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Top-Down Projections Direct the Gradual Progression of Alzheimer-Related Tau Pathology Throughout the Neocortex

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Tau Biology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1184))

Abstract

In sporadic Alzheimer’s disease (sAD), tau pathology gradually but relentlessly progresses from the transentorhinal region of the temporal lobe into both the allocortex and temporal high order association areas of the neocortex. From there, it ultimately reaches the primary sensory and motor fields of the neocortex. The brunt of the changes seen during neurofibrillary stages (NFT) I–VI is borne by top-down projection neurons that contribute to cortico-cortical connectivities between different neocortical fields. Very early changes develop in isolated pyramidal cells in layers III and V, and these cells are targets of top-down projections terminating in association areas of the first temporal gyrus or in peristriate regions of the occipital lobe. Neurofibrillary pathology in these regions is routinely associated with late NFT stages. Sequential changes occur in different cell compartments (dendritic, somatic, axonal) of these early-involved neurons. Tau pathology first develops in distal segments of basal dendrites, then in proximal dendrites, the soma, and, finally, in the axon of affected pyramidal neurons. This sequence of abnormal changes supports the concept that axons of cortico-cortical top-down neurons may carry and spread abnormal tau seeds in a focused manner (transsynaptically) into the distal dendritic segments of nerve cells directly following in the neuronal chain, thereby sustaining tau-seeded templating in sAD.

In commemoration of Korbinian Brodmann (November 17, 1868 – August 22, 1918).

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Acknowledgments

This chapter was made possible by support from the Hans and Ilse Breuer Foundation (Frankfurt am Main, Germany) and the Braak Collection (Frankfurt am Main, Germany). We thank Ms. Simone Feldengut (immunoreactions) and Mr. David Ewert (University of Ulm) for technical assistance with the graphics.

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Authors and Affiliations

  1. Clinical Neuroanatomy Section/Department of Neurology, Center for Biomedical Research, University of Ulm, Ulm, Germany

    Heiko Braak & Kelly Del Tredici

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  1. Heiko Braak
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  2. Kelly Del Tredici
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Correspondence to Kelly Del Tredici .

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Editors and Affiliations

  1. Department of Life Sciences, Gakushuin University, Tokyo, Japan

    Akihiko Takashima

  2. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA

    Benjamin Wolozin

  3. University of Lille, INSERM, CHU-Lille, Alzheimer & Tauopathies, LabEx DISTALZ, Lille, France

    Luc Buee

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Braak, H., Del Tredici, K. (2019). Top-Down Projections Direct the Gradual Progression of Alzheimer-Related Tau Pathology Throughout the Neocortex. In: Takashima, A., Wolozin, B., Buee, L. (eds) Tau Biology. Advances in Experimental Medicine and Biology, vol 1184. Springer, Singapore. https://doi.org/10.1007/978-981-32-9358-8_22

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