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P2‐229: Structures of Grb2‐AICD peptides reveal a conformational switch
Author(s) -
Das Samir,
Sen Udayaditya,
Mukhopadhyay Debashis
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1278
Subject(s) - grb2 , sh2 domain , chemistry , peptide , phosphorylation , biophysics , cleavage (geology) , phosphopeptide , proteolysis , biochemistry , microbiology and biotechnology , biology , signal transducing adaptor protein , proto oncogene tyrosine protein kinase src , paleontology , fracture (geology) , enzyme
neurodegenerative diseases prompted us to identify and characterize the expression of CD44 splice variants in brain samples from AD and healthy patients as well as AD mice models. Methods: Hippocampal samples from 10 AD patients and 10 age and sex-matched healthy controls were obtained from the Netherland’s Brain Bank (NBB) following approval of a local ethics committee. Mouse hippocampi were isolated from TAU441 and APP751 transgenic strains (JSW). cDNA was prepared from total RNA and PCR was performed using primers derived from variable and constant CD44 exon sequences. Real-time PCR was done using SYBR green or Taqman probes. Immunohistochemistry (IHC) staining was done on fixed sections using commercial antibodies. Results: Various CD44 splice variants were identified by RT-PCR in RNA from AD patients and age and sex-matched normal controls. Real-time PCR analysis of three splice variants which included a single variant exon (CD44V3, CD44V6 and CD44V10) showed significantly higher expression in AD patients compared to normal controls. IHC staining on hippocampal sections revealed neuronal intracellular-perinuclear staining for the three variants. Expression of CD44S, which does not exhibit variant exons, was also elevated. Using IHC it was localized to normal-appearing non-neuronal cells as well as senile plaques, and degenerating neurons and their processes. CD44V6 transcript was elevated in hTAU and hAPP transgenic mice compared to their non-transgenic counterparts. Conclusions: CD44 splice variants may play a role in AD pathology. The neuronal localization of the specific CD44 variants suggests direct involvement of these proteins in neuronal death and/or survival. Further studies are required to evaluate the role of CD44 variants in AD.