My Lab works on three closely interrelated research objectives in the field of neurodegenerative disorders, with a focus on Alzheimer’s type dementia.
We do basic research to understand the innate function of amyloid-beta (Aβ) peptides in relation to the neuronal and non-neuronal cholinergic signaling and Alzheimer’s disease.
We also work on developing novel positron emission tomography (PET) imaging probes targeted at the core-cholinergic enzyme to map the cholinergic neuronal networks e.g. in the brain for early diagnosis of dementia in living human subjects.
Finally, my group works on different strategies to increase the production of acetylcholine, and thereby increase the survival and function of cholinergic neurons in the brain. For instance, we have developed a new class of compounds that we call ChAT Potentiating Ligands (CPLs). As the name infers these compounds bind to the enzyme and strongly increase the production rate of acetylcholine. These compounds should also be useful for treatment of another devastating cholinergic disorder, namely ALS which is caused by degeneration of cholinergic motor-neurons.
Collaborations
- We are in close collaboration with Professor Maria Eriksdotter’s Lab (at KI) on a project involved in Nerve Growth Factor (NGF) replacement therapy.
- We also collaborate with Professor Bengt Långströrm (Uppsala University), Professor Agneta Nordberg’s Lab (at KI), and Professor Christer Halldin’s Lab (at KI) on a project involved in developing novel PET tracers for cholinergic system.
- We are also collaborating with Professor Pétur Henry Petersen (University of Iceland); Professor Jón Snædal (University of Iceland) on a project involved in evaluation of an EEG defined Cholinergic Index in relation to the Cholinergic Index calculated in cerebrospinal fluid of patients with dementia.
- We are currently in close collaboration with Professor Mange Ram Yadav and Assistant Professor Prashant Murumkar from Faculty of Pharmacy, The Maharaja Sayajirao University of Baroda, India, on a project involved in the development of a new class of compounds that potentiate acetylcholine biosynthesis by the enzyme, choline-acetyltransferase.
Research Projects
My Lab works on three closely interrelated main research objectives in the field of neurodegenerative disorders, with a focus on Alzheimer’s type dementia.
1. Basic studies on Aβ-Cholinergic Loop in health and dementia.
The cholinergic neurons have widespread projections throughout the brain and body. In the brain, they play important role in various cognitive functions of the brain, such as memory and attention. It is well-established that the cholinergic neuronal projections start degenerating early in several dementia disorders. As a matter of facts the main currently available treatment options in dementia are the so called cholinesterase inhibitors, which are designed to prevent degradation of acetylcholine when it is released into synapses, and thereby enhance the cholinergic output. There are however accumulating evidence indicating that the production and release of acetylcholine is greatly reduced in the affected brain. Amyloid-beta (Aβ) peptides seems to play a role in this regard. Our basic studied aim at understanding the innate function of amyloid-beta (Aβ) peptides in relation to the neuronal and non-neuronal cholinergic signaling, particularly in the context of Alzheimer’s disease.
2. Development of ChAT tracers for PET imaging technique
Given that the cholinergic system is affected early in the course of Alzheimer’s disease, we also work on developing novel imaging probes for positron emission tomography (PET) technique to map the cholinergic neuronal networks e.g. in the brain for early diagnosis of dementia in living human subjects. We are currently working on several promising Lead compounds that we have identified. These compounds show high selectivity and binding affinity to the principal cholinergic enzyme, choline acetyltransferase (simply also called ChAT). This enzyme is responsible for biosynthesis of the cholinergic signaling substance, acetylcholine, and thereby the most specific biomarker of this neuronal system.
3. Development of therapeutic candidates designed to enhance Acetylcholine production
Furthermore, we are working on developing new therapeutic compounds against Alzheimer’s disease and the related dementia disorders. We are therefore working on different strategies to increase the production of acetylcholine. Thus, once more our focus is on the cholinergic system and its principal enzyme, ChAT. For instance, we have currently developed a new class of compounds that we call ChAT Potentiating Ligands (CPLs). As the name infers these compounds bind to the enzyme and strongly increase the production rate of acetylcholine. These compounds should also be useful for treatment of another devastating cholinergic disorder, namely ALS which is caused by degeneration of cholinergic motor-neurons. Currently we are doing preclinical characterization of these novel compounds using different cellular models.
Research support
With special thanks to the following donors for the support they provide or earlier provided to our research:
- Swedish Research Council (project no 2016-01806).
- Alzheimer Association, USA (2016-NIRG-391599)
- Swedish Brain Foundation (FO2016-0059)
- Stockholm County Council (ALF project)
- Karolinska Institutet
- Åhlén Foundation
- Magnus Bergvall Foundation;
- Foundation for Old Servants
- Gunvor and Josef Anér Foundation;
- Demensfonden
- Gun and Bertil Stohne Foundation
- Loo & Hans Österman Foundation
- Olle Engkvist Byggmästare Foundation
- Åke Wibergs Foundation
- Lars Hierta Memorial Foundation
- Tore Nilsson Foundation
- Foundation for Sigurd & Elsa Golje Memory