TY - JOUR
T1 - Increased 4R-Tau Induces Pathological Changes in a Human-Tau Mouse Model
AU - Schoch, Kathleen M M.
AU - DeVos, Sarah L L.
AU - Miller, Rebecca L L.
AU - Chun, Seung J J.
AU - Norrbom, Michaela
AU - Wozniak, David F F.
AU - Dawson, Hana N N.
AU - Bennett, C. Frank
AU - Rigo, Frank
AU - Miller, Timothy M M.
N1 - Funding Information:
We wish to recognize and thank Dr. Bradley Hyman for the resources necessary to complete the biochemical tau experiments. We also thank the behavioral expertise provided by the Animal Behavior Core at Washington University in St. Louis, Dr. Peter Davies for his generous gift of the PHF-1 tau antibody, and Elena Fisher for her assistance in editing and preparing this manuscript. This work was supported by the Tau Consortium (T.M.M.), The National Institutes of Health (P50 AG05681 to T.M.M., J.C. Morris, PI; National Institute of Neurological Disorders and Stroke R01NS078398 to T.M.M. and F32 NS089225 to K.M.S.; and National Institute on Aging R21AG044719-01 to T.M.M.), Cure PSP (T.M.M.), and a Paul B. Beeson Career Development Award (NINDS K08NS074194 to T.M.M.). Microscopy was supported by the Hope Center Alafi Neuroimaging Laboratory and P30 Neuroscience Blueprint Interdisciplinary Center Core award to Washington University (P30 NS057105). Additional support was provided by the Gene Johnson Weston Brain Institute Advisor Fellowship to K.M.S. Antisense oligonucleotides used for experimental studies were generously provided by Ionis Pharmaceuticals. Washington University in St. Louis has filed patents in conjunction with Ionis Pharmaceuticals regarding use of Tau ASOs in neurodegenerative syndrome. S.J.C., M.N., C.F.B., and F.R. are paid employees of Ionis Pharmaceuticals.
Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/6/1
Y1 - 2016/6/1
N2 - Pathological evidence for selective four-repeat (4R) tau deposition in certain dementias and exon 10-positioned MAPT mutations together suggest a 4R-specific role in causing disease. However, direct assessments of 4R toxicity have not yet been accomplished in vivo. Increasing 4R-tau expression without change to total tau in human tau-expressing mice induced more severe seizures and nesting behavior abnormality, increased tau phosphorylation, and produced a shift toward oligomeric tau. Exon 10 skipping could also be accomplished in vivo, providing support for a 4R-tau targeted approach to target 4R-tau toxicity and, in cases of primary MAPT mutation, eliminate the disease-causing mutation.
AB - Pathological evidence for selective four-repeat (4R) tau deposition in certain dementias and exon 10-positioned MAPT mutations together suggest a 4R-specific role in causing disease. However, direct assessments of 4R toxicity have not yet been accomplished in vivo. Increasing 4R-tau expression without change to total tau in human tau-expressing mice induced more severe seizures and nesting behavior abnormality, increased tau phosphorylation, and produced a shift toward oligomeric tau. Exon 10 skipping could also be accomplished in vivo, providing support for a 4R-tau targeted approach to target 4R-tau toxicity and, in cases of primary MAPT mutation, eliminate the disease-causing mutation.
UR - http://www.scopus.com/inward/record.url?scp=84975519193&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2016.04.042
DO - 10.1016/j.neuron.2016.04.042
M3 - Article
C2 - 27210553
AN - SCOPUS:84975519193
SN - 0896-6273
VL - 90
SP - 941
EP - 947
JO - Neuron
JF - Neuron
IS - 5
ER -