Pathogenic Tangles

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Science  31 Mar 2000:
Vol. 287, Issue 5462, pp. 2377
DOI: 10.1126/science.287.5462.2377f

One of the hallmarks of Alzheimer's disease (AD) is the accumulation of intracellular neurofibrillary tangles in the brain. These fibrils contain phosphorylated forms of tau, a protein that normally binds to microtubules but, when hyperphosphorylated, detaches and aggregates. Ahlijanian et al. observe pathologic argyrophilic neurons, indicative of altered tau protein, in transgenic mice expressing human p25, the soluble activator domain of a membrane-bound protein called p35. Also, the cytologic abnormalities in the amygdala of the transgenic mice and the regional profile of p25 expression correlated with diminished anxiety in behavioral tests, reflective of compromised amygdala function. Previously, Patrick et al. have connected high levels of p25 in brain tissue from AD patients with elevated activity of Cdk5, a cell-cycle protein kinase known to phosphorylate tau. Thus, the constitutive stimulation of Cdk5 by inappropriately generated p25 may be an important trigger in the development of AD.—PAK

Proc. Natl. Acad. Sci. U.S.A.97, 2910 (2000); Nature402, 615 (1999).

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