23 August 2001. Two papers in tomorrow's Science provide long-awaited evidence
for the notion that the two pathological hallmarks of Alzheimer's disease are
interconnected. Using different approaches, teams led by Mike Hutton at the
Mayo Clinic in Jacksonville, Florida, and R. M. Nitsch at the University of
Zurich both report that amyloid-β influences the formation of neurofibrillary
tangles in brain areas affected by AD. This work "provides convincing evidence
that a causal connection exists between the two pathologies," writes Virginia
Lee in an accompanying Perspective article.
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
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
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