Altered regulation of tau phosphorylation in a mouse model of down syndrome aging

Olivia Sheppard; Florian Plattner; Anna Rubin; Amy Slender; Jacqueline M. Linehan; Sebastian Brandner; Victor L J Tybulewicz; Elizabeth M C Fisher; Frances K. Wiseman

doi:10.1016/j.neurobiolaging.2011.06.025

Altered regulation of tau phosphorylation in a mouse model of down syndrome aging

Olivia Sheppard, Florian Plattner, Anna Rubin, Amy Slender, Jacqueline M. Linehan, Sebastian Brandner, Victor L J Tybulewicz, Elizabeth M C Fisher, Frances K. Wiseman

Psychiatry

Research output: Contribution to journal › Article › peer-review

45 Scopus citations

Abstract

Down syndrome (DS) results from trisomy of human chromosome 21 (Hsa21) and is associated with an increased risk of Alzheimer's disease (AD). Here, using the unique transchromosomic Tc1 mouse model of DS we investigate the influence of trisomy of Hsa21 on the protein tau, which is hyperphosphorylated in Alzheimer's disease. We show that in old, but not young, Tc1 mice increased phosphorylation of tau occurs at a site suggested to be targeted by the Hsa21 encoded kinase, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A). We show that DYRK1A is upregulated in young and old Tc1 mice, but that young trisomic mice may be protected from accumulating aberrantly phosphorylated tau. We observe that the key tau kinase, glycogen synthase kinase3-β (GSK-3β) is aberrantly phosphorylated at an inhibitory site in the aged Tc1 brain which may reduce total glycogen synthase kinase3-β activity. It is possible that a similar mechanism may also occur in people with DS.

Original language	English (US)
Pages (from-to)	828.e31-828.e44
Journal	Neurobiology of Aging
Volume	33
Issue number	4
DOIs	https://doi.org/10.1016/j.neurobiolaging.2011.06.025
State	Published - Apr 2012

Keywords

Alzheimer disease
DYRK1A
Down syndrome
GSK-3β
Phosphorylation
Tau

ASJC Scopus subject areas

Clinical Neurology
Geriatrics and Gerontology
Aging
General Neuroscience
Developmental Biology

Access to Document

10.1016/j.neurobiolaging.2011.06.025

Cite this

@article{8ec280d492304a82b2b56567b70f33ff,

title = "Altered regulation of tau phosphorylation in a mouse model of down syndrome aging",

abstract = "Down syndrome (DS) results from trisomy of human chromosome 21 (Hsa21) and is associated with an increased risk of Alzheimer's disease (AD). Here, using the unique transchromosomic Tc1 mouse model of DS we investigate the influence of trisomy of Hsa21 on the protein tau, which is hyperphosphorylated in Alzheimer's disease. We show that in old, but not young, Tc1 mice increased phosphorylation of tau occurs at a site suggested to be targeted by the Hsa21 encoded kinase, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A). We show that DYRK1A is upregulated in young and old Tc1 mice, but that young trisomic mice may be protected from accumulating aberrantly phosphorylated tau. We observe that the key tau kinase, glycogen synthase kinase3-β (GSK-3β) is aberrantly phosphorylated at an inhibitory site in the aged Tc1 brain which may reduce total glycogen synthase kinase3-β activity. It is possible that a similar mechanism may also occur in people with DS.",

keywords = "Alzheimer disease, DYRK1A, Down syndrome, GSK-3β, Phosphorylation, Tau",

author = "Olivia Sheppard and Florian Plattner and Anna Rubin and Amy Slender and Linehan, {Jacqueline M.} and Sebastian Brandner and Tybulewicz, {Victor L J} and Fisher, {Elizabeth M C} and Wiseman, {Frances K.}",

note = "Funding Information: We thank Ray Young for help with preparation of the figures, Kate Alford (NIMR, London) for assistance with Tc1 and control samples, and Wendy Noble (Kings College, London) and Selina Wray (University College, London) for helpful discussion. We thank Catherine O'Malley and Caroline Powell for technical assistance. We also thank Drs. P. Davies (Einstein College, New York) and S.M. Dilworth (Imperial College, London) for antibodies. V.L.J.T. is funded by the UK Medical Research Council (programme number U117527252 ), the AnEUploidy grant from Framework Programme 6 from the European Union Commission , and the Wellcome Trust; F.K.W., O.S., and E.M.C.F. are funded by the UK Medical Research Council, the Wellcome Trust, the AnEUploidy grant from Framework Programme 6 from the European Union Commission and the Fidelity Foundation. These funding bodies had no role in the design of this study or the decision to publish these data. ",

year = "2012",

month = apr,

doi = "10.1016/j.neurobiolaging.2011.06.025",

language = "English (US)",

volume = "33",

pages = "828.e31--828.e44",

journal = "Neurobiology of Aging",

issn = "0197-4580",

publisher = "Elsevier Inc.",

number = "4",

}

TY - JOUR

T1 - Altered regulation of tau phosphorylation in a mouse model of down syndrome aging

