ART Web page - information on member
Christian Hölscher , PhD
Senior Lecturer in Neuroscience
School of Biomedica Sciences
University of Ulster,
Coleraine BT52 1SA, UK
email c.holscher@ulster.ac.uk
Tel.: 0044-28-70324178
Fax: 0044-28-70324375
1. Research Interests
Effects of beta-amyloid on neurons
I am investigating the effects of beta-amyloid fragments on neuronal degeneration, synaptic plasticity, and cognitive processes such as memory formation.
Beta-amyloid has several physiological effects. Recently, it has been observed that soluble oligomers of beta-amyloid already has detrimental effects. Indeed, we found that icv injection of beta-amyloid in rats has reversible effects on synaptic plasticity and on learning processes (Holscher at al., 2007). Beta-amyloid oligomers have been shown to activate Calcium channels, increase free radical production, and block NGF and glutamate receptors (Holscher, 2005).
The aim is to characterise these early impairments in order to find ways to block them. It is hoped that by preventing the early (and still reversible) effects of beta-amyloid, the degenerative downstream effects (that are irreversible) can also be prevented.
Several animal models are used for these investigations. A transgenic mouse model that expresses the human Swedish familial double mutation of APP (670/671) and a human mutation of presenilin-1 (L166P) (see Radde et al. 2006 for details). Studies are ongoing to characterise changes in neurotransmission and memory formation in this model.
A second transgenic mouse strain expressing the Swedish familial double mutation of APP and the deltaE9 human mutation of presenilin-1 is also used to investigate changes induced by the overexpression of APP, increased beta amyloid production and plaque formation.
Both models develop plaques early after ca. 2 months, followed by gliosis and memory impairments.
Diabetes and AD
I am further interested in the interaction between type 2 Diabetes and Alzheimer’s Disease. Insulin receptors are expressed in the brain and have growth factor like functions on neurodevelopment and repair. People with type 2 diabetes have a much higher risk of developing AD, and 80% of AD patients have type 2 diabetes or show borderline symptoms. In AD patients, insulin receptors of the brain are desensitised, and this lack of growth factor activity could contribute to accelerated neurodegeneration.
Current projects analyse the effect of insulin-like analogues on neuronal transmission and on neurodegeneration. A collaboration with Prof. Calum Sutherland funded by the ART is currently analysing the insulin receptor coupled second messenger pathways in transgenic mice.
Further projects include the investigation of stem cell proliferation in the transgenic mouse model of AD.
Techniques used:
- In vivo recording of hippocampal field excitatory postsynaptic potentials (EPSPs) to test changes in neurotransmission, synaptic plasticity and in cortical EEG.
- anatomical studies using immuno-histochemistry and electron microscopy to study plaque development, gliosis, stem cell development, and anatomical changes on synapse and dendrite level. Unbiased 3D stereology is used to quantify the changes.
- Behavioural studies to investigate the ability to form new memories during the development of plaques, using a battery of tasks such as the water maze, conditioning tasks, T-maze and 8-arm maze tasks.
2. Current funding
2007-2008 ......Alzheimer Research Trust pilot project grant (£19,000), collaboration with Prof Sutherland from University of Dundee
title: "desensitisation of insulin receptors in a mouse model of AD"
2008-2011 .......Alzheimer Socitey research project, post-doctoral position
title: "Effects of insulin-like analogues on neurodegeneration in a mouse model of AD"
2008-2011 .......Alzheimer Research Trust research project, PhD studentship
title: "effects of novel GIP analogues on neurodegeneration in a mouse model of AD"
2008-2011 .......Alzheimer Research Trust research equipment grant for an X-ray machine.
title: "neuronal stem cell proliferation in a mouse model of AD"
2008-2011 .......EU FP7 NeuroNanotoxicology grant
title: "Effects of nanoparticles on protein aggregation in a mouse model of AD"
3. List of recent AD research - related Publications
Victor A. Gault and Christian Hölscher (2008): A novel GIP agonist facilitates hippocampal LTP and reverses the impairment of LTP induced by beta-amyloid, J. Neurophysiol. in press
Victor A. Gault and Christian Hölscher (2008): GLP-1 agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloid, EJP, in press.
Gengler S., V A. Gault, P Harriott, C Hölscher (2007). Beta-amyloid (25-35) induced impairments of hippocampal synaptic plasticityare dependent on stimulation-protocol, genetic background, and aggregation state. Exp Brain Res., 179:621-630.
Holscher C, Gengler S, Gault VA, Patrick Harriott, Hanspeter Mallot HA (2007). Soluble beta-amyloid[25-35] reversibly impairs hippocampal synaptic plasticity and spatial learning. Eur J Pharmacol, 561:85-90.
Radde R, T Bolmont, S A Käser, J Coomaraswamy, D Lindau, L Stoltze, ME Calhoun, F Jäggi, H Wolburg, S Gengler, C Haass, B Ghetti, C Czech, C Hölscher, PM Mathews, M Jucker (2006). Aß42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Report, 7:940-946.
Gengler S., V A. Gault, P Harriott, C Hölscher (2006). Beta-amyloid (25-35) induced impairments of hippocampal synaptic plasticityare dependent on stimulation-protocol, genetic background, and aggregation state. Exp Brain Res., DOI10.1007/s00221-00006-00819-00226.
Hölscher C, Schmid S, Pilz P, van der Putten H, Plappert C (2005): Lack of the metabotropic glutamate receptor subtype 7 selectively modulates theta rhythm and working memory. Learning and Memory, 12:450-455.
Hölscher C, Jacob W, Mallot HA (2004): Learned association of allocentric and egocentric information in the hippocampus. Exp Brain Res, 158:233-240
Hölscher C, Schmid S, Pilz P, van der Putten H, Plappert C (2004): Metabotropic glutamate receptor subtype 7 ablation causes a selective deficit in working memory but not long-term memory formation. Behav Brain Res, 154:473-481
Hölscher C, Jacob W, Mallot HA (2003): Reward modulates neuronal activity in the hippocampus of the rat. Behav. Brain Res., 142:181-191.
Hölscher C., Rolls ETR and J-Z Xiang (2003): Perirhinal cortex neuronal activity related to long term memory in the macaque. Eur J Neurosci 18:2037-2046.
Hölscher C. (2003): Time, space, and hippocampal functions. Reviews in the Neurosciences, 14:253-284.
Hölscher C. (2002): Metabotropic glutamate receptors control gating of spike transmission in the hippocampus. Pharmacol Biochem Behavior, 73(2):307-316.
Hölscher C., Rolls ETR (2002): Perirhinal cortex neuronal activity related to working memory in the macaque. Neural Plasticity, 9:51-61.
Hölscher C (2002): Different strains of rats show different sensitivity to block of LTP by nitric oxide synthase inhibitors. Eur. J Pharmacol., 457:99-106.
Freir DB, Herron CE and Hölscher C (2001): Blockade of LTP by beta-amyloid fragments in the CA1 region of the rat hippocamus in vivo. J Neurophysiol., 85:708-713.