Probes and Potential Drugs for Lysosomal Diseases and Alzheimer´s

The World Alzheimer Report 2011 gives an estimated number of 36 million people living with dementia today, with Alzheimer`s disease accounting for about 60 percent of this figure. Despite intense research into dementia from so-called tauopathies, which are diseases caused by the deposition of insoluble, pathological conformations of tau protein, called "senile plaques", their connection with the "Greater Lysosomal System" of catabolism and recycling, and, in particular, their relationships to metabolic mismanagement caused by various hereditary lysosomal storage diseases has remained enigmatic. Some lysosomal storage diseases, for example, Gaucher`s and Fabry`s, have become accessible by methods of glycosidase inhibitor treatment such as substrate reduction therapy. More recently, in a noteworthy paradigm change, such inhibitors have also been exploited in sub-inhibitory concentrations to help misfolded glycosidases to reach the lysosome and to take up catalytic activity, supported by the template effect of the inhibitor on the folding process (chaperone mediated therapy; still experimental). Tauopathies and lysosomal diseases have, amongst other factors, in common that glycosphingolipid turnover and recycling is grossly disturbed. With the recently made observation that various lysosomal enzymes including ß-galactosidase and N- acetylhexosaminidase are distinctly up-regulated in Alzheimer`s patients and, that lysosomal ß-glucosidase (the lack of which causes Gaucher`s disease) can accumulate in senile plaques, it is by no means unlikely, that selected inhibitors of lysosomal enzymes regulating glycosphingolipid turnover may beneficially interfere with complex metabolic feedback cycles which are out of balance in the onset and development of Alzheimer`s, Parkinsons`s as well as other tauopathies but also in lysosomal storage disorders. It can be envisaged that inhibition and/or activation of single enzymes or enzyme cascades affects downstream catabolic and recycling steps which are significant for peptide and glycolipid homestasis and, thus, may re-balance the glycosphingolipid metabolism. In the course of this project, a series of new modulators (inhibitors and/or activators) of glycosphingolipid processing glycosidases will be synthesised and screened by leading groups. Thus, this project will provide established inhibitors and pharmacological chaperones which can be probed at various concentrations concerning their effects on experimental symptoms of tauopathy development. With time, compounds and distinct biochemical steps of their interference may be discovered that influence the onset of tauopathy symptoms by up- or downregulating hydrolytic activities in the endosome/lysosome system with a view to a better understanding of the early stages of Alzheimer`s development and to possible biochemical targets of intervention in this disease.

In context with the hereditary lysosomal storage diseases, GM1-gangliosidosis and Morquio B which both are manifestations of the same gene defect, the project was aimed at identifying new compounds with potential to ameliorate disease symptoms by activation of the compromised enzyme and, thus, reducing toxic deposits in cells. As a starting point, 4-epi-isofagomine, an iminosugar and potent ?-galactosidase inhibitor had been identified and efforts were directed towards chemical modifications of this molecule in order to improve its biological properties.After having met a variety of synthetic challenges which were found intrinsic en route to the desired galacto configuration, a range of final products was successfully prepared and biologically screened as enzyme inhibitors as well as so-called pharmacological chaperones in patients cell lines.Two of the products were found the most potent inhibitors of the addressed enzyme and the most effective chaperones known to date for the purpose.As a side project, for the first time, aminocyclopentanes could be discovered effective pharmacological chaperones for GM1-gangliosidosis and a range of such compounds was prepared and biologically evaluated.Overall, we have succeeded in the first synthesis of a C-5a-chain-extended 4-epi- isofagomine with superior biological properties and have also introduced a novel, fourth family of pharmacological chaperones based on the amino(hydroxymethyl)cyclopentane core structure.Final products have been deposited in a European compound collection and data bank and are currently pooled for complex, more in-depth investigations of GM1-ganglioside metabolism in context with Alzheimers.