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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00051

Acute down-regulation of BDNF signaling does not replicate exacerbated amyloid-β levels and cognitive impairment induced by cholinergic basal forebrain lesion

 Marion T. Turnbull1, Zoran Boskovic1 and  Elizabeth J. Coulson1, 2*
  • 1The University of Queensland, Australia
  • 2Faculty of Medicine, School of Biomedical Sciences, The University of Queensland, Australia

Degeneration of basal forebrain cholinergic neurons (BFCNs) precedes hippocampal degeneration and pathological amyloid-beta (Aβ accumulation and underpins the development of cognitive dysfunction in sporadic Alzheimer’s disease (AD). We hypothesized that degeneration of BFCNs causes a decrease in neurotrophin levels in innervated brain areas, which in turn promotes the development of Aβ pathology and cognitive impairment. Here we show that lesion of septo-hippocampal BFCNs in a pre-symptomatic transgenic amyloid AD mouse model (APP/PS1 mice) increases soluble Aβ levels in the hippocampus, and induces cognitive deficits in a spatial memory task that are not seen in either unlesioned APP/PS1 or wildtype littermate control mice. Furthermore, the BFCN lesions result in decreased levels of brain-derived neurotrophic factor (BDNF). However, viral knockdown of neuronal BDNF in the hippocampus of APP/PS1 mice (in the absence of BFCN loss) neither increased the levels of Aβ nor caused cognitive deficits. These results suggest that the cognitive decline and Aβ pathology induced by BFCN loss occur independent of dysfunctional neuronal BDNF signaling, and may therefore be directly underpinned by reduced cholinergic neurotransmission.

Keywords: Alzheimer’s disease, basal forebrain, Cholinergic neuron, Transgenic mouse, Brain-Derived Neurotrophic Factor, Amyloid beta-Peptides

Received: 14 Nov 2017; Accepted: 06 Feb 2018.

Edited by:

Oliver Wirths, Universitätsmedizin Göttingen, Germany

Reviewed by:

Wolfgang Härtig, Leipzig University, Germany
Rebecca J. Rylett, University of Western Ontario, Canada  

Copyright: © 2018 Turnbull, Boskovic and Coulson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Elizabeth J. Coulson, The University of Queensland, Faculty of Medicine, School of Biomedical Sciences, Brisbane, Australia, e.coulson@uq.edu.au