title: Alzheimer's Disease: Characterization of the Brain Sites of the Initial Tau Cytoskeletal Pathology Will Improve the Success of Novel Immunological Anti-Tau Treatment Approaches.
abstract: Alzheimer's disease (AD) represents the most frequent neurodegenerative disease of the human brain worldwide. Currently practiced treatment strategies for AD only include some less effective symptomatic therapeutic interventions, which unable to counteract the disease course of AD. New therapeutic attempts aimed to prevent, reduce, or remove the extracellular depositions of the amyloid-β protein did not elicit beneficial effects on cognitive deficits or functional decline of AD. In view of the failure of these amyloid-β-based therapeutic trials and the close correlation between the brain pathology of the cytoskeletal tau protein and clinical AD symptoms, therapeutic attention has since shifted to the tau cytoskeletal protein as a novel drug target. The abnormal hyperphosphorylation and intraneuronal aggregation of this protein are early events in the evolution of the AD-related neurofibrillary pathology, and the brain spread of the AD-related tau aggregation pathology may possibly follow a corruptive protein templating and seeding-like mechanism according to the prion hypothesis. Accordingly, immunotherapeutic targeting of the tau aggregation pathology during the very early pre-tangle phase is currently considered to represent an effective and promising therapeutic approach for AD. Recent studies have shown that the initial immunoreactive tau aggregation pathology already prevails in several subcortical regions in the absence of any cytoskeletal changes in the cerebral cortex. Thus, it may be hypothesized that the subcortical brain regions represent the "port of entry" for the pathogenetic agent from which the disease ascends anterogradely as an "interconnectivity pathology".
authors.affiliation: Dr. Senckenbergisches Chronomedizinisches Institut, Goethe-University, Frankfurt/Main, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Rüb
authors.affiliation: Dr. Senckenbergisches Chronomedizinisches Institut, Goethe-University, Frankfurt/Main, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Stratmann
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Würzburg, Germany.|Department of Pathology, Ageing Brain Study Group, University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: Helmut
authors.initials: H
authors.lastname: Heinsen
authors.affiliation: Dr. Senckenbergisches Chronomedizinisches Institut, Goethe-University, Frankfurt/Main, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Seidel
authors.affiliation: Dr. Senckenbergisches Chronomedizinisches Institut, Goethe-University, Frankfurt/Main, Germany.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bouzrou
authors.affiliation: Dr. Senckenbergisches Chronomedizinisches Institut, Goethe-University, Frankfurt/Main, Germany.
authors.forename: Horst-Werner
authors.initials: HW
authors.lastname: Korf
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D016875:tau Proteins / Q000276:immunology* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins
keywords: Alzheimer’s disease; amyloid-β protein; cytoskeletal pathology; immunotherapy; prion-like diseases; tau protein