13 September 2004. …X11, that is, a nuclear adaptor protein that binds to the intracellular domain of amyloid-β precursor protein (AβPP). Last year, Christopher Miller and colleagues at Kings College London reported that overexpression of X11α in a mouse model of Alzheimer disease (AD) reduced Aβ1-40 levels by 20 percent (see Lee et al., 2003). Now, in the Journal of Biological Chemistry in press, the same group shows that the β isoform can offer similar protection.
First author Ju-Hyun Lee and coworkers tested the potential plaque reducing factor in mice expressing human AβPP with the Swedish mutation (the Tg2576 mice). These animals have increased levels of Aβ (over 100-fold compared to normal mice) and develop plaques similar to those seen in humans. Lee and colleagues bred these mice with cousins that overexpress factor X11β in brain neurons. They found that the offspring had statistically significant reductions in levels of both Aβ peptides and Aβ-positive deposits.
Lee found that at 10 months, an age when Tg2576 mice begin to exhibit dramatic increases in Aβ and plaque load, soluble Aβ1-40 and Aβ1-42 were reduced by 35 and 16 percent, respectively, in animals expressing X11β. Levels of insoluble peptides were also reduced—by 18 and 45 percent for the short and long variants, respectively. In addition, X11β reduced the number of Aβ-positive brain deposits by half, while the size of these deposits was reduced from a mean diameter of 34 micrometers to 20 micrometers.
“…our results demonstrate that altering [X11β] expression can reduce Aβ levels and Aβ deposition in the brain. As such, modulation of X11β function may represent a novel therapeutic strategy for Alzheimer’s disease,” state the authors.
Exactly how X11β protects these transgenic animals is unclear. But the X11s (also called Mints, for Munc-8 INTeracting protein) have been implicated in AβPP processing (see, for example, Biederer et al., 2002) and it has recently been shown that in cell cultures X11α can inhibit γ-secretase (see King et al., 2004), which is, of course, essential for production of Aβ peptides.—Tom Fagan.
Lee J-H, Lau K-F, Perkinton MS, Standen CL, Rogelj B, Falinska A, McLoughlin DM, Miller CCJ. The neuronal adaptor protein X11β reduces Abeta levels and amyloid plaque formation in the brains of transgenic mice. J Biol Chem. 2004 Sep 3 [Epub ahead of print] Abstract