Interplay between Cyclin-Dependent Kinase 5 and Glycogen Synthase Kinase 3β Mediated by Neuregulin Signaling Leads to Differential Effects on Tau Phosphorylation and Amyloid Precursor Protein Processing
Open accessAbstract
Cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase 3β (GSK3β) have been implicated in pathogenic processes associated with Alzheimer's disease because both kinases regulate tau hyperphosphorylation and enhance amyloid precursor protein (APP) processing leading to an increase in amyloid β (Aβ) production. Here we show that young p25 overexpressing mice have enhanced cdk5 activity but reduced GSK3β activity attributable to phosphorylation at the inhibitory GSK3β–serine 9 (GSK3β–S9) site. Phosphorylation at this site was mediated by enhanced activity of the neuregulin receptor complex, ErbB, and activation of the downstream phosphatidylinositol 3 kinase/Akt pathway. Young p25 mice had elevated Aβ peptide levels, but phospho-tau levels were decreased overall. Thus, cdk5 appears to play a dominant role in the regulation of amyloidogenic APP processing, whereas GSK3β plays a dominant role in overall tau phosphorylation. In older mice, GSK3β inhibitory phosphorylation at S9 was reduced relative to young mice. Aβ peptide levels were still elevated but phospho-tau levels were either unchanged or showed a trend to increase, suggesting that GSK3β activity increases with aging. Inhibition of cdk5 by a specific inhibitor reduced cdk5 activity in p25 mice, leading to reduced Aβ production in both young and old mice. However, in young mice, cdk5 inhibition reversed GSK3β inhibition, leading to an increase in overall tau phosphorylation. When cdk5 inhibitor was administered to very old, nontransgenic mice, inhibition of cdk5 reduced Aβ levels, and phospho-tau levels showed a trend to increase. Thus, cdk5 inhibitors may not be effective in targeting tau phosphorylation in the elderly.
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Ser(P)-235 was considered a CDK5-specific epitope because p25 transgenic mice had significantly higher levels of Ser(P)-235-positive tau than non-transgenic mice.
“In p25 transgenic mice, significantly higher levels of Ser(P)235-positive tau relative to those in non-transgenic mice were present, and therefore Ser(P)-235 was considered to be a CDK5-specific epitope (13).”
From An Unbiased Approach to Identifying Tau Kinases That Phosphorylate Tau at Sites Associated with Alzheimer Disease (2013) · cites this paper as [13]
The “Phosphorylation status of tau in p25 mice” section reports significantly higher pS235-positive tau in p25 mice than in non-transgenic mice. But it calls S235 cdk5-responsive, not cdk5-specific, and says it could not determine whether cdk5 acted directly at that site. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCDK5 is a well established tau kinase.
“Because CDK5 is a well established tau kinase, we included this epitope in our screen.”
From An Unbiased Approach to Identifying Tau Kinases That Phosphorylate Tau at Sites Associated with Alzheimer Disease (2013) · cites this paper as [13]
Prior to initiating the screen, the robustness of the protocol was examined using two well characterized tau kinases, CDK5 and GSK3β, as well as GFP, the negative control.
“Prior to initiating the screen, the robustness of the protocol was examined using two well characterized tau kinases, CDK5 (13) and GSK3 𝛃 (18), as well as GFP, the negative control.”
From An Unbiased Approach to Identifying Tau Kinases That Phosphorylate Tau at Sites Associated with Alzheimer Disease (2013) · cites this paper as [13]
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“Prior to initiating the screen the robustness of the protocol was examined using two well characterized tau kinases CDK5 (13) and GSK3β (18) as well as GFP, the negative control.”
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- Authors
- Wen, Y., Planel, E., Herman, M., Figueroa, H. Y., Wang, L., Liu, L., Lau, L.-F., Yu, W. H., & Duff, K. E.
- Affiliations
- Columbia University Irving Medical Center (US)
- Pfizer (United States) (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-03-05
- Volume
- 28
- Issue
- 10
- Pages
- 2624-2632
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6671193
- OpenAlex
- W2082905363
- Cited by
- 145
- References
- 2
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 7 · 2023: 8 · 2022: 8 · 2021: 4 · 2020: 10 · 2019: 2 · 2018: 7 · 2017: 4 · 2016: 9 · 2015: 9 · 2014: 12 · 2013: 12 · 2012: 6
- FWCI
- 9.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Association
- National Institutes of Health
- National Institute on Aging (AG172116)
- National Institute of Neurological Disorders and Stroke (NS48447, P01NS048447)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- cyclin-dependent kinase 5, glycogen synthase kinase-3β, neuregulin signaling, tau phosphorylation, APP processing, amyloid-beta, PI3K/Akt signaling, CDK5 inhibitors, Alzheimer's disease, aging
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Age Factors, Animals, Humans, Mice, Transgenic, Nerve Tissue Proteins, Phosphorylation, Phosphotransferases, Signal Transduction, Down-Regulation, Amyloid beta-Protein Precursor, tau Proteins, Oncogene Proteins v-erbB, Phosphatidylinositol 3-Kinases, Neuregulins, Protein Interaction Mapping, Glycogen Synthase Kinase 3, Cell Line, Tumor, Protein Kinase Inhibitors, Cyclin-Dependent Kinase 5, Mice
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