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

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.

N1 - Copyright: © 2019 The Author(s).

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 - https://www.scopus.com/pages/publications/85076043048

U2 - 10.1016/j.celrep.2019.11.044

DO - 10.1016/j.celrep.2019.11.044

M3 - Article

C2 - 31825838

AN - SCOPUS:85076043048

SN - 2211-1247

VL - 29

SP - 3592-3604.e5

JO - Cell Reports

JF - Cell Reports

IS - 11

ER -