Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer's Disease

Eleanor K. Pickett, Abigail G. Herrmann, Jamie McQueen, Kimberly Abt, Owen Dando, Jane Tulloch, Pooja Jain, Sophie Dunnett, Sadaf Sohrabi, Maria P. Fjeldstad, Will Calkin, Leo Murison, Rosemary J. Jackson, Makis Tzioras, Anna Stevenson, Marie d'Orange, Monique Hooley, Caitlin Davies, Marti Colom-Cadena, Alejandro Anton-FernandezDeclan King, Iris Oren, Jamie Rose, Chris Anne McKenzie, Elizabeth Allison, Colin Smith, Oliver Hardt, Christopher M. Henstridge, Giles E. Hardingham, Tara L. Spires-Jones

Research output: Contribution to journalArticle

18 Downloads (Pure)

Abstract

A key knowledge gap blocking development of effective therapeutics for Alzheimer's disease (AD) is the lack of understanding of how amyloid beta (Aβ) peptide and pathological forms of the tau protein cooperate in causing disease phenotypes. Within a mouse tau-deficient background, we probed the molecular, cellular, and behavioral disruption triggered by the influence of wild-type human tau on human Aβ-induced pathology. We find that Aβ and tau work cooperatively to cause a hyperactivity behavioral phenotype and to cause downregulation of transcription of genes involved in synaptic function. In both our mouse model and human postmortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau reduction in the mice initiated after behavioral deficits emerge corrects behavioral deficits, reduces synaptic tau levels, and substantially reverses transcriptional perturbations, suggesting that lowering synaptic tau levels may be beneficial in AD. One of the mysteries of Alzheimer's disease is how the two key pathological proteins, amyloid beta and tau, interact. Pickett et al. use a mouse model to show that these proteins cooperate to change behavior and gene expression and that these phenotypes recover when tau levels are lowered.

Original languageEnglish
Pages (from-to)3592-3604.e5
JournalCell Reports
Volume29
Issue number11
DOIs
Publication statusPublished - 10 Dec 2019

Fingerprint

Amyloid
Alzheimer Disease
Amyloid beta-Peptides
Phenotype
tau Proteins
Synaptic Potentials
Pathology
Transcription
Gene expression
Synapses
Down-Regulation
Genes
Tissue
Gene Expression
Peptides
Proteins
Therapeutics

Keywords

  • Alzheimer
  • amyloid beta
  • array tomography
  • microglia
  • synapse
  • tau

Cite this

Pickett, E. K., Herrmann, A. G., McQueen, J., Abt, K., Dando, O., Tulloch, J., ... Spires-Jones, T. L. (2019). Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer's Disease. Cell Reports, 29(11), 3592-3604.e5. https://doi.org/10.1016/j.celrep.2019.11.044
Pickett, Eleanor K. ; Herrmann, Abigail G. ; McQueen, Jamie ; Abt, Kimberly ; Dando, Owen ; Tulloch, Jane ; Jain, Pooja ; Dunnett, Sophie ; Sohrabi, Sadaf ; Fjeldstad, Maria P. ; Calkin, Will ; Murison, Leo ; Jackson, Rosemary J. ; Tzioras, Makis ; Stevenson, Anna ; d'Orange, Marie ; Hooley, Monique ; Davies, Caitlin ; Colom-Cadena, Marti ; Anton-Fernandez, Alejandro ; King, Declan ; Oren, Iris ; Rose, Jamie ; McKenzie, Chris Anne ; Allison, Elizabeth ; Smith, Colin ; Hardt, Oliver ; Henstridge, Christopher M. ; Hardingham, Giles E. ; Spires-Jones, Tara L. / Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer's Disease. In: Cell Reports. 2019 ; Vol. 29, No. 11. pp. 3592-3604.e5.
@article{0960974f415f43f3aa439a439f45274a,
title = "Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer's Disease",
abstract = "A key knowledge gap blocking development of effective therapeutics for Alzheimer's disease (AD) is the lack of understanding of how amyloid beta (Aβ) peptide and pathological forms of the tau protein cooperate in causing disease phenotypes. Within a mouse tau-deficient background, we probed the molecular, cellular, and behavioral disruption triggered by the influence of wild-type human tau on human Aβ-induced pathology. We find that Aβ and tau work cooperatively to cause a hyperactivity behavioral phenotype and to cause downregulation of transcription of genes involved in synaptic function. In both our mouse model and human postmortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau reduction in the mice initiated after behavioral deficits emerge corrects behavioral deficits, reduces synaptic tau levels, and substantially reverses transcriptional perturbations, suggesting that lowering synaptic tau levels may be beneficial in AD. One of the mysteries of Alzheimer's disease is how the two key pathological proteins, amyloid beta and tau, interact. Pickett et al. use a mouse model to show that these proteins cooperate to change behavior and gene expression and that these phenotypes recover when tau levels are lowered.",
keywords = "Alzheimer, amyloid beta, array tomography, microglia, synapse, tau",
author = "Pickett, {Eleanor K.} and Herrmann, {Abigail G.} and Jamie McQueen and Kimberly Abt and Owen Dando and Jane Tulloch and Pooja Jain and Sophie Dunnett and Sadaf Sohrabi and Fjeldstad, {Maria P.} and Will Calkin and Leo Murison and Jackson, {Rosemary J.} and Makis Tzioras and Anna Stevenson and Marie d'Orange and Monique Hooley and Caitlin Davies and Marti Colom-Cadena and Alejandro Anton-Fernandez and Declan King and Iris Oren and Jamie Rose and McKenzie, {Chris Anne} and Elizabeth Allison and Colin Smith and Oliver Hardt and Henstridge, {Christopher M.} and Hardingham, {Giles E.} and Spires-Jones, {Tara L.}",
year = "2019",
month = "12",
day = "10",
doi = "10.1016/j.celrep.2019.11.044",
language = "English",
volume = "29",
pages = "3592--3604.e5",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier",
number = "11",

