Forget, for a moment, about the familiar APP mutations that produce excess β amyloid in the brain and cause Alzheimer's disease. There are some mutations that do not cause the full range of AD pathology, despite producing β amyloid peptides. The E693Q mutation, for example, causes a dementing disorder called hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). In these patients, amyloid build-up is predominantly vascular, and a report in this month’s Nature Neuroscience suggests that the difference between brain parenchymal amyloidosis and cerebral amyloid angiopathy is all in the Aβ40/Aβ42 ratio.
In their new transgenic mouse model of HCSWA-D, Mathias Jucker and first author Martin Herzig of the University of Tübingen in Germany, along with collaborators from several other institutions, find that the E693Q mutants recapitulate the human condition by accumulating mostly vascular amyloid. Significantly, Herzig found that the animals produce mainly Aβ40, and when the authors examined autopsy samples from HCHWA-D patients, they found that they, too, had more Aβ40 than Aβ42—18 times more.
The evidence supports the notion that different Aβ species have very different interactions with their extracellular environments, and that parenchymal amyloid build-up requires Aβ42 seeding, while a surfeit of Aβ40 can drive vascular amyloid build-up. This finding leads Herzig and colleagues to raise the concern that therapeutic approaches based on reducing Aβ42 could have the unintended effect of promoting Aβ40-driven vascular amyloidosis. In support of this, Herzig found that crossing the E693Q transgenic mice with a strain harboring a presenilin-1 mutant that preferentially cleaves AβPP at the 42 position, results in offspring that make predominantly Aβ42 and produce amyloid mainly in the brain parenchyma. This suggests that the reverse, promoting Aβ40 over Aβ42, could cause vascular amyloidoses.
Beyond these insights into the effects of favoring different Aβ species, studies in this new animal model should prove very valuable, because vascular amyloidosis may be a contributing factor to cognitive decline both in AD and in normal aging.—Hakon Heimer
No Available References
- Herzig MC, Winkler DT, Burgermeister P, Pfeifer M, Kohler E, Schmidt SD, Danner S, Abramowski D, Stürchler-Pierrat C, Bürki K, van Duinen SG, Maat-Schieman ML, Staufenbiel M, Mathews PM, Jucker M. Abeta is targeted to the vasculature in a mouse model of hereditary cerebral hemorrhage with amyloidosis. Nat Neurosci. 2004 Sep;7(9):954-60. PubMed.