Evidence for Altered Numb Isoform Levels in Alzheimer's Disease Patients and a Triple Transgenic Mouse Model

    Authors

    S. Chigurupati; M. Madan; E. Okun; Z. L. Wei; J. V. Pattisapu; M. R. Mughal; M. P. Mattson;S. L. Chan

    Comments

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    Abbreviated Journal Title

    J. Alzheimers Dis.

    Keywords

    Alzheimer's disease; amyloid-beta peptide; endocytosis; endosomes; protein trafficking; AMYLOID-PRECURSOR-PROTEIN; MAMMALIAN NUMB; BETA-PEPTIDE; INTRACELLULAR; DOMAIN; ASYMMETRIC DIVISION; BINDING-SPECIFICITY; ENDOCYTIC PROTEIN; ADAPTER PROTEIN; CELL FATE; IN-VIVO; Neurosciences

    Abstract

    The cell fate determinant Numb exists in four alternatively spliced variants that differ in the length of their PTB (phosphotyrosine-binding domain, either lacking or containing an 11 amino acid insertion) and PRR (proline-rich region, either lacking or containing a 48 amino acid insertion). We previously reported that Numb switches from isoforms containing the PTB insertion to isoforms lacking this insertion in neural cultures subjected to stress induced by trophic factor withdrawal. The switch in Numb isoforms enhances the generation of amyloid-beta peptide (A beta), the principle component of senile plaques in Alzheimer's disease (AD). Here we examine the expression of the Numb isoforms in brains from AD patients and triple transgenic (3xTg) AD mice. We found that levels of the Numb isoforms lacking the PTB insertion are significantly elevated in the parietal cortex but not in the cerebellum of AD patients when compared to control subjects. Levels of Numb isoforms lacking the PTB insertion were also elevated in the cortex but not cerebellum of 12 month-old 3xTg AD mice with A beta deposits compared to younger 3xTg-AD mice and to non-transgenic mice. Exposure of cultured neurons to A beta resulted in an increase in the levels of Numb isoforms lacking the PTB domain, consistent with a role for A beta in the aberrant expression of Numb in vulnerable brain regions of AD patients and mice. Collectively, the data show that altered expression of Numb isoforms in vulnerable neurons occurs during AD pathogenesis and suggest a role for Numb in the disease process.

    Journal Title

    Journal of Alzheimers Disease

    Volume

    24

    Issue/Number

    2

    Publication Date

    1-1-2011

    Document Type

    Article

    Language

    English

    First Page

    349

    Last Page

    361

    WOS Identifier

    WOS:000289352400014

    ISSN

    1387-2877

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