The neuropathology of Alzheimer´s disease (AD) is distinguished by neuronal loss, intracellular neurofibrillary tangles and the deposition of amyloid-beta (Abeta) plaques in the brain parenchyma. Overwhelming evidence indicates that aberrant production of Abeta peptides plays a causal role in the pathogenesis of the disease. Abeta is a proteolytic fragment of the amyloid precursor protein (APP), a ubiquitously expressed type I transmembrane protein. The final step in the generation of Abeta from APP is catalyzed by the multiprotein complex gamma-secretase, which constitutes a prime drug target in AD. Gamma-secretase produces Abeta peptides of varying length, but strong evidence indicates that the longer and more toxic Abeta42 isoform is the key pathogenic species and could be the ideal therapeutic target in AD.
In 2001, it was discovered that certain non-steroidal anti-inflammatory drugs (NSAIDs) including ibuprofen specifically inhibit the cellular production of Abeta42 peptides without affecting other substrates of gamma-secretase. These findings proved for the first time that pharmacological suppression of Abeta42 production with small molecules is feasible, and established a new class of potential AD therapeutics called GSMs. Subsequently, GSMs with nanomolar potency and favorable pharmacological properties were reported, some of which are now in clinical development for AD. Recently, we have shown that these second-generation GSMs interact with presenilin, the catalytic subunit of the gamma-secretase complex. However, the molecular details of the mode of action of GSMs are far from resolved.
Ongoing efforts in our laboratory concentrate on full understanding of the molecular mechanism of gamma-secretase modulators, and the chemical development and preclinical testing of improved gamma-secretase modulators. We are further interested in cellular pathways controlling Abeta production, the mechanism of presenilin mutations in familial Alzheimer´s disease (eFAD), the role of inflammation and microglia cells in the disease, and the molecular biology of and therapeutic strategies for frontotemporal dementia.
The group primarily uses techniques of cell and molecular biology and protein biochemistry. Synthetic chemistry is performed in collaboration with medicinal chemists. Most recently, our laboratory has acquired a Biomek FXP robotic workstation, which allows us to conduct high-throughput chemical and genetic (RNAi) screens.