Verheijen BM, Stevens JA, Gentier RJ, van 't Hekke CD, van den Hove DL, Hermes DJ, Steinbusch HW, Ruijter JM, Grimm MO, Haupenthal VJ, Annaert W, Hartmann T, van Leeuwen FW. Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model. Neurobiol Aging. 2018 Dec;72:62-71. Epub 2018 Aug 18 PubMed.
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University of Southern California
Fred van Leeuwen continues his frame-shifting thinking with further findings on how a UBB+1 transgene could slow brain amyloid accumulation in ADtg mice. This story began 35 years ago with studies on the Brattleboro rat, which has congenital polyuria due to a germ-line frame-shift in the vasopressin gene. Richards et al. (1985) noted sporadic wild-type vasopressin neurons that were further shown by van Leeuwen et al. (1989) to accumulate progressively with age. Van Leeuwen then looked at Alzheimer brains, and showed plus-one frame shifts in scattered cells for amyloid precursor protein (APP+1) and ubiquitin (UBB+1) in neuritic plaques and tangles (van Leeuwen et al., 1998). The molecular origins of the frame-shift revertants are incompletely understood (van Leeuwen et al 2000; Finch and Goodman, 1997; Finch 2000).
Meanwhile, the van Leeuwen group showed that introducing a UBB+1 transgene to ADtg mice (APPS1) unexpectedly decreased the amyloid plaque load (van Tijn et al., 2012). Now, using the same mouse, they report a slight increase of γ-secretase by UBB+1 and a larger decrease in the C99 C-terminal fragment of APP. Both findings support the role of the ubiquitin-proteosome proteolytic pathway in the accumulation the amyloid peptide. Van Leeuwen and colleagues are considering other components of the proteasome for the rescue effects of UBB+1. The role of the APP+1 in AD brains (van Leeuwen et al., 1989) also merits further study.
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