Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's disease

Rachel E. Bennett, Ashley B. Robbins, Miwei Hu, Xinrui Cao, Rebecca Betensky, Tim Clark, Sudeshna Das, Bradley T. Hyman

Research output: Contribution to journalArticle

Abstract

Mixed pathology, with both Alzheimer's disease and vascular abnormalities, is the most common cause of clinical dementia in the elderly. While usually thought to be concurrent diseases, the fact that changes in cerebral blood flow are a prominent early and persistent alteration in Alzheimer's disease raises the possibility that vascular alterations and Alzheimer pathology are more directly linked. Here, we report that aged tau-overexpressing mice develop changes to blood vessels including abnormal, spiraling morphologies; reduced blood vessel diameters; and increased overall blood vessel density in cortex. Blood flow in these vessels was altered, with periods of obstructed flow rarely observed in normal capillaries. These changes were accompanied by cortical atrophy as well as increased expression of angiogenesis-related genes such as Vegfa, Serpine1, and Plau in CD31-positive endothelial cells. Interestingly, mice overexpressing nonmutant forms of tau in the absence of frank neurodegeneration also demonstrated similar changes. Furthermore, many of the genes we observe in mice are also altered in human RNA datasets from Alzheimer patients, particularly in brain regions classically associated with tau pathology such as the temporal lobe and limbic system regions. Together these data indicate that tau pathological changes in neurons can impact brain endothelial cell biology, altering the integrity of the brain's microvasculature.

Original languageEnglish (US)
Pages (from-to)E1289-E1298
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number6
DOIs
StatePublished - Feb 6 2018

Fingerprint

Transgenic Mice
Blood Vessels
Alzheimer Disease
Gene Expression
Pathology
Cerebrovascular Circulation
Brain
Endothelial Cells
Limbic System
Temporal Lobe
Microvessels
Genes
Atrophy
Cell Biology
Dementia
RNA
Neurons

Keywords

  • Alzheimer's disease
  • Angiogenesis
  • Blood vessels
  • Brain microvessels
  • Tau

ASJC Scopus subject areas

  • General

Cite this

Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's disease. / Bennett, Rachel E.; Robbins, Ashley B.; Hu, Miwei; Cao, Xinrui; Betensky, Rebecca; Clark, Tim; Das, Sudeshna; Hyman, Bradley T.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 6, 06.02.2018, p. E1289-E1298.

Research output: Contribution to journalArticle

Bennett, Rachel E. ; Robbins, Ashley B. ; Hu, Miwei ; Cao, Xinrui ; Betensky, Rebecca ; Clark, Tim ; Das, Sudeshna ; Hyman, Bradley T. / Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 6. pp. E1289-E1298.
@article{d6cf5c7acd1c4fa5bca1e6291702c09e,
title = "Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's disease",
abstract = "Mixed pathology, with both Alzheimer's disease and vascular abnormalities, is the most common cause of clinical dementia in the elderly. While usually thought to be concurrent diseases, the fact that changes in cerebral blood flow are a prominent early and persistent alteration in Alzheimer's disease raises the possibility that vascular alterations and Alzheimer pathology are more directly linked. Here, we report that aged tau-overexpressing mice develop changes to blood vessels including abnormal, spiraling morphologies; reduced blood vessel diameters; and increased overall blood vessel density in cortex. Blood flow in these vessels was altered, with periods of obstructed flow rarely observed in normal capillaries. These changes were accompanied by cortical atrophy as well as increased expression of angiogenesis-related genes such as Vegfa, Serpine1, and Plau in CD31-positive endothelial cells. Interestingly, mice overexpressing nonmutant forms of tau in the absence of frank neurodegeneration also demonstrated similar changes. Furthermore, many of the genes we observe in mice are also altered in human RNA datasets from Alzheimer patients, particularly in brain regions classically associated with tau pathology such as the temporal lobe and limbic system regions. Together these data indicate that tau pathological changes in neurons can impact brain endothelial cell biology, altering the integrity of the brain's microvasculature.",
keywords = "Alzheimer's disease, Angiogenesis, Blood vessels, Brain microvessels, Tau",
author = "Bennett, {Rachel E.} and Robbins, {Ashley B.} and Miwei Hu and Xinrui Cao and Rebecca Betensky and Tim Clark and Sudeshna Das and Hyman, {Bradley T.}",
year = "2018",
month = "2",
day = "6",
doi = "10.1073/pnas.1710329115",
language = "English (US)",
volume = "115",
pages = "E1289--E1298",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "6",

