Many genetic mutations are known to increase the risk of Alzheimer's disease, but it remains controversial whether these mutations have common functional effects. One common site for mutations that predispose individuals to the early onset form of Alzheimer's disease is the gene for amyloid precursor protein. Previously characterized mutations of this type were known to result in increased production of the amyloid b-protein (Ab), a fragment of amyloid precursor protein that is a major component of the large 'amyloid plaques' found at lesions within the diseased brain. The increased production of Ab was thought to favor plaque formation and lead to disease onset.
A study by Lannfelt and colleagues in this issue (Nature Neuroscience, Vol. 4, No. 9, Sep 01) suggests, however, that this theory may need to be revised. The authors report that individuals expressing the 'arctic' Alzheimer's mutation (identified in a family from northern Sweden) actually show decreased production of Ab. The apparent paradox was resolved by further biochemical analysis, which revealed that 'arctic' mutant Ab (the mutation is located within the Ab sequence) actually displayed increased rates of protofibril formation. Protofibrils are small protein complexes that are an intermediate step in the formation of the larger amyloid plaques. Thus, even though patients with this mutation show reduced production of Ab, the pathway to plaque formation is still accelerated.
The authors conclude that it is not simply the levels of Ab that are important, but also the formation of protofibrils. This is an important distinction because it both unifies the mechanism of disease onset for a variety of different mutations and suggests a new target for therapeutic intervention, the formation of protofibrils.
Christian Haass and Harald Steiner discuss these findings in an accompanying News & Views article.
Dr. Lars Lannfelt
Department of Neurotec, Geriatric Medicine
Huddinge, S-141 86
tel: +46 8 585 864 72
fax: +46 8 585 838 80
Dr. Christian Haass
Department of Biochemistry
tel: +49 49 89 5996 471/472
fax: +49 89 5996 415
(C) Nature Neuroscience press release.
Message posted by: Trevor M. D'Souza
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