Increases of SET level and translocation are correlated with tau hyperphosphorylation at ser202/thr205 in CA1 of Ts65Dn mice

Topic: Brain proteins, microglia and lab models

SET is a multifunctional protein, but when present in the cytoplasm, acts as a powerful inhibitor of phosphatase 2A. We previously observed that in CA1 of Down syndrome (DS) patients, the level of SET is increased, and SET is translocated to the cytoplasm and associated with the hyperphosphorylation of tau at ser202/thr205. The presence of SET in the cytoplasm in DS brains may play a role in the progression of the disease. Here, we show that in CA1 of 3-month-old Ts65Dn mice modeling DS, SET level is increased, and SET is translocated to the cytoplasm and associated with tau hyperphosphorylations at ser202/thr205 and with amyloid precursor protein caspase cleaved as observed in Alzheimer disease brains. Tau hyperphosphorylation at ser356 and activation of other phosphatase 2A targets such as the mammalian target of rapamycin and adenosine monophosphate protein kinases were also observed, suggesting deleterious mechanisms. We propose Ts65Dn mice as a model for therapeutic approaches focused on SET overexpression and its cytoplasmic translocation to slow down disease progression.

Key findings

• We previously observed that in CA1 of Down syndrome (DS) patients, the level of SET is increased, and SET is translocated to the cytoplasm and associated with the hyperphosphorylation of tau at ser202/thr205.
• Here, we show that in CA1 of 3-month-old Ts65Dn mice modeling DS, SET level is increased, and SET is translocated to the cytoplasm and associated with tau hyperphosphorylations at ser202/thr205 and with amyloid precursor protein caspase cleaved as observed in Alzheimer disease brains.

Why it matters

In 3-month-old Ts65Dn mice modeling Down syndrome, SET protein levels were increased and SET moved to the cytoplasm, where it was associated with tau hyperphosphorylation at ser202/thr205 and with caspase-cleaved amyloid precursor protein. The authors propose these mice as a model for therapeutic approaches focused on SET overexpression and its cytoplasmic translocation to slow disease progression, but this is animal work and no treatment was tested in people.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1016/j.neurobiolaging.2016.06.010
• PubMed: 27460148
• Original source →
• Free full text: HAL (Le Centre pour la Communication Scientifique Directe) →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{dorard2016-27460148,
  author  = {Dorard, E. and Gorisse-Hussonnois, L. and Guihenneuc-Jouyaux, C. and Albac, C. and Potier, M. C. and Allinquant, B.},
  title   = {{Increases of SET level and translocation are correlated with tau hyperphosphorylation at ser202/thr205 in CA1 of Ts65Dn mice}},
  journal = {Neurobiology of aging},
  year    = {2016},
  doi     = {10.1016/j.neurobiolaging.2016.06.010},
  pmid    = {27460148},
  url     = {https://doi.org/10.1016/j.neurobiolaging.2016.06.010}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• A mouse model for Down syndrome exhibits learning and behaviour deficits Nature genetics · 1995-10-01 · usefulness score 54/100 · Down syndrome and Alzheimer's
• A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads Acta neuropathologica · 1994-01-01 · usefulness score 53/100 · Brain tissue and pathology
• The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease Human molecular genetics · 2006-11-29 · usefulness score 49/100 · Genetics
• DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease The Journal of biological chemistry · 2007-09-28 · usefulness score 46/100 · Down syndrome and Alzheimer's
• Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2008-05-28 · usefulness score 46/100 · Down syndrome and Alzheimer's
• Morphological and biochemical assessment of DNA damage and apoptosis in Down syndrome and Alzheimer disease, and effect of postmortem tissue archival on TUNEL Neurobiology of aging · 2000-07-01 · usefulness score 44/100 · Down syndrome and Alzheimer's
• Constitutive Dyrk1A is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models Neurobiology of disease · 2005-11-01 · usefulness score 44/100 · Down syndrome and Alzheimer's
• mTOR Hyperactivation in down syndrome hippocampus appears early during development Journal of neuropathology and experimental neurology · 2014-07-01 · usefulness score 44/100 · Down syndrome and Alzheimer's
• SET translocation is associated with increase in caspase cleaved amyloid precursor protein in CA1 of Alzheimer and Down syndrome patients Neurobiology of aging · 2013-11-05 · usefulness score 39/100 · Down syndrome and Alzheimer's
• Degeneration in vivo of rat hippocampal neurons by wild-type Alzheimer amyloid precursor protein overexpressed by adenovirus-mediated gene transfer The Journal of neuroscience : the official journal of the Society for Neuroscience · 1998-04-01 · usefulness score 36/100 · Risk genes beyond APOE

Later studies that cite this one

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• mTOR in Down syndrome: Role in Aß and tau neuropathology and transition to Alzheimer disease-like dementia Free radical biology & medicine · 2017-08-12 · usefulness score 45/100 · Down syndrome and Alzheimer's

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• Nerve growth factor increases mRNA levels for the prion protein and the beta-amyloid protein precursor in developing hamster brain Proceedings of the National Academy of Sciences of the United States of America · 1988-12-01 · usefulness score 43/100

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