. Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model. Neurobiol Aging. 2018 Aug 18;72:62-71. PubMed.

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  1. 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 2000Finch and Goodman, 1997Finch 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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    . Rat 'DI 10' on the long road from diabetes insipidus to Alzheimer disease. Neurobiol Aging. 2000 Nov-Dec;21(6):893-5; discussion 903-4. PubMed.

    . Solitary magnocellular neurons in the homozygous Brattleboro rat have vasopressin and glycopeptide immunoreactivity. Neuroscience. 1985 Nov;16(3):617-23. PubMed.

    . Age-related development of a heterozygous phenotype in solitary neurons of the homozygous Brattleboro rat. Proc Natl Acad Sci U S A. 1989 Aug;86(16):6417-20. PubMed.

    . Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. Science. 1998 Jan 9;279(5348):242-7. PubMed.

    . Molecular misreading: a new type of transcript mutation expressed during aging. Neurobiol Aging. 2000 Nov-Dec;21(6):879-91. PubMed.

    . Mutant ubiquitin decreases amyloid β plaque formation in a transgenic mouse model of Alzheimer's disease. Neurochem Int. 2012 Oct;61(5):739-48. Epub 2012 Jul 14 PubMed.

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