Alzheimer Disease: Therapeutic Strategies (Advances in by Ezio Giacobini, D.L. Smith, J.M. Barton, Robert E. Becker

By Ezio Giacobini, D.L. Smith, J.M. Barton, Robert E. Becker

Because the apoE4 allele is a danger issue or susceptibility gene in late-onset familial and sporadic advert, the mechanism of sickness expression may well contain metabolic results which are isoform particular. Isoform-specific interactions of apoE as a result develop into severe within the mechanism of advert pathogenesis. designated characterization of the binding of the apoE isoforms with proteins and peptides proper to the pathology of the illness could be severe in figuring out affliction pathogenesis. those serious isoform-specific interactions of apoE may perhaps contain interactions with proteins and pep tides within the defining neuropathologic lesions of the ailment, the neurofibrillary tangle and senile plaque. different attainable serious isoform-specific interactions contain the mechanism of internalization, intracellular trafficking, and next metabolism. furthermore, differential post-translational transformations of apoE isoforms could ascertain variations in metabolism contributing to the pathogenesis of the disorder. Oxidation of apoE might confer a number of isoform-specific, biochemically designated houses. seeing that {3A peptide binds apoE within the lipoprotein binding area of the protein and never within the receptor-binding area, apoE may perhaps objective certain {3A4 peptide to neurons through the LRP receptor. Internalization of the apoEI {3A peptide advanced into the mobile, via an analogous course because the apoE-containing lipoproteins, could lead to incorporation into basic lysosomes and pH based dissociation. The demonstration of apoE within the cytoplasm of neurons, with isoform-specific interactions of apoE with the microtubule-binding protein tau validated in vitro, recommend extra, testable hypotheses of illness pathogenesis.

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Extra resources for Alzheimer Disease: Therapeutic Strategies (Advances in Alzheimer Disease Therapy)

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Studies on site-specific dephosphorylation by protein phosphatases have revealed that the soluble abnormally phosphorylated tau isolated from AD brain is rapidly dephosphorylated at the abnormal sites Ser 46, Ser 199/Ser 202, Ser 235, and Ser 396/Ser 404 by protein phosphatase PP-2B, at all the above sites except Ser 235 by PP-2A, and at only Ser 199/Ser 202 and Ser 396/Ser 404 by PP-l. e. PP-2B, PP-2A and PP-l towards the abnormally phosphorylated tau are markedly increased by the presence of Mn2+.

A second, and probably related problem, often quoted against the cascade hypothesis, is that there are many subjects who come to autopsy who have large numbers of neuritic plaques, but little or no evidence of dementia. The simplest, albeit weak, explanation for these cases are that they represent preclinical cases of AD: that is, they are persons in which the disease process is just beginning. , 1989). DEFICIENCIES The amyloid cascade hypothesis has many deficiencies as an explanation of the the etiology and pathogenesis of AD.

J Bioi Chem 261:6084-6089. Grundke-Iqbal I, Iqbal K, Tung Y-C, Quinlan M, Wisniewski HM and Binder LI (l986b): Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913-1917. Iqbal K, Zaidi T, Thompson CH, Merz PA and Wisniewski HM (1984): Alzheimer paired helical filaments: bulk isolation, solubility and protein composition. Acta Neuropathol (Berl) 62: 167-177. Neurofibrillary Degeneration 33 Iqbal K, Grundke-Iqbal I, Zaidi T, Merz PA, Wen GY, Shaikh SS, Wisniewski HM, Alafuzoff I and Winblad B (1986): Defective brain microtubule assembly in Alzheimer's disease.

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