Greengard, Paul

Grant Detail

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ALZHEIMER NEUROFIBRILLARY DEGENERATION

Iqbal, Khalid

1 August 1995 - 31 January 2003
FOGARTY INTERNATIONAL CENTER
Total Funding: $ 156,000

The objective of this Fogarty International Research Collaboration Award (FIRCA) proposal is to elucidate the mechanism of neurofibrillary degeneration in Alzheimer's disease (AD) by (I) studying the association of the AD abnormally hyperphosphorylated tau (AD P-tau) to various normal human tau isoforms, and (2) identifying the protein kinase(s) the phosphorylation of normal tau by which converts it to an AD-like state in sequestering normal microtubule associated proteins (MAP), MAP1 and MAP2 and depolymerizing microtubles. For Aim #1, each of the six recombinant human tau isoforms will be purified by column chromatography. The AD P-tau will be isolated from unfixed AD autopsied brains obtained within six hours postmortem and stored at -75 degrees C. The association between the AD P-tau and various recombinant tau isoforms will be assayed both by dot overlay and by the sedimentation assays, followed by quantitation of normal and AD P-tau with a radioimmuno-dot-blot assay using phosphorylation-dependent tau antibody, Tau-1, as the primary antibody. For Aim #2, we will isolate protein kinase C and CaM kinase-II from rat brain, glycogen synthase kinase-3, cyclin-dependent kinase-5 and casein kinase-I from bovine brain. The tau isoform found to associate the most to the AD P-tau will be in vitro phosphorylated by the above kinases and as well as protein kinase-A (PKA) and mitogen activated kinase (MAP kinase) obtained commercially, and the association of this in vitro phosphorylated tau with MAP1 and MAP2, and as a control with tau, will be examined as in Aim #1. Furthermore, the ability of the phosphorylated tau to depolymerize microtubules assembled by MAP1 and MAP2 will be investigated. The microtubule assembly and disassembly studies will be carried out by light scattering/turbidimeteric changes at 350 mm in microcuvettes, and by negative stain electron microscopy. These studies will help identify the role of different tau isoforms, the abnormai hyperphosphorylation of which convert them to a toxic molecule that can depolymerize the microtubule network, and identify the protein kinase(s) the phosphorylation of tau by which convert it into AD-like state and lead to neurofibrillary degeneration. This information will not only elucidate the mechanism of Alzheimer neurofibrillary degeneration but also provide a lead towards developing a rational therapeutical approach to the disease.

5 Resulting Publications

• 1.

  2004

  Alejandra del C Alonso; Anna Mederlyova; Michal Novak; Inge Grundke-Iqbal; Khalid Iqbal

  Promotion of hyperphosphorylation by frontotemporal dementia tau mutations.

  The Journal of biological chemistry 2004;279(33):34873-81.

• 2.

  2001

  A D Alonso; T Zaidi; M Novak; H S Barra; I Grundke-Iqbal; K Iqbal

  Interaction of tau isoforms with Alzheimer's disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the disease-like protein.

  The Journal of biological chemistry 2001;276(41):37967-73.

• 3.

  2001

  A Alonso ; T Zaidi; M Novak; I Grundke-Iqbal; K Iqbal

  Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments.

  Proceedings of the National Academy of Sciences of the United States of America 2001;98(12):6923-8.

• 4.

  1997

  A D Alonso; I Grundke-Iqbal; H S Barra; K Iqbal

  Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau.

  Proceedings of the National Academy of Sciences of the United States of America 1997;94(1):298-303.

• 5.

  1996

  A C Alonso; I Grundke-Iqbal; K Iqbal

  Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules.

  Nature medicine 1996;2(7):783-7.

Scientific Context

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