Alzheimer´s disease - The molecular clockwork of a ticking time bomb

Article by Christian Haass Department of Biochemistry, Adolf-Butenandt-Institute, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians-University

Alzheimer’s Disease is by far the most frequent age dependent neurodegenerative disorder and heavily threatens public health in our senescing society. Cure is desperately required, however conventional symptomatic attempts failed. In contrast, novel mechanism based therapeutic approaches are now providing strong hope that progression of Alzheimer’s disease may be slowed or even prevented. These novel therapeutic approaches are based on the identification of a variety of key enzymes, the secretases, which allow the proteolytic generation of the disease characterizing Amyloid ß-peptide.

The amyloid cascade
It is precisely 100 years ago that Auguste D. reported to Alois Alzheimer, a German psychiatrist in Frankfurt, with her famous words: "I lost myself”. This is probably the best description of the disease symptoms, a slow progression of memory loss. As the major risk factor for AD is aging, one must expect a sharp increase of the number of patients in the near future.

Based on the abundant deposition of senile plaques and neurofibrillar tangles, a cascade of events was described, which is now known as the Amyloid Cascade (Hardy and Selkoe, 2002). Amyloid stands for Amyloid ß-peptide (Aß) and describes a highly hydrophobic peptide, which aggregates to form small oligomers (Glenner and Wong, 1984). These oligomers are still soluble and may cause first detrimental effects on memory (Walsh et al., 2002). If these oligomers aggregate further they start forming fibers, which eventually precipitate and accumulate in the disease defining amyloid plaques (Fig. 1). While the fibers are deposited in the brain parenchyma additional toxic aggregation events appear to be induced within the cell. Tau, a protein, which stabilizes microtubules dissociates from the cytoskeleton and aggregates within the soma of neurons to form the intracellular tangles (Mandelkow and Mandelkow, 1998) (Fig. 1). This process may then initiate a variety of less understood toxic insults, ultimately leading to the tremendous neuronal loss observed in AD brains (Gotz et al., 2001). This process, which appears to be initiated by the oligomerization of Aß (Gotz et al., 2001) is now known as the amyloid cascade (Aguzzi and Haass, 2003; Hardy and Selkoe, 2002).