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6th ESACP Congress, Heidelberg, April 7-11, 1999 |
A005
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.
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