6th ESACP Congress, Heidelberg, April 7-11, 1999

A005
AGEING WITHOUT ALZHEIMER'S DISEASE - MOVING FROM MOLECULAR PATHOLOGY TO PREVENTION
Beyreuther K, Masters CL *

ZMBH, Univ.Heidelberg, Heidelberg, Germany; * Dept.Pathology, Univ.Melbourne, Parkville, Victoria, Australia

There is a noticeable air of optimism in the research community studying Alzheimer's disease (AD). This because the molecular basis of AD is rapidly being elucidated. From these molecular insights, it is likely that effective therapeutic and preventive strategies will be developed within the next 10 years. Future treatment will probably be based on combination therapies such as neurotransmitter replacement combined with a drug to protect against the toxic effect of Aß amyloid whereas prevention will probably include cholesterol lowering and estrogen replacement strategies. Genotype screening, analysis and counseling will bring forward the emerging field of pharmaco-genetics, in which these treatment and preventive strategies will be tailored to the genetic profile of an individual. Many lines of evidence confirm that the generation of Aß is the central pathway in AD neurodegeneration. The clinching evidence has come from the recognition that rare genetic mutations in the gene encoding Aß as part of the amyloid precursor protein (APP) that can cause AD at an early age enhance the production of the amyloid peptide Aß42. The latter is a metabolic product of APP and the major subunit of amyloid plaques which are characteristic of AD. Because both, the apoEe4 allele and lower estrogen may be associated with higher cholesterol levels and risk of developing AD, we studied the influence of cholesterol on neuronal generation of Aß. By reducing the cellular cholesterol level of living hippocampal neurons with lovastatin and methoyl-ß-cyclodextrin, we found that the formation of secretory and intracellular Aß42 is drastically reduced (Simons et al. Proc. Natl. Acad. Sci. USA 95, 6460-6464, 1988). This shows that cholesterol is required for Aß formation to occur and implies a link between cholesterol, Aß and Alzheimer's disease. To unravel this link, we have tried to consider what the physiolgocal functions of the Aß peptide are. Our finding that the Aß domain functions as axonal targeting signal of APP suggests that Aß formation regulates APP transport, that this regulation is linked to cholesterol and that Aß accumulation may disturb axonal transport of APP and thus cause neurodegeneration.