This translational neuroscience programme will explore the most promising drug target for treatment of cognitive dysfunction: The nicotinic alpha7 acetylcholine (ACh) receptor (α7nAChR). The aim is to identify subpopulations of patients with cognitive dysfunction [i.e. diagnosed for Alzheimer's disease (AD) or schizophrenia (SCZ)] that will benefit from treatment with α7nAChR modulators. Our results, supported by the literature, suggest that only some patients will benefit from this treatment. Therefore, application of human model systems and selection of well-defined patient groups, based on their biomarker profiles, are instrumental to select the right compound(s) for future clinical trials. We hypothesize that the differential effects in patients are due to a) differences in the composition and expression of a α7nAChR duplicate hybrid gene acting as a dominant negative, and b) functional variability of the receptor is due to the presence of interacting proteins and peptides (i.e. β-amyloids) in the diseased brain.

The involved partners have a strong background in combining basic neuroscience, industrial drug-discovery, molecular brain imaging, biomarker discovery and clinical research. In this project we will take advantage of this translational approach and investigate the effects of α7nAChR positive modulators using human neuronal extracts, porcine/human stem cells, novel translational animal models, and transgenic animals. We will also screen for the presence, sequence, and copy number of the dominant negative CHRFAM7A gene in well-defined patient populations with cognitive disturbances. We will determine how synthetic amyloids and extracts of CSF samples from individual patients with dementia interact with the receptor.

Furthermore, we have discovered an α7nAChR radiotracer for brain imaging - 11C-NS14492 - and we will develop this tracer and the accompanying method in pigs with the intention of using it in human trials in the end of this programme. All together this is a focused translational project that within the 5 year period will help to define selected patient groups based on biomarkers
profiles and sensitivity to novel treatments of cognitive dysfunction.

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Poul Hyttel
Department of Veterinary Clinical and Animal Sciences,
Faculty of Health and Medical Sciences, 
University of Copenhagen


Center for Neuropsychiatric Schizophrenia Research
Birte Glenthøj
Ndr. Ringvej
2600 Glostrup
Department of Health Science and Technology 
University of Aalborg

Jacek Lichota

Laboratory of Neurobiology
Biomedicine, Aalborg University
Fredrik Bajers Vej 3 B
9220 Aalborg Øst

Neurobiology Research Unit 
Jens D. Mikkelsen
The Neuroscience Centre
Rigshospitalet, building 6931
Copenhagen University Hospital
Blegdamsvej 9
2100 København Ø 

The Kennedy Center
Zeynep Tümer
Center for Anvendt Human Molekylærgenetik
Gl. Landevej 7
2600 Glostrup