Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles
Open accessAbstract
Cyclin-dependent kinase 5 (Cdk5) and its regulatory subunit p35 are integral players in the proper development of the mammalian central nervous system. Proteolytic cleavage of p35 generates p25, leading to aberrant Cdk5 activation. The accumulation of p25 is implicated in several neurodegenerative diseases. In primary neurons, p25 causes apoptosis and tau hyperphosphorylation. Current mouse models expressing p25, however, fail to rigorously recapitulate these phenotypes in vivo. Here, we generated inducible transgenic mouse lines overexpressing p25 in the postnatal forebrain. Induction of p25 preferentially directed Cdk5 to pathological substrates. These animals exhibited neuronal loss in the cortex and hippocampus, accompanied by forebrain atrophy, astrogliosis, and caspase-3 activation. Endogenous tau was hyperphosphorylated at many epitopes, aggregated tau accumulated, and neurofibrillary pathology developed progressively in these animals. Our cumulative findings provide compelling evidence that in vivo deregulation of Cdk5 by p25 plays a causative role in neurodegeneration and the development of neurofibrillary pathology.
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A11 treatment improved performance of CK-p25 mice in the Y maze, increasing novel