Researchers from the Ludwig-Maximilians-Universität München and the IIMCB Warsaw have identified a novel class of multifunctional drugs for treatment of Alzheimer´s disease.
Alzheimer´s disease (AD), the most common form of dementia, is a growing threat to our aging society. There is still no cure for AD and the available treatments are very inadequate. Current AD drug development attempts mainly focus on targeting two major hallmarks of the disease, beta-amyloid and tangle pathologies. Calcium dysregulation is a proximal event in AD progression playing a key role in synaptic failure and neuronal loss. Notably, the later irreversible pathological events correlate best with the stages of dementia. Disrupted calcium homeostasis is present early in AD development, long before the onset of disease hallmarks or cognitive deficits. Long-term disruption of calcium homeostasis has been shown to both trigger and accelerate amyloid and tangle pathology. The recent unexceptional failure of AD drug candidates targeting amyloid and tangle pathologies in late clinical phases has led to perspective change in AD drug development. Therefore we examined the possibility of restoring the altered cal ium homeostasis - particularly in intracellular calcium stores, e.g. endoplasmic reticulum (ER) - in context of AD drug discovery.
Picture: In vivo interaction between neurons (green) and abeta plaques (blue) in the brain of a living AD mouse model
In order to identify compounds that target the disrupted ER calcium homeostasis, we established an elegant FRET calcium-imaging-based live cell highthroughput compound screening assay.Screening a large diverse library of small molecules led to identification of a new class of compounds which stabilize the altered ER homeostasis. The compounds showed beneficial effects on several other central aspects of AD pathology as well. For the first time we present a multifunctional lead structure which by simultaneously stabilizing intracellular calcium homeostasis, enhancing mitochondrial function and lowering beta-amyloid levels promises a potential for becoming an AD blockbuster. As oppose to other disease modifying drug development approaches which focus on only one pathophysiological aspect of AD, our lead structure shows beneficial effects at multiple levels.
Currently 35.6 million people are estimated to suffer from AD worldwide. The global economic impact of AD exceeds 300 billion USD annually. Despite huge investments of pharmaceutical industry in AD drug development, there is still no effective therapy for this disease. The very few approved AD drugs on the market show symptomatic relief at best and can only delay the progression of the disease temporarily. The annual market for AD drugs was 8 billion USD in 2011. Given the advantages of our lead structures compared to other technologies, we see a high potential for our lead structure to become an effective medication in AD therapy market.
The lead structure has been identified and fine-tuned. Several analogues were synthesized and their structure-activity relationships were determined. Currently we are trying to further understand the mode of action of the lead structure. We intend to identify the direct protein target(s) and better understand its impact on the signalling cascade which led to observed downstream effects on amyloid-beta levels and mitochondrial activity. After determining the in vivo toxicology and pharmacokinetic profile of the lead structure, we will perform proof of concept studies in several transgenic mouse models of AD.