Propagation of tau pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies

Jada Lewis, Dennis W Dickson

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Tau is a microtubule-associated protein and a key regulator of microtubule stabilization as well as the main component of neurofibrillary tangles—a principle neuropathological hallmark of Alzheimer’s disease (AD)—as well as pleomorphic neuronal and glial inclusions in neurodegenerative tauopathies. Cross-sectional studies of neurofibrillary pathology in AD reveal a stereotypic spatiotemporal pattern of neuronal vulnerability that correlates with disease severity; however, the relationship of this pattern to disease progression is less certain and exceptions to the typical pattern have been described in a subset of AD patients. The basis for the selective vulnerability of specific populations of neurons to tau pathology and cell death is largely unknown, although there have been a number of hypotheses based upon shared properties of vulnerable neurons (e.g., degree of axonal myelination or synaptic plasticity). A recent hypothesis for selective vulnerability takes into account the emerging science of functional connectivity based upon resting state functional magnetic resonance imaging, where subsets of neurons that fire synchronously define patterns of degeneration similar to specific neurodegenerative disorders, including various tauopathies. In the past 6 years, the concept of tau propagation has emerged from numerous studies in cell and animal models suggesting that tau moves from cell-to-cell and that this may trigger aggregation and region-to-region spread of tau pathology within the brain. How the spread of tau pathology relates to functional connectivity is an area of active investigation. Observations of templated folding and propagation of tau have prompted comparisons of tau to prions, the pathogenic proteins in transmissible spongiform encephalopathies. In this review, we discuss the most compelling studies in the field, discuss their shortcomings and consider their implications with respect to human tauopathies as well as the controversy that tauopathies may be prion-like disorders.

Original languageEnglish (US)
Pages (from-to)27-48
Number of pages22
JournalActa Neuropathologica
Volume131
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

Tauopathies
Pathology
Alzheimer Disease
Brain
Neurons
Prion Diseases
Neuronal Plasticity
Microtubule-Associated Proteins
Prions
Microtubules
Neuroglia
Neurodegenerative Diseases
Disease Progression
Cell Death
Animal Models
Cross-Sectional Studies
Magnetic Resonance Imaging
Population

Keywords

  • Conformational templating
  • Macropinocytosis
  • Neurofibrillary tangles
  • Prion
  • Propagation
  • Seeding
  • Selective vulnerability
  • Tau

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Propagation of tau pathology : hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. / Lewis, Jada; Dickson, Dennis W.

In: Acta Neuropathologica, Vol. 131, No. 1, 01.01.2016, p. 27-48.

Research output: Contribution to journalArticle

@article{ca8693abef14470fa51300048bbfd287,
title = "Propagation of tau pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies",
abstract = "Tau is a microtubule-associated protein and a key regulator of microtubule stabilization as well as the main component of neurofibrillary tangles—a principle neuropathological hallmark of Alzheimer’s disease (AD)—as well as pleomorphic neuronal and glial inclusions in neurodegenerative tauopathies. Cross-sectional studies of neurofibrillary pathology in AD reveal a stereotypic spatiotemporal pattern of neuronal vulnerability that correlates with disease severity; however, the relationship of this pattern to disease progression is less certain and exceptions to the typical pattern have been described in a subset of AD patients. The basis for the selective vulnerability of specific populations of neurons to tau pathology and cell death is largely unknown, although there have been a number of hypotheses based upon shared properties of vulnerable neurons (e.g., degree of axonal myelination or synaptic plasticity). A recent hypothesis for selective vulnerability takes into account the emerging science of functional connectivity based upon resting state functional magnetic resonance imaging, where subsets of neurons that fire synchronously define patterns of degeneration similar to specific neurodegenerative disorders, including various tauopathies. In the past 6 years, the concept of tau propagation has emerged from numerous studies in cell and animal models suggesting that tau moves from cell-to-cell and that this may trigger aggregation and region-to-region spread of tau pathology within the brain. How the spread of tau pathology relates to functional connectivity is an area of active investigation. Observations of templated folding and propagation of tau have prompted comparisons of tau to prions, the pathogenic proteins in transmissible spongiform encephalopathies. In this review, we discuss the most compelling studies in the field, discuss their shortcomings and consider their implications with respect to human tauopathies as well as the controversy that tauopathies may be prion-like disorders.",
keywords = "Conformational templating, Macropinocytosis, Neurofibrillary tangles, Prion, Propagation, Seeding, Selective vulnerability, Tau",
author = "Jada Lewis and Dickson, {Dennis W}",
year = "2016",
month = "1",
day = "1",
doi = "10.1007/s00401-015-1507-z",
language = "English (US)",
volume = "131",
pages = "27--48",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Propagation of tau pathology

