Evidence for altered Numb isoform levels in Alzheimer's disease patients and a triple transgenic mouse model.

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.

• Authors: Srinivasulu Chigurupati, Meenu Madan, Eitan Okun, Zelan Wei, Jogi V Pattisapu, Mohamed R Mughal, Mark P Mattson, Sic L Chan
• Journal: Journal of Alzheimer's disease : JAD (J Alzheimers Dis) Vol. 24 Issue 2 Pg. 349-61 ( 2011) ISSN: 1875-8908 [Electronic] Netherlands
• PMID: 21258150 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Glial Fibrillary Acidic Protein
• Intercellular Signaling Peptides and Proteins
• Membrane Proteins
• Nerve Tissue Proteins
• NUMB protein, human
• PSEN1 protein, human
• Peptide Fragments
• Presenilin-1
• Protein Isoforms
• amyloid beta-protein (1-42)
• tau Proteins
• rab5 GTP-Binding Proteins
• Phosphopyruvate Hydratase

Topics

• Aged
• Aged, 80 and over
• Alzheimer Disease (genetics, metabolism)
• Amyloid beta-Peptides (pharmacology)
• Amyloid beta-Protein Precursor (genetics)
• Analysis of Variance
• Animals
• Animals, Newborn
• Astrocytes (drug effects, metabolism)
• Cerebral Cortex (cytology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Female
• Gene Expression Regulation (genetics)
• Glial Fibrillary Acidic Protein (metabolism)
• Humans
• Immunoprecipitation (methods)
• Intercellular Signaling Peptides and Proteins (metabolism)
• Male
• Membrane Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Nerve Tissue Proteins (genetics, metabolism)
• Peptide Fragments (pharmacology)
• Phosphopyruvate Hydratase (metabolism)
• Presenilin-1 (genetics)
• Protein Isoforms (genetics, metabolism)
• Time Factors
• Transfection (methods)
• rab5 GTP-Binding Proteins (metabolism)
• tau Proteins (genetics)