The effects of anticholinesterases and β-amyloid pathology on neurotrophin signaling in the mouse brain

Alzheimer s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. One promising approach to tackle AD is the protection of neurons and restoration of synaptic connections with neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). The first aim of this study was to examine the effects of cholinesterase inhibitors (ChEi), the first-line drugs for AD, on Trk neurotrophin receptor activity in the mouse brain. We show that donepezil and galantamine, two clinically used ChEis, rapidly phosphorylated Trk receptors in the mouse hippocampus. Subsequent pharmacological studies suggest that cholinergic activation of Trk receptors required simultaneous stimulation of nicotinic and muscarinic acetylcholine receptors. Moreover, we report that drug-induced Trk receptor phosphorylation response was unaltered in Sortilin1-/- mice and Bdnf+/- mice, which show defects in anterograde transport and synaptic targeting of Trk receptors and BDNF signaling, respectively. Our results show that drugs commonly used to treat AD activate neurotrophin receptors in the mouse brain. In the second part of this work, we studied the molecular mechanisms underlying impairment of BDNF-TrkB signaling in a mouse model of AD. We discovered that Aβ accumulation in the APdE9 mouse model of early-onset familial AD resulted in an age-dependent increase in the levels of TrkB.T1, a dominant-negative form of TrkB in the brain. Furthermore, we detected aberrant accumulation of BDNF protein in the cortex of APdE9 mice. Moreover, we show that overexpression of TrkB.T1 and Bdnf gene deficiency aggravated the memory impairment in APdE9 mice, whereas overexpression of TrkB alleviated this memory deficit. These findings may in part explain the failure of synaptic plasticity in APdE9 mice and suggest that activation of TrkB signaling could alleviate memory impairment in patients with AD. Finally, we developed an assay to detect signaling of p75 neurotrophin receptor in vivo. We show that our assay detects p75 signaling in vitro and present our strategy to generate a p75 signaling reporter mouse based on the same methodology. Our knock-in mouse will enable accurate temporal and spatial localization of p75 activity in healthy, aging and injured nervous systems, and serve as a screening platform to discover novel drugs to inhibit the detrimental effects of p75 signaling.

Grantor dc:publisher

Helsingin yliopisto

Year dc:date.issued

2013

Author dc:creator

• Autio, Henri

• farmakologia

Statement dc:rights

• Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
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• Publikationen är skyddad av upphovsrätten. Den får läsas och skrivas ut för personligt bruk. Användning i kommersiellt syfte är förbjuden.

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/10138/40751

OAI record oai:identifier

https://helda.helsinki.fi/server/oai/request?verb=GetRecord&metadataPrefix=dim&identifier=oai%3Ahelda.helsinki.fi%3A10138%2F40751