T2 - hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies

AU - Lewis, Jada

AU - Dickson, Dennis W

PY - 2016/1/1

Y1 - 2016/1/1

N2 - Tau is a microtubule-associated protein and a key regulator of microtubule stabilization as well as the main component of neurofibrillary tangles—a principle neuropathological hallmark of Alzheimer’s disease (AD)—as well as pleomorphic neuronal and glial inclusions in neurodegenerative tauopathies. Cross-sectional studies of neurofibrillary pathology in AD reveal a stereotypic spatiotemporal pattern of neuronal vulnerability that correlates with disease severity; however, the relationship of this pattern to disease progression is less certain and exceptions to the typical pattern have been described in a subset of AD patients. The basis for the selective vulnerability of specific populations of neurons to tau pathology and cell death is largely unknown, although there have been a number of hypotheses based upon shared properties of vulnerable neurons (e.g., degree of axonal myelination or synaptic plasticity). A recent hypothesis for selective vulnerability takes into account the emerging science of functional connectivity based upon resting state functional magnetic resonance imaging, where subsets of neurons that fire synchronously define patterns of degeneration similar to specific neurodegenerative disorders, including various tauopathies. In the past 6 years, the concept of tau propagation has emerged from numerous studies in cell and animal models suggesting that tau moves from cell-to-cell and that this may trigger aggregation and region-to-region spread of tau pathology within the brain. How the spread of tau pathology relates to functional connectivity is an area of active investigation. Observations of templated folding and propagation of tau have prompted comparisons of tau to prions, the pathogenic proteins in transmissible spongiform encephalopathies. In this review, we discuss the most compelling studies in the field, discuss their shortcomings and consider their implications with respect to human tauopathies as well as the controversy that tauopathies may be prion-like disorders.

AB - Tau is a microtubule-associated protein and a key regulator of microtubule stabilization as well as the main component of neurofibrillary tangles—a principle neuropathological hallmark of Alzheimer’s disease (AD)—as well as pleomorphic neuronal and glial inclusions in neurodegenerative tauopathies. Cross-sectional studies of neurofibrillary pathology in AD reveal a stereotypic spatiotemporal pattern of neuronal vulnerability that correlates with disease severity; however, the relationship of this pattern to disease progression is less certain and exceptions to the typical pattern have been described in a subset of AD patients. The basis for the selective vulnerability of specific populations of neurons to tau pathology and cell death is largely unknown, although there have been a number of hypotheses based upon shared properties of vulnerable neurons (e.g., degree of axonal myelination or synaptic plasticity). A recent hypothesis for selective vulnerability takes into account the emerging science of functional connectivity based upon resting state functional magnetic resonance imaging, where subsets of neurons that fire synchronously define patterns of degeneration similar to specific neurodegenerative disorders, including various tauopathies. In the past 6 years, the concept of tau propagation has emerged from numerous studies in cell and animal models suggesting that tau moves from cell-to-cell and that this may trigger aggregation and region-to-region spread of tau pathology within the brain. How the spread of tau pathology relates to functional connectivity is an area of active investigation. Observations of templated folding and propagation of tau have prompted comparisons of tau to prions, the pathogenic proteins in transmissible spongiform encephalopathies. In this review, we discuss the most compelling studies in the field, discuss their shortcomings and consider their implications with respect to human tauopathies as well as the controversy that tauopathies may be prion-like disorders.

KW - Conformational templating

KW - Macropinocytosis

KW - Neurofibrillary tangles

KW - Prion

KW - Propagation

KW - Seeding

KW - Selective vulnerability

KW - Tau

UR - http://www.scopus.com/inward/record.url?scp=84952976186&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84952976186&partnerID=8YFLogxK

U2 - 10.1007/s00401-015-1507-z

DO - 10.1007/s00401-015-1507-z

M3 - Article

C2 - 26576562

AN - SCOPUS:84952976186

VL - 131

SP - 27

EP - 48

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 1

ER -