The long term objective of tis proposal is to learn the etiology and the pathogenesis of Alzheimer disease/senile dementia of the Alzheimer type (AD/SDAT) which constitutes one of the major public health problems in modern society. In the United States alone presently over three million senior citizens are affected and these numbers will keep increasing at a frightening rate unless the disease is understood and prevented. Several lines of evidence suggest that the state of phosphorylation/ dephosphorylation of neuronal proteins including the microtubule associated proteins tau might be affected in AD/SDAT and that the Alzheimer paired helical filaments (PHF) might contain abnormally phosphorylated tau.
The specific aims of this project are 1) a thorough investigation of the ability of Alzheimer brain tau and PHF, with or without prior in vitro dephosphorylation, to stimulate in vitro assembly of microtubules from bovine tubulin-determined by turbidimetric measurements, negative stain electron microscopy and SDS-PAGE; 2) identification of the protein kinase/s responsible for the phosphorylation of tau and PHF in AD/SDAT brain and measurements of this kinase activity in AD/SDAT and in age-matched unaffected brains-- determined by autoradiography and Western blots of SDS-PAGE; and 3) study the effect of phosphorylation on the self assembly of tau into filaments -- determined by negative stain electron microscopy, turbidimetric measurements and SDS-PAGE. The studies will test whether the abnormal phosphorylation of tau might be the cause of the microtubule assembly defect in AD/SDAT brain and whether dephosphorylation of tau/PHF can reverse this defect in vitro. Identification of the protein kinase/s responsible for the phosphorylation of tau in AD/SDAT brain and determination of the conditions for the self assembly of tau into filaments and their depolymerization might be critical to devise a rational approach in correcting this defect. These studies will help eluciate how alterations of the normal cytoskeleton might contribute to neurofibrillary pathology and functional deficits in AD/SDAT brain.
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|Iqbal, Khalid; Grundke-Iqbal, Inge (2002) Neurofibrillary pathology leads to synaptic loss and not the other way around in Alzheimer disease. J Alzheimers Dis 4:235-8|
|Pei, Jin-Jing; Braak, Heiko; Gong, Cheng-Xin et al. (2002) Up-regulation of cell division cycle (cdc) 2 kinase in neurons with early stage Alzheimer's disease neurofibrillary degeneration. Acta Neuropathol (Berl) 104:369-76|
|Pei, Jin-Jing; Braak, Heiko; An, Wen-Lin et al. (2002) Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer's disease. Brain Res Mol Brain Res 109:45-55|
|Hu, Yuan Yuan; He, Shan Shu; Wang, Xiaochuan et al. (2002) Levels of nonphosphorylated and phosphorylated tau in cerebrospinal fluid of Alzheimer's disease patients : an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay. Am J Pathol 160:1269-78|
|Liu, Fei; Zaidi, Tanweer; Iqbal, Khalid et al. (2002) Role of glycosylation in hyperphosphorylation of tau in Alzheimer's disease. FEBS Lett 512:101-6|
|Iqbal, K; Alonso, A del C; El-Akkad, E et al. (2002) Pharmacological targets to inhibit Alzheimer neurofibrillary degeneration. J Neural Transm Suppl :309-19|
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