Alzheimer Research

According to the World Health Organisation the AD prevalence equals 5.5 % above 60 year of age and increases for elderly people (clinical AD: 16% 85y, 22% 90y). Thus age is the dominant risk factor overruling even the positive impacts of nutrition and education. Despite all efforts, the exact cause of Alzheimer's disease is still unknown, although a number of factors have been suggested. These include the metabolism and regulation of the amyloid precursor protein, plaque-related proteins, tau proteins, zinc, copper and aluminium cations.

Acetyl cholinesterase inhibitors and general therapy moderate symptoms at the onset of the disease, they improve cognitive function, as expressed in Alzheimer’s Disease Assessment Scale (ADAS-COG), but these drugs do not address the severe mortality at the final stage. Promising results were obtained with nonsteroidal anti-inflammatory drugs (NSAID). Immunization therapies against Ab hold high potential and are under investigation by several companies.

Gene mutations linked to early-onset Alzheimer’s disease afflicted families in London and Sweden and additional polymorphisms, that either cause or further AD, provided some insight into the biological pathways and the involvement of the amyloid precursor protein (APP). A rational approach to a successful, causal therapy is based on a detailed understanding of Ab formation, deposition and the inflammatory consequences. Decisive functions were assigned to the amyloid precursor protein (APP) and its degrading aspartic proteases: β-secretase (BACE) and the presenilins (PS is also called ϒ-secretase), which are in the focus of our research efforts.

The current hypothesis for the modulation of ϒ-secretase is depicted below. The modulator binding to the substrate C99 interferes with substrate dimerization. The monomeric substrate is then metabolized to non-pathological fragments.