TY - JOUR
T1 - Enhanced phosphorylation of T153 in soluble tau is a defining biochemical feature of the A152T tau risk variant
AU - Carlomagno, Yari
AU - Chung, Dah Eun Chloe
AU - Yue, Mei
AU - Kurti, Aishe
AU - Avendano, Nicole M.
AU - Castanedes-Casey, Monica
AU - Hinkle, Kelly M.
AU - Jansen-West, Karen
AU - Daughrity, Lillian M.
AU - Tong, Jimei
AU - Phillips, Virginia
AU - Rademakers, Rosa
AU - DeTure, Michael
AU - Fryer, John D.
AU - Dickson, Dennis W.
AU - Petrucelli, Leonard
AU - Cook, Casey
N1 - Funding Information:
This work was supported by the Florida Department of Health/Ed and Ethel Moore Alzheimer’s Disease Research Program [7AZ21 (CC)], Mayo Clinic Foundation (LP), National Institutes of Health/National Institute on Aging [ADRC 2 P50 AG016574–16 (LP, CC)], National Institutes of Health/National Institute of Neurological Disorders and Stroke [R21NS094489 (CC), U54NS100693 (LP, CC, DD), R35NS097273 (LP), R01NS089544 (LP)].
PY - 2019/1/23
Y1 - 2019/1/23
N2 - Pathogenic mutations in the tau gene (microtubule associated protein tau, MAPT) are linked to the onset of tauopathy, but the A152T variant is unique in acting as a risk factor for a range of disorders including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB). In order to provide insight into the mechanism by which A152T modulates disease risk, we developed a novel mouse model utilizing somatic brain transgenesis with adeno-associated virus (AAV) to drive tau expression in vivo, and validated the model by confirming the distinct biochemical features of A152T tau in postmortem brain tissue from human carriers. Specifically, TauA152T-AAV mice exhibited increased tau phosphorylation that unlike animals expressing the pathogenic P301L mutation remained localized to the soluble fraction. To investigate the possibility that the A152T variant might alter the phosphorylation state of tau on T152 or the neighboring T153 residue, we generated a novel antibody that revealed significant accumulation of soluble tau species that were hyperphosphorylated on T153 (pT153) in TauA152T-AAV mice, which were absent the soluble fraction of TauP301L-AAV mice. Providing new insight into the role of A152T in modifying risk of tauopathy, as well as validating the TauA152T-AAV model, we demonstrate that the presence of soluble pT153-positive tau species in human postmortem brain tissue differentiates A152T carriers from noncarriers, independent of disease classification. These results implicate both phosphorylation of T153 and an altered solubility profile in the mechanism by which A152T modulates disease risk.
AB - Pathogenic mutations in the tau gene (microtubule associated protein tau, MAPT) are linked to the onset of tauopathy, but the A152T variant is unique in acting as a risk factor for a range of disorders including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB). In order to provide insight into the mechanism by which A152T modulates disease risk, we developed a novel mouse model utilizing somatic brain transgenesis with adeno-associated virus (AAV) to drive tau expression in vivo, and validated the model by confirming the distinct biochemical features of A152T tau in postmortem brain tissue from human carriers. Specifically, TauA152T-AAV mice exhibited increased tau phosphorylation that unlike animals expressing the pathogenic P301L mutation remained localized to the soluble fraction. To investigate the possibility that the A152T variant might alter the phosphorylation state of tau on T152 or the neighboring T153 residue, we generated a novel antibody that revealed significant accumulation of soluble tau species that were hyperphosphorylated on T153 (pT153) in TauA152T-AAV mice, which were absent the soluble fraction of TauP301L-AAV mice. Providing new insight into the role of A152T in modifying risk of tauopathy, as well as validating the TauA152T-AAV model, we demonstrate that the presence of soluble pT153-positive tau species in human postmortem brain tissue differentiates A152T carriers from noncarriers, independent of disease classification. These results implicate both phosphorylation of T153 and an altered solubility profile in the mechanism by which A152T modulates disease risk.
KW - A152T
KW - Neuropathology
KW - Phosphorylation
KW - Risk factor
KW - Solubility
KW - Tauopathy
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UR - http://www.scopus.com/inward/citedby.url?scp=85060399730&partnerID=8YFLogxK
U2 - 10.1186/s40478-019-0661-2
DO - 10.1186/s40478-019-0661-2
M3 - Article
C2 - 30674342
AN - SCOPUS:85060399730
SN - 2051-5960
VL - 7
SP - 10
JO - Acta Neuropathologica Communications
JF - Acta Neuropathologica Communications
IS - 1
ER -