Amyloid-β-independent regulators of tau pathology in Alzheimer disease

Rik van der Kant, Lawrence S. B. Goldstein, Rik Ossenkoppele

Research output: Contribution to journalReview articleAcademicpeer-review

Abstract

The global epidemic of Alzheimer disease (AD) is worsening, and no approved treatment can revert or arrest progression of this disease. AD pathology is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. Genetic data, as well as autopsy and neuroimaging studies in patients with AD, indicate that Aβ plaque deposition precedes cortical tau pathology. Because Aβ accumulation has been considered the initial insult that drives both the accumulation of tau pathology and tau-mediated neurodegeneration in AD, the development of AD therapeutics has focused mostly on removing Aβ from the brain. However, striking preclinical evidence from AD mouse models and patient-derived human induced pluripotent stem cell models indicates that tau pathology can progress independently of Aβ accumulation and arises downstream of genetic risk factors for AD and aberrant metabolic pathways. This Review outlines novel insights from preclinical research that implicate apolipoprotein E, the endocytic system, cholesterol metabolism and microglial activation as Aβ-independent regulators of tau pathology. These factors are discussed in the context of emerging findings from clinical pathology, functional neuroimaging and other approaches in humans. Finally, we discuss the implications of these new insights for current Aβ-targeted strategies and highlight the emergence of novel therapeutic strategies that target processes upstream of both Aβ and tau.
Original languageEnglish
Pages (from-to)21-35
JournalNature Reviews Neuroscience
Volume21
Issue number1
Early online date28 Nov 2019
DOIs
Publication statusPublished - Jan 2020

Cite this

@article{b97dfef34bb2442485199e28b7991f24,
title = "Amyloid-β-independent regulators of tau pathology in Alzheimer disease",
abstract = "The global epidemic of Alzheimer disease (AD) is worsening, and no approved treatment can revert or arrest progression of this disease. AD pathology is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. Genetic data, as well as autopsy and neuroimaging studies in patients with AD, indicate that Aβ plaque deposition precedes cortical tau pathology. Because Aβ accumulation has been considered the initial insult that drives both the accumulation of tau pathology and tau-mediated neurodegeneration in AD, the development of AD therapeutics has focused mostly on removing Aβ from the brain. However, striking preclinical evidence from AD mouse models and patient-derived human induced pluripotent stem cell models indicates that tau pathology can progress independently of Aβ accumulation and arises downstream of genetic risk factors for AD and aberrant metabolic pathways. This Review outlines novel insights from preclinical research that implicate apolipoprotein E, the endocytic system, cholesterol metabolism and microglial activation as Aβ-independent regulators of tau pathology. These factors are discussed in the context of emerging findings from clinical pathology, functional neuroimaging and other approaches in humans. Finally, we discuss the implications of these new insights for current Aβ-targeted strategies and highlight the emergence of novel therapeutic strategies that target processes upstream of both Aβ and tau.",
author = "{van der Kant}, Rik and Goldstein, {Lawrence S. B.} and Rik Ossenkoppele",
year = "2020",
month = "1",
doi = "10.1038/s41583-019-0240-3",
language = "English",
volume = "21",
pages = "21--35",
journal = "Nature Reviews Neuroscience",
issn = "1471-003X",
publisher = "Nature Publishing Group",
number = "1",

}

Amyloid-β-independent regulators of tau pathology in Alzheimer disease. / van der Kant, Rik; Goldstein, Lawrence S. B.; Ossenkoppele, Rik.

In: Nature Reviews Neuroscience, Vol. 21, No. 1, 01.2020, p. 21-35.

Research output: Contribution to journalReview articleAcademicpeer-review

TY - JOUR

T1 - Amyloid-β-independent regulators of tau pathology in Alzheimer disease

AU - van der Kant, Rik

AU - Goldstein, Lawrence S. B.

AU - Ossenkoppele, Rik

PY - 2020/1

Y1 - 2020/1

N2 - The global epidemic of Alzheimer disease (AD) is worsening, and no approved treatment can revert or arrest progression of this disease. AD pathology is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. Genetic data, as well as autopsy and neuroimaging studies in patients with AD, indicate that Aβ plaque deposition precedes cortical tau pathology. Because Aβ accumulation has been considered the initial insult that drives both the accumulation of tau pathology and tau-mediated neurodegeneration in AD, the development of AD therapeutics has focused mostly on removing Aβ from the brain. However, striking preclinical evidence from AD mouse models and patient-derived human induced pluripotent stem cell models indicates that tau pathology can progress independently of Aβ accumulation and arises downstream of genetic risk factors for AD and aberrant metabolic pathways. This Review outlines novel insights from preclinical research that implicate apolipoprotein E, the endocytic system, cholesterol metabolism and microglial activation as Aβ-independent regulators of tau pathology. These factors are discussed in the context of emerging findings from clinical pathology, functional neuroimaging and other approaches in humans. Finally, we discuss the implications of these new insights for current Aβ-targeted strategies and highlight the emergence of novel therapeutic strategies that target processes upstream of both Aβ and tau.

AB - The global epidemic of Alzheimer disease (AD) is worsening, and no approved treatment can revert or arrest progression of this disease. AD pathology is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain. Genetic data, as well as autopsy and neuroimaging studies in patients with AD, indicate that Aβ plaque deposition precedes cortical tau pathology. Because Aβ accumulation has been considered the initial insult that drives both the accumulation of tau pathology and tau-mediated neurodegeneration in AD, the development of AD therapeutics has focused mostly on removing Aβ from the brain. However, striking preclinical evidence from AD mouse models and patient-derived human induced pluripotent stem cell models indicates that tau pathology can progress independently of Aβ accumulation and arises downstream of genetic risk factors for AD and aberrant metabolic pathways. This Review outlines novel insights from preclinical research that implicate apolipoprotein E, the endocytic system, cholesterol metabolism and microglial activation as Aβ-independent regulators of tau pathology. These factors are discussed in the context of emerging findings from clinical pathology, functional neuroimaging and other approaches in humans. Finally, we discuss the implications of these new insights for current Aβ-targeted strategies and highlight the emergence of novel therapeutic strategies that target processes upstream of both Aβ and tau.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85075929965&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/31780819

U2 - 10.1038/s41583-019-0240-3

DO - 10.1038/s41583-019-0240-3

M3 - Review article

VL - 21

SP - 21

EP - 35

JO - Nature Reviews Neuroscience

JF - Nature Reviews Neuroscience

SN - 1471-003X

IS - 1

ER -