title: Precortical Phase of Alzheimer's Disease (AD)-Related Tau Cytoskeletal Pathology.
abstract: Alzheimer's disease (AD) represents the most frequent progressive neuropsychiatric disorder worldwide leading to dementia. We systematically investigated the presence and extent of the AD-related cytoskeletal pathology in serial thick tissue sections through all subcortical brain nuclei that send efferent projections to the transentorhinal and entorhinal regions in three individuals with Braak and Braak AD stage 0 cortical cytoskeletal pathology and fourteen individuals with Braak and Braak AD stage I cortical cytoskeletal pathology by means of immunostainings with the anti-tau antibody AT8. These investigations revealed consistent AT8 immunoreactive tau cytoskeletal pathology in a subset of these subcortical nuclei in the Braak and Braak AD stage 0 individuals and in all of these subcortical nuclei in the Braak and Braak AD stage I individuals. The widespread affection of the subcortical nuclei in Braak and Braak AD stage I shows that the extent of the early subcortical tau cytoskeletal pathology has been considerably underestimated previously. In addition, our novel findings support the concept that subcortical nuclei become already affected during an early 'pre-cortical' evolutional phase before the first AD-related cytoskeletal changes occur in the mediobasal temporal lobe (i.e. allocortical transentorhinal and entorhinal regions). The very early involved subcortical brain regions may represent the origin of the AD-related tau cytoskeletal pathology, from where the neuronal cytoskeletal pathology takes an ascending course toward the secondarily affected allocortex and spreads transneuronally along anatomical pathways in predictable sequences.
authors.affiliation: Dr. Senckenbergisches Chronomedizinisches Institut, Goethe University, Frankfurt/Main, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Stratmann
authors.affiliation: Morphological Brain Research Unit, Psychiatric Clinic, Julius Maximilians University Würzburg, Würzburg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Heinsen
authors.affiliation: Dr. Senckenbergisches Chronomedizinisches Institut, Goethe University, Frankfurt/Main, Germany.
authors.forename: Horst-Werner
authors.initials: HW
authors.lastname: Korf
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe University, Frankfurt/Main, Germany.
authors.forename: Domenico
authors.initials: D
authors.lastname: Del Turco
authors.affiliation: Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe University, Frankfurt/Main, Germany.
authors.forename: Estifanos
authors.initials: E
authors.lastname: Ghebremedhin
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: Department of Neurology, Memory and Aging Center, University of California at San Francisco, San Francisco, CA.|Department of Pathology, University of Sao Paulo Medical School, Sao Paulo, Brazil.
authors.forename: Lea T
authors.initials: LT
authors.lastname: Grinberg
authors.affiliation: Neuropathology Division, University Clinic of Mainz, Mainz, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bohl
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wharton
authors.affiliation: Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Wilfred
authors.initials: W
authors.lastname: den Dunnen
authors.affiliation: Dr. Senckenbergisches Chronomedizinisches Institut, Goethe University, Frankfurt/Main, Germany.
authors.forename: Udo
authors.initials: U
authors.lastname: Rüb
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D003599:Cytoskeleton / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016875:tau Proteins
chemical_list: D016875:tau Proteins
keywords: Alzheimer's disease; allocortex; cytoskeletal pathology; entorhinal region; prion-like diseases; subcortical nuclei; tau protein