Evidence for altered numb isoform levels in alzheimer's disease patients and a triple transgenic mouse model

Srinivasulu Chigurupati, Meenu Madan, Eitan Okun, Zelan Wei, Jogi V. Pattisapu, Mohamed R. Mughal, Mark P. Mattson, Sic L. Chana

Research output: Contribution to journalArticle

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-β peptide (Aβ), 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 Aβ deposits compared to younger 3xTg-AD mice and to non-transgenic mice. Exposure of cultured neurons to Aβ resulted in an increase in the levels of Numb isoforms lacking the PTB domain, consistent with a role for Aβ 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.

Original languageEnglish (US)
Pages (from-to)349-361
Number of pages13
JournalJournal of Alzheimer's Disease
Volume24
Issue number2
DOIs
StatePublished - 2011
Externally publishedYes

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Keywords

  • Alzheimer's disease
  • amyloid-β peptide
  • endocytosis
  • endosomes
  • protein trafficking

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

Cite this

Chigurupati, S., Madan, M., Okun, E., Wei, Z., Pattisapu, J. V., Mughal, M. R., Mattson, M. P., & Chana, S. L. (2011). Evidence for altered numb isoform levels in alzheimer's disease patients and a triple transgenic mouse model. Journal of Alzheimer's Disease, 24(2), 349-361. https://doi.org/10.3233/JAD-2011-101797