The research partly resolves a longstanding controversy about whether extracellular amyloid deposits containing the Aβ42 peptide or intraneuronal tau tangles cause AD, and what, if any, relationship they bear to each other. Debate arose because the four genes known to underlie familial early-onset AD (FAD) all increase Aβ production, yet mouse models carrying mutations in these genes exhibited amyloid plaques without concomitant tangles or neuronal loss. Tau, on the other hand, can cause neurodegeneration, as when mutated in certain tauopathies, but is not known to be mutated in AD.

The present studies link Aβ and tau together, suggesting that Aβ pathology precedes and then accelerates tau pathology. The Hutton team crossed JNPL3 mice expressing a mutant tau protein with Tg2576 transgenic mice expressing mutant APP. The bigenic mice developed amyloid plaques similar in number and distribution to those of Tg2576 mice. Neurofibrillary tangles, however, appeared earlier and in much higher numbers in the bigenic mice than the JNPL3 mice. The most pronounced increase, up to sevenfold, occurred in limbic areas, such as the olfactory cortex, the entorhinal cortex, and amygdala.

Interestingly, tangles appeared to be physically separated from amyloid plaques, even in areas known to be vulnerable to both kinds of lesions early on in AD, for example the entorhinal cortex. The archetypal, mature AD plaque, in which an amyloid core is surrounded by tangle-bearing neurites, was not seen in this study.

This separation in particular stood out in the study from Switzerland, in which the researchers injected synthetic Aβ42 fibrils into the hippocampus of P301L tau transgenic mice. They also saw copious neurofibrillary tangles develop, even as early as 18 days after injection, but not near the injection site. Instead, the tangles appeared in neurons of the amygdala that project to the hippocampus. The scientists speculate that Aβ fibrils might damage the presynaptic terminals or axons of projecting neurons, leading to impaired axonal transport of tau.

Taken together, both studies show that Aβ42 can speed up tangle formation in P301L mice. While the mice are still not a perfect model for AD-for one, the experiment worked only in mice with tau mutations, not wildtype tau mice-they may make it possible to test experimental therapies for their ability not only to decrease Aβ levels but also to prevent tangle formation and neuronal loss.

The same issue of Science also contains an AD article by William Esler and Michael Wolfe of Harvard Medical School. In it, they review recent work into identifying and characterizing APP secretases, and describe new insights this research has provided into the seemingly separate fields of notch signaling and cholesterol metabolism.-Gabrielle Strobel.


Reference:Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L, Yager D, Eckman C, Hardy J, Hutton M, McGowan E. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science. 2001 Aug 24;293(5534):1487-91. Abstract

Goetz J, Chen F, Nitsch RM. Formation of neurofibrillary tangles in P301L tau transgenic mice induced by Ab42 Fibrils. Science 2001 August 24;293. Abstract

Esler WP, Wolfe MS. A portrait of Alzheimer's secretases—new features and familiar faces. Science 2001 August 24;293. Abstract