Abstract
Cognitive decline, the hallmark of Alzheimer's disease, and accompanying neuropsychiatric symptoms share dysfunctions of synaptic processes as a common cellular pathomechanism. Long-term potentiation has proven to be a sensitive tool for the "diagnosis" of such synaptic dysfunctions. Much less, however, is known about how long-term depression (LTD), an alternative mechanism for the storage of memory, is affected by Alzheimer's disease progression. Here, we demonstrate that impaired late LTD (>3hours) in THY-Tau22 mice can be rescued by either inhibition of glycogen synthase kinase-3 (GSK3β) activity or by application of the protein-phosphatase 2A agonist selenate. In line with these findings, we observed increased phosphorylation of GSK3β at Y216 and reduced total phosphatase activity in biochemical assays of hippocampal tissue of THY-Tau22 mice. Interestingly, LTD induction and pharmacologic inhibition of GSK3β appeared to downregulate GSK3ß activity via a marked upregulation of phosphorylation at the inhibitory Ser9 residue. Our results point to alterations in phosphorylation and/or dephosphorylation homeostasis as key mechanisms underlying the deficits in LTD and hippocampus-dependent learning found in THY-Tau22 mice.
| Original language | English |
|---|---|
| Pages (from-to) | 730-739 |
| Number of pages | 10 |
| Journal | Neurobiology of Aging |
| Volume | 36 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 1 Feb 2015 |
| Externally published | Yes |
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Keywords
- Alzheimer's disease
- CA1-region
- Glycogen synthase kinase-3
- Hippocampus
- Long-term depression
- LTD
- Okadaic acid
- Protein-phosphatase 2A
- SB216763
- Sodium selenate
- Synaptic plasticity
- Tauopathy
ASJC Scopus subject areas
- Clinical Neurology
- Neuroscience(all)
- Ageing
- Developmental Biology
- Geriatrics and Gerontology
- Medicine(all)
Cite this
Rescue of impaired late-phase long-term depression in a tau transgenic mouse model. / Ahmed, Tariq; Blum, David; Burnouf, Sylvie; Demeyer, Dominique; Buée-Scherrer, Valérie; D'Hooge, Rudi; Buée, Luc; Balschun, Detlef.
In: Neurobiology of Aging, Vol. 36, No. 2, 01.02.2015, p. 730-739.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Rescue of impaired late-phase long-term depression in a tau transgenic mouse model
AU - Ahmed, Tariq
AU - Blum, David
AU - Burnouf, Sylvie
AU - Demeyer, Dominique
AU - Buée-Scherrer, Valérie
AU - D'Hooge, Rudi
AU - Buée, Luc
AU - Balschun, Detlef
PY - 2015/2/1
Y1 - 2015/2/1
N2 - Cognitive decline, the hallmark of Alzheimer's disease, and accompanying neuropsychiatric symptoms share dysfunctions of synaptic processes as a common cellular pathomechanism. Long-term potentiation has proven to be a sensitive tool for the "diagnosis" of such synaptic dysfunctions. Much less, however, is known about how long-term depression (LTD), an alternative mechanism for the storage of memory, is affected by Alzheimer's disease progression. Here, we demonstrate that impaired late LTD (>3hours) in THY-Tau22 mice can be rescued by either inhibition of glycogen synthase kinase-3 (GSK3β) activity or by application of the protein-phosphatase 2A agonist selenate. In line with these findings, we observed increased phosphorylation of GSK3β at Y216 and reduced total phosphatase activity in biochemical assays of hippocampal tissue of THY-Tau22 mice. Interestingly, LTD induction and pharmacologic inhibition of GSK3β appeared to downregulate GSK3ß activity via a marked upregulation of phosphorylation at the inhibitory Ser9 residue. Our results point to alterations in phosphorylation and/or dephosphorylation homeostasis as key mechanisms underlying the deficits in LTD and hippocampus-dependent learning found in THY-Tau22 mice.
AB - Cognitive decline, the hallmark of Alzheimer's disease, and accompanying neuropsychiatric symptoms share dysfunctions of synaptic processes as a common cellular pathomechanism. Long-term potentiation has proven to be a sensitive tool for the "diagnosis" of such synaptic dysfunctions. Much less, however, is known about how long-term depression (LTD), an alternative mechanism for the storage of memory, is affected by Alzheimer's disease progression. Here, we demonstrate that impaired late LTD (>3hours) in THY-Tau22 mice can be rescued by either inhibition of glycogen synthase kinase-3 (GSK3β) activity or by application of the protein-phosphatase 2A agonist selenate. In line with these findings, we observed increased phosphorylation of GSK3β at Y216 and reduced total phosphatase activity in biochemical assays of hippocampal tissue of THY-Tau22 mice. Interestingly, LTD induction and pharmacologic inhibition of GSK3β appeared to downregulate GSK3ß activity via a marked upregulation of phosphorylation at the inhibitory Ser9 residue. Our results point to alterations in phosphorylation and/or dephosphorylation homeostasis as key mechanisms underlying the deficits in LTD and hippocampus-dependent learning found in THY-Tau22 mice.
KW - Alzheimer's disease
KW - CA1-region
KW - Glycogen synthase kinase-3
KW - Hippocampus
KW - Long-term depression
KW - LTD
KW - Okadaic acid
KW - Protein-phosphatase 2A
KW - SB216763
KW - Sodium selenate
KW - Synaptic plasticity
KW - Tauopathy
UR - http://www.scopus.com/inward/record.url?scp=84922802062&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84922802062&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2014.09.015
DO - 10.1016/j.neurobiolaging.2014.09.015
M3 - Article
C2 - 25443285
AN - SCOPUS:84922802062
VL - 36
SP - 730
EP - 739
JO - Neurobiology of Aging
JF - Neurobiology of Aging
SN - 0197-4580
IS - 2
ER -