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Articles by Inge Grundke-Iqbal
Total Records ( 3 ) for Inge Grundke-Iqbal
  Khalid Iqbal and Inge Grundke-Iqbal
  Alzheimer’s disease (AD) is multifactorial and apparently involves several different etiopathogenic mechanisms. There are at least five subgroups of AD based on cerebrospinal fluid levels of Aβ1–42, a marker of beta-amyloid (Aβ) plaques, and tau and ubiquitin, two markers of neurofibrillary tangles. These different AD subgroups may respond differently to a given disease-modifying drug, and hence, different therapeutic drugs for different disease subgroups might be required. Stratification of AD patients by disease subgroups in clinical trials is critical to the successful development of potent disease-modifying drugs. Levels of disease markers in the cerebrospinal fluid are promising, both in identifying various subgroups of AD and in monitoring the response to therapeutic drugs.
  She Chen , Bin Li , Inge Grundke-Iqbal and Khalid Iqbal
  In Alzheimer disease (AD) brain, the level of I PP2A1, a 249-amino acid long endogenous inhibitor of protein phosphatase 2A (PP2A), is increased, the activity of the phosphatase is decreased, and the microtubule-associated protein Tau is abnormally hyperphosphorylated. However, little is known about the detailed regulatory mechanism by which PP2A activity is inhibited by I PP2A1 and the consequent events in mammalian cells. In this study, we found that both I PP2A1 and its N-terminal half I PP2A(1–120)1, but neither I PP2A(1–163)1 nor I PP2A(164–249)1, inhibited PP2A activity in vitro, suggesting an autoinhibition by amino acid residues 121–163 and its neutralization by the C-terminal region. Furthermore, transfection of NIH3T3 cells produced a dose-dependent inhibition of PP2A activity by I PP2A1. I PP2A1 and PP2A were found to colocalize in PC12 cells. I PP2A1 could only interact with the catalytic subunit of PP2A (PP2Ac) and had no interaction with the regulatory subunits of PP2A (PP2A-A or PP2A-B) using a glutathione S-transferase-pulldown assay. The interaction was further confirmed by coimmunoprecipitation of I PP2A1 and PP2Ac from lysates of transiently transfected NIH3T3 cells. The N-terminal isotype specific region of I PP2A1 was required for its association with PP2Ac as well as PP2A inhibition. In addition, the phosphorylation of Tau was significantly increased in PC12/Tau441 cells transiently transfected with full-length I PP2A1 and with PP2Ac-interacting I PP2A1 deletion mutant 1–120 (I PP2A1ΔC2). Double immunofluorescence staining showed that I PP2A1 and I PP2A1ΔC2 increased Tau phosphorylation and impaired the microtubule network and neurite outgrowth in PC12 cells treated with nerve growth factor.
  Jianhua Shi , Tianyi Zhang , Chunlei Zhou , Muhammad Omar Chohan , Xiaosong Gu , Jerzy Wegiel , Jianhua Zhou , Yu-Wen Hwang , Khalid Iqbal , Inge Grundke-Iqbal , Cheng-Xin Gong and Fei Liu
  Two groups of tau, 3R- and 4R-tau, are generated by alternative splicing of tau exon 10. Normal adult human brain expresses equal levels of them. Disruption of the physiological balance is a common feature of several tauopathies. Very early in their life, individuals with Down syndrome (DS) develop Alzheimer-type tau pathology, the molecular basis for which is not fully understood. Here, we demonstrate that Dyrk1A, a kinase encoded by a gene in the DS critical region, phosphorylates alternative splicing factor (ASF) at Ser-227, Ser-234, and Ser-238, driving it into nuclear speckles and preventing it from facilitating tau exon 10 inclusion. The increased dosage of Dyrk1A in DS brain due to trisomy of chromosome 21 correlates to an increase in 3R-tau level, which on abnormal hyperphosphorylation and aggregation of tau results in neurofibrillary degeneration. Imbalance of 3R- and 4R-tau in DS brain by Dyrk1A-induced dysregulation of alternative splicing factor-mediated alternative splicing of tau exon 10 represents a novel mechanism of neurofibrillary degeneration and may help explain early onset tauopathy in individuals with DS.
 
 
 
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