Spreading of pathology in neurodegenerative diseases: a focus on human studies

Journal name:
Nature Reviews Neuroscience
Year published:
Published online


The progression of many neurodegenerative diseases is thought to be driven by the template-directed misfolding, seeded aggregation and cell–cell transmission of characteristic disease-related proteins, leading to the sequential dissemination of pathological protein aggregates. Recent evidence strongly suggests that the anatomical connections made by neurons — in addition to the intrinsic characteristics of neurons, such as morphology and gene expression profile — determine whether they are vulnerable to degeneration in these disorders. Notably, this common pathogenic principle opens up opportunities for pursuing novel targets for therapeutic interventions for these neurodegenerative disorders. We review recent evidence that supports the notion of neuron–neuron protein propagation, with a focus on neuropathological and positron emission tomography imaging studies in humans.

At a glance


  1. Hypothetical molecular mechanisms of prion-like disease protein transmission in neurodegenerative diseases.
    Figure 1: Hypothetical molecular mechanisms of prion-like disease protein transmission in neurodegenerative diseases.

    In template-directed misfolding, the deposited pathological disease proteins are transformed from their normal conformation, via intermediates, into fibrillar species. These species have the properties of amyloid (for instance, a fibrillar ultrastructure that consists of sheets of β-strands) and serve as templates to drive normal physiological versions of the protein to adopt similar structural alterations13. In a self-perpetuating process, the progressive seeded aggregation of conformationally changed proteins results in intracellular aggregates that fragment into 'daughter seeds'. Finally, in cell–cell transmission, pathological proteins spread to anatomically interconnected neurons and adjacent glial cells via an autocatalytic chain-reaction-like process11.

  2. Sequential topographical dissemination of non-prion proteins in neurodegenerative diseases.
    Figure 2: Sequential topographical dissemination of non-prion proteins in neurodegenerative diseases.

    In all panels, the pathology is first detected in areas delineated by darker colours and subsequently in regions shown in lighter colours. a, b | In Alzheimer disease, tau aggregates develop in the locus coeruleus (LC), then in the transentorhinal and entorhinal regions and subsequently in the hippocampal formation and in broad areas of the neocortex (NC)69. c, d | In contrast to tau pathology, amyloid-β deposits in Alzheimer disease are first observed in the NC and are then detected in allocortical, diencephalic and basal ganglia structures (in a caudal direction) and in the brainstem, and occasionally in the cerebellum (CB)71. e, f | The progression of α-synuclein-immunoreactive Lewy body and Lewy neurite pathology in Parkinson disease follows an ascending pattern from the brainstem to the telencephalon80. The earliest lesions can be detected in the olfactory bulb (OB), as well as in the dorsal motor nucleus of the vagus nerve (DMX) in the medulla oblongata. At later stages, the α-synuclein aggregate pathology is found more rostrally through the brainstem via the pons and midbrain, in the basal forebrain and, ultimately, in the NC. g, h | In amyotrophic lateral sclerosis cases with a low burden of TAR DNA-binding protein 43 (TDP43) pathology, TDP43 inclusions are seen in the agranular motor cortex (AGN), in the brainstem motor nuclei of cranial nerves XII–X, VII and V, and in α-motor neurons in the spinal cord. Later stages of disease are characterized by the presence of TDP43 pathology in the prefrontal neocortex (PFN), brainstem reticular formation, precerebellar nuclei, pontine grey and the red nucleus. Subsequently, prefrontal and postcentral neocortices, as well as striatal neurons, are affected by pathological TDP43, before the pathology is found in anteromedial portions of the temporal lobe, including the hippocampus96. AC, allocortex; BFB, basal forebrain; BN, brainstem nuclei; BSM, brainstem somatomotor nuclei; ENT, entorhinal cortex; MTC, mesiotemporal cortex; SC9, spinal cord grey-matter lamina IX; SN, substantia nigra; TH, thalamus. Part f reprinted from Neurobiology of Aging, 24, Braak, H. et al. Staging of brain pathology related to sporadic Parkinson's disease, 197211, © 2003, with permission from Elsevier.


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Author information


  1. Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3rd Floor Maloney Building, 3400 Spruce Street, Philadelphia, Pennsylvania 19104, USA.

    • Johannes Brettschneider,
    • Virginia M.-Y. Lee &
    • John Q. Trojanowski
  2. Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical Research, University of Ulm, Helmholtzstrasse 8/1, 89081 Ulm, Germany.

    • Johannes Brettschneider &
    • Kelly Del Tredici
  3. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, 3rd Floor Maloney Building, 3400 Spruce Street, Philadelphia, Pennsylvania 19104, USA.

    • Virginia M.-Y. Lee &
    • John Q. Trojanowski

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The authors declare no competing interests.

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Author details

  • Johannes Brettschneider

    Johannes Brettschneider obtained his M.D. from the University of Tuebingen, Germany, in 2001. He is currently a senior physician in the Department of Neurology at the University of Ulm, Germany. His research focuses on clinicopathological correlations and cerebrospinal fluid biomarkers of neurodegenerative diseases.

  • Kelly Del Tredici

    Kelly Del Tredici is a native of San Francisco, USA, and went to Germany in 1989 on a Fredrick Sheldon Travelling Fellowship from Harvard University, Cambridge, Massachusetts, USA. She attended medical school at the University of Frankfurt, Germany, where she graduated in 2004. She was a medical resident at the Clinic for Psychiatry and Neurology in Winnenden, Germany, until 2006, when she became a postdoctoral fellow at the Dr Senckenberg Anatomy Institute for Clinical Neuroanatomy, University of Frankfurt. Since 2009, she has been a senior research fellow in neurology at Ulm University, Germany.

  • Virginia M.-Y. Lee

    Virginia M.-Y. Lee has a Ph.D. in biochemistry from the University of California San Francisco, USA, in 1973, an M.B.A. from the Wharton School, University of Pennsylvania, USA, in 1984, and an M.Sc. in biochemistry from the University of London, UK, in 1968. She is the John H. Ware 3rd Professor in Alzheimer's Research, Director of the Center for Neurodegenerative Disease Research, and Co-Director of the Marian S. Ware Alzheimer Drug Discovery Program at the University of Pennsylvania School of Medicine. Her research focuses on Alzheimer disease and Parkinson disease, frontotemporal degeneration and amyotrophic lateral sclerosis.

    Center for Neurodegenerative Disease Research homepage

  • John Q. Trojanowski

    John Q. Trojanowski gained his M.D. and Ph.D from Tufts University, Massachusetts, USA, in 1976, and trained in pathology and neuropathology at Harvard Medical School, Cambridge, Massachusetts, USA, and at the University of Pennsylvania, USA. In 1981 he joined the Penn faculty, where he pursues translational and basic research on Alzheimer disease and Parkinson disease, motor neuron disease, dementia with Lewy bodies, frontotemporal degeneration and related disorders.

    Center for Neurodegenerative Disease Research homepage

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