BMC Seminar Wednesday 5th October 2016, at 11:00 in room 124, Læknagarður
Speaker: Taher Darreh-Shori, Pharmacologist, PhD, Associate Professor, Deputy Head, Division of Translational Alzheimer Neurobiology, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Sweden
Title: Emerging new findings on Cholinergic signaling in inflammatory diseases - Potential as therapeutics and in vivo functional biomarker
Abstract: The main therapeutic agents in dementia are cholinesterase inhibitors (ChEIs). Attempts on reviving the cholinergic neuronal networks by nerve growth factor-releasing cell implants, or by deep brain stimulation of nucleus basalis have also shown clinical effect, particularly in patients who were able to increase the activity of the acetylcholine-synthesizing enzyme, choline acetyltransferase (ChAT). All other therapeutic strategies have so far failed.
Considering that several registered drugs with anti-cholinergic activities do not merely produce dementia symptoms but actually increase the risk of developing dementia, together with the aforementioned facts suggest that imbalances in the cholinergic signaling is (if not the cause) at least a vulnerability factor rather than a consequence of the pathological events leading to dementia. This is also in line with the fact that cholinergic system exhibits decline with advancing-age, which is the most important risk factor for developing Alzheimer’s disease (AD).
In context of the disease mechanism, new reports show that intra-neuronal amyloid-beta (Aβ) peptides is a preferential feature of the cholinergic neurons, regardless of the subjects’ age and disease status. This is in turn in-line with our report that Aβ functions as an allosterically modulator of the activity of the acetylcholine -degrading enzymes, cholinesterases.
Further reports have revealed another piece of puzzle, namely that the acetylcholine-synthesizing enzyme, ChAT is not merely expressed but it is secreted by lymphocytes, astrocytes and human embryonic stem cells into extracellular fluids, including plasma and CSF. Hypothetically, the function of soluble ChAT is to maintain through continuous in situ resynthesis an extracellular tune of acetylcholine that is demanded to suppress inflammatory responses. Nonetheless, soluble ChAT level is found highest in patients suffering of neuroinflammatory diseases, such as multiple sclerosis or AD, in whom CSF ChAT levels also show high positive correlation with several complement factors of native immune system. These appear in paradox to the putative view ascribing an anti-inflammatory and/or immune suppressive action to acetylcholine.
In conclusion, although these observations picture a complex and paradoxical pattern they provide clues on the importance of cholinergic signaling for healthy aging and preventive strategies in dementia and/or degenerative disorders.