}

TY - JOUR

T1 - Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer's disease

AU - Bennett, Rachel E.

AU - Robbins, Ashley B.

AU - Hu, Miwei

AU - Cao, Xinrui

AU - Betensky, Rebecca

AU - Clark, Tim

AU - Das, Sudeshna

AU - Hyman, Bradley T.

PY - 2018/2/6

Y1 - 2018/2/6

N2 - Mixed pathology, with both Alzheimer's disease and vascular abnormalities, is the most common cause of clinical dementia in the elderly. While usually thought to be concurrent diseases, the fact that changes in cerebral blood flow are a prominent early and persistent alteration in Alzheimer's disease raises the possibility that vascular alterations and Alzheimer pathology are more directly linked. Here, we report that aged tau-overexpressing mice develop changes to blood vessels including abnormal, spiraling morphologies; reduced blood vessel diameters; and increased overall blood vessel density in cortex. Blood flow in these vessels was altered, with periods of obstructed flow rarely observed in normal capillaries. These changes were accompanied by cortical atrophy as well as increased expression of angiogenesis-related genes such as Vegfa, Serpine1, and Plau in CD31-positive endothelial cells. Interestingly, mice overexpressing nonmutant forms of tau in the absence of frank neurodegeneration also demonstrated similar changes. Furthermore, many of the genes we observe in mice are also altered in human RNA datasets from Alzheimer patients, particularly in brain regions classically associated with tau pathology such as the temporal lobe and limbic system regions. Together these data indicate that tau pathological changes in neurons can impact brain endothelial cell biology, altering the integrity of the brain's microvasculature.

AB - Mixed pathology, with both Alzheimer's disease and vascular abnormalities, is the most common cause of clinical dementia in the elderly. While usually thought to be concurrent diseases, the fact that changes in cerebral blood flow are a prominent early and persistent alteration in Alzheimer's disease raises the possibility that vascular alterations and Alzheimer pathology are more directly linked. Here, we report that aged tau-overexpressing mice develop changes to blood vessels including abnormal, spiraling morphologies; reduced blood vessel diameters; and increased overall blood vessel density in cortex. Blood flow in these vessels was altered, with periods of obstructed flow rarely observed in normal capillaries. These changes were accompanied by cortical atrophy as well as increased expression of angiogenesis-related genes such as Vegfa, Serpine1, and Plau in CD31-positive endothelial cells. Interestingly, mice overexpressing nonmutant forms of tau in the absence of frank neurodegeneration also demonstrated similar changes. Furthermore, many of the genes we observe in mice are also altered in human RNA datasets from Alzheimer patients, particularly in brain regions classically associated with tau pathology such as the temporal lobe and limbic system regions. Together these data indicate that tau pathological changes in neurons can impact brain endothelial cell biology, altering the integrity of the brain's microvasculature.

KW - Alzheimer's disease

KW - Angiogenesis

KW - Blood vessels

KW - Brain microvessels

KW - Tau

UR - http://www.scopus.com/inward/record.url?scp=85041693437&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85041693437&partnerID=8YFLogxK

U2 - 10.1073/pnas.1710329115

DO - 10.1073/pnas.1710329115

M3 - Article

VL - 115

SP - E1289-E1298

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 6

ER -