FWF - Drugs for Lysosomal Deseases - Probes and Potential Drugs for Lysosomal Diseases and Alzheimers

Project: Research project

Description

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

-galactosidase and N-
acetylhexosaminidase are distinctly up-regulated in Alzheimer's patients and, that lysosomal

-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.
StatusFinished
Effective start/end date1/08/1231/07/15