Year: 2018
Type: dissertation
Abstract: The aim of this thesis was to investigate the role of brain derived neurotrophic factor (BDNF) in memory impairment manifested in Alzheimer's disease (AD), and to study the potential of cerebral dopamine neurotrophic factor (CDNF) in preventing the memory decline.BDNF contributes to memory processes by its established role in synaptic plasticity.Since impaired synaptic activity, synapse loss and decreased BDNF levels have been reported in the AD brain it was worth investigating the involvement of BDNF in AD further.This study employed transgenic mice harboring familial AD linked gene mutation (APPswe/PS1dE9) with altered BDNF signaling: overexpression of truncated TrkB.T1 receptor, overexpression of functional TrkB.TK receptor or heterozygous deletion of BDNF.CDNF has shown strong neuroprotective properties in animal models of Parkinson's disease, which motivated studies on its potential also in an AD model.CDNF was infused as a pure protein or in a viral vector directly into hippocampi of APP/PS1 mice.Mice with modifications in BDNF signaling on top of AD transgenes and APP/PS1 mice treated with CDNF underwent an extensive behavioral test battery to measure neurotrophic factor effects on memory functions.Overexpression of truncated TrkB.T1 receptor and heterozygous depletion of BDNF aggravated the memory impairment in APP/PS1 mice, whereas overexpression of the functional TrkB.TK receptor alleviated it, consistent with the idea that reduced BDNF signaling might be behind synaptic dysfunction and memory decline in AD.Intrahippocampal CDNF administration improved performance of APP/PS1 and wild-type mice selectively in a memory retention paradigm, suggesting a specific role of CDNF consolidating long-term memories.None of the neurotrophic factor manipulations influenced amyloid plaque pathology while they all had effects on memory function, also in wild-type mice without amyloid-β pathology.These findings demonstrate neurotrophic factor effects on synaptic plasticity and memory independent of amyloid accumulation, and moreover, a possibility to enhance memory in AD models without amyloid-β clearance.APP/PS1 mice were found to have increased BDNF levels in cortical areas, without a corresponding increase in BDNF mRNA or TrkB activation.Further, immunohistology showed BDNF to be co-localized with amyloid plaques.This finding together with the behavioral impairment in APP/PS1 x BDNF+/-mice suggest that BDNF is "trapped" in plaques and is therefore unable to participate in signaling.If this is the case also in human AD, the reportedly reduced BDNF levels are functionally even lower.In conclusion, the results of this thesis point to a significant role of neurotrophic factor signaling in AD related memory decline.Thus, by enhancing neurotrophic factor signaling it would be possible to improve memory functions without altering brain amyloid burden.
Author: Susanna Kemppainen
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3210307879