}

Pickett, EK, Herrmann, AG, McQueen, J, Abt, K, Dando, O, Tulloch, J, Jain, P, Dunnett, S, Sohrabi, S, Fjeldstad, MP, Calkin, W, Murison, L, Jackson, RJ, Tzioras, M, Stevenson, A, d'Orange, M, Hooley, M, Davies, C, Colom-Cadena, M, Anton-Fernandez, A, King, D, Oren, I, Rose, J, McKenzie, CA, Allison, E, Smith, C, Hardt, O, Henstridge, CM, Hardingham, GE & Spires-Jones, TL 2019, 'Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer's Disease', Cell Reports, vol. 29, no. 11, pp. 3592-3604.e5. https://doi.org/10.1016/j.celrep.2019.11.044

Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer's Disease. / Pickett, Eleanor K.; Herrmann, Abigail G.; McQueen, Jamie; Abt, Kimberly; Dando, Owen; Tulloch, Jane; Jain, Pooja; Dunnett, Sophie; Sohrabi, Sadaf; Fjeldstad, Maria P.; Calkin, Will; Murison, Leo; Jackson, Rosemary J.; Tzioras, Makis; Stevenson, Anna; d'Orange, Marie; Hooley, Monique; Davies, Caitlin; Colom-Cadena, Marti; Anton-Fernandez, Alejandro; King, Declan; Oren, Iris; Rose, Jamie; McKenzie, Chris Anne; Allison, Elizabeth; Smith, Colin; Hardt, Oliver; Henstridge, Christopher M.; Hardingham, Giles E.; Spires-Jones, Tara L.

In: Cell Reports, Vol. 29, No. 11, 10.12.2019, p. 3592-3604.e5.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Amyloid Beta and Tau Cooperate to Cause Reversible Behavioral and Transcriptional Deficits in a Model of Alzheimer's Disease

AU - Pickett, Eleanor K.

AU - Herrmann, Abigail G.

AU - McQueen, Jamie

AU - Abt, Kimberly

AU - Dando, Owen

AU - Tulloch, Jane

AU - Jain, Pooja

AU - Dunnett, Sophie

AU - Sohrabi, Sadaf

AU - Fjeldstad, Maria P.

AU - Calkin, Will

AU - Murison, Leo

AU - Jackson, Rosemary J.

AU - Tzioras, Makis

AU - Stevenson, Anna

AU - d'Orange, Marie

AU - Hooley, Monique

AU - Davies, Caitlin

AU - Colom-Cadena, Marti

AU - Anton-Fernandez, Alejandro

AU - King, Declan

AU - Oren, Iris

AU - Rose, Jamie

AU - McKenzie, Chris Anne

AU - Allison, Elizabeth

AU - Smith, Colin

AU - Hardt, Oliver

AU - Henstridge, Christopher M.

AU - Hardingham, Giles E.

AU - Spires-Jones, Tara L.

PY - 2019/12/10

Y1 - 2019/12/10

N2 - A key knowledge gap blocking development of effective therapeutics for Alzheimer's disease (AD) is the lack of understanding of how amyloid beta (Aβ) peptide and pathological forms of the tau protein cooperate in causing disease phenotypes. Within a mouse tau-deficient background, we probed the molecular, cellular, and behavioral disruption triggered by the influence of wild-type human tau on human Aβ-induced pathology. We find that Aβ and tau work cooperatively to cause a hyperactivity behavioral phenotype and to cause downregulation of transcription of genes involved in synaptic function. In both our mouse model and human postmortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau reduction in the mice initiated after behavioral deficits emerge corrects behavioral deficits, reduces synaptic tau levels, and substantially reverses transcriptional perturbations, suggesting that lowering synaptic tau levels may be beneficial in AD. One of the mysteries of Alzheimer's disease is how the two key pathological proteins, amyloid beta and tau, interact. Pickett et al. use a mouse model to show that these proteins cooperate to change behavior and gene expression and that these phenotypes recover when tau levels are lowered.

AB - A key knowledge gap blocking development of effective therapeutics for Alzheimer's disease (AD) is the lack of understanding of how amyloid beta (Aβ) peptide and pathological forms of the tau protein cooperate in causing disease phenotypes. Within a mouse tau-deficient background, we probed the molecular, cellular, and behavioral disruption triggered by the influence of wild-type human tau on human Aβ-induced pathology. We find that Aβ and tau work cooperatively to cause a hyperactivity behavioral phenotype and to cause downregulation of transcription of genes involved in synaptic function. In both our mouse model and human postmortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau reduction in the mice initiated after behavioral deficits emerge corrects behavioral deficits, reduces synaptic tau levels, and substantially reverses transcriptional perturbations, suggesting that lowering synaptic tau levels may be beneficial in AD. One of the mysteries of Alzheimer's disease is how the two key pathological proteins, amyloid beta and tau, interact. Pickett et al. use a mouse model to show that these proteins cooperate to change behavior and gene expression and that these phenotypes recover when tau levels are lowered.

KW - Alzheimer

KW - amyloid beta

KW - array tomography

KW - microglia

KW - synapse

KW - tau

UR - http://www.scopus.com/inward/record.url?scp=85076043048&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.11.044

DO - 10.1016/j.celrep.2019.11.044

M3 - Article

C2 - 31825838

AN - SCOPUS:85076043048

VL - 29

SP - 3592-3604.e5

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 11

ER -