AU - Sheppard, Olivia

AU - Plattner, Florian

AU - Rubin, Anna

AU - Slender, Amy

AU - Linehan, Jacqueline M.

AU - Brandner, Sebastian

AU - Tybulewicz, Victor L J

AU - Fisher, Elizabeth M C

AU - Wiseman, Frances K.

N1 - Funding Information: We thank Ray Young for help with preparation of the figures, Kate Alford (NIMR, London) for assistance with Tc1 and control samples, and Wendy Noble (Kings College, London) and Selina Wray (University College, London) for helpful discussion. We thank Catherine O'Malley and Caroline Powell for technical assistance. We also thank Drs. P. Davies (Einstein College, New York) and S.M. Dilworth (Imperial College, London) for antibodies. V.L.J.T. is funded by the UK Medical Research Council (programme number U117527252 ), the AnEUploidy grant from Framework Programme 6 from the European Union Commission , and the Wellcome Trust; F.K.W., O.S., and E.M.C.F. are funded by the UK Medical Research Council, the Wellcome Trust, the AnEUploidy grant from Framework Programme 6 from the European Union Commission and the Fidelity Foundation. These funding bodies had no role in the design of this study or the decision to publish these data.

PY - 2012/4

Y1 - 2012/4

N2 - Down syndrome (DS) results from trisomy of human chromosome 21 (Hsa21) and is associated with an increased risk of Alzheimer's disease (AD). Here, using the unique transchromosomic Tc1 mouse model of DS we investigate the influence of trisomy of Hsa21 on the protein tau, which is hyperphosphorylated in Alzheimer's disease. We show that in old, but not young, Tc1 mice increased phosphorylation of tau occurs at a site suggested to be targeted by the Hsa21 encoded kinase, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A). We show that DYRK1A is upregulated in young and old Tc1 mice, but that young trisomic mice may be protected from accumulating aberrantly phosphorylated tau. We observe that the key tau kinase, glycogen synthase kinase3-β (GSK-3β) is aberrantly phosphorylated at an inhibitory site in the aged Tc1 brain which may reduce total glycogen synthase kinase3-β activity. It is possible that a similar mechanism may also occur in people with DS.

AB - Down syndrome (DS) results from trisomy of human chromosome 21 (Hsa21) and is associated with an increased risk of Alzheimer's disease (AD). Here, using the unique transchromosomic Tc1 mouse model of DS we investigate the influence of trisomy of Hsa21 on the protein tau, which is hyperphosphorylated in Alzheimer's disease. We show that in old, but not young, Tc1 mice increased phosphorylation of tau occurs at a site suggested to be targeted by the Hsa21 encoded kinase, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A). We show that DYRK1A is upregulated in young and old Tc1 mice, but that young trisomic mice may be protected from accumulating aberrantly phosphorylated tau. We observe that the key tau kinase, glycogen synthase kinase3-β (GSK-3β) is aberrantly phosphorylated at an inhibitory site in the aged Tc1 brain which may reduce total glycogen synthase kinase3-β activity. It is possible that a similar mechanism may also occur in people with DS.

KW - Alzheimer disease

KW - DYRK1A

KW - Down syndrome

KW - GSK-3β

KW - Phosphorylation

KW - Tau

UR - http://www.scopus.com/inward/record.url?scp=84856955428&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84856955428&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2011.06.025

DO - 10.1016/j.neurobiolaging.2011.06.025

M3 - Article

C2 - 21843906

AN - SCOPUS:84856955428

SN - 0197-4580

VL - 33

SP - 828.e31-828.e44

JO - Neurobiology of Aging

JF - Neurobiology of Aging

IS - 4

ER -

Altered regulation of tau phosphorylation in a mouse model of down syndrome aging

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this