A study we first reported from the 2004 Society for Neuroscience annual meeting in San Diego has just been published in the May 2 PNAS. Dale Bredesen and colleagues at the Buck Institute for Age Research, Novato, California, have determined that asparagine 664 in the C-terminal of amyloid-β (Aβ) precursor protein (AβPP) is essential for much of the pathology seen in transgenic mice expressing human AβPP.
First author Veronica Galvan and colleagues report that an asparagine-to-alanine mutation at position 664 of human AβPP (B21 and B254 strains) has no effect on amyloid production and plaque formation in PDAPP transgenic mice (which harbor Swedish and Indiana mutations). But despite this, the asparagine mutants (D664A) show no synaptic loss or behavioral abnormalities. In the Morris water maze, for example, the animals perform as well as normal control mice. Because asparagine 664 is part of a caspase cleavage site, the work suggests that proteolytic cleavage of the C-terminal of AβPP may play a role in toxicity. An alternative explanation is that loss of asparagine 664 disrupts protein-protein interactions that play a role in pathology. For more on this story, see our original report from San Diego.—Tom Fagan
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- Galvan V, Gorostiza OF, Banwait S, Ataie M, Logvinova AV, Sitaraman S, Carlson E, Sagi SA, Chevallier N, Jin K, Greenberg DA, Bredesen DE. Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc Natl Acad Sci U S A. 2006 May 2;103(18):7130-5. PubMed.