
tetracycline responsive element (Tet)-diphtheria toxin A-chain (DTA)+/+ mice were bred with Thy1-GFP-M+/2, and subsequent generations were genotyped by Southern blot and interbred until animals that were homozygous for both transgenes were produced
To ensure that the presence of GFP or new background strain elements did not disrupt the functioning of the CaM/Tet-DTA lesion system, hippocampal and cortical lesions were induced in 3
Summary
The interaction between brain-derived neurotrophic factor (BDNF) and its high-affinity receptor, TrkB, initiates downstream signaling that is critical for plasticity and memory [1,2,3,4]. Such work has demonstrated that TrkB activation improves cognition, and this improvement is associated with increased synapse density. The effects of TrkB activation on cognition are typically independent of any effect on Ab or tau pathology [5,6]. 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]. Even in mild AD, there is already a loss of over half of neurons in CA1 and layer II of the entorhinal cortex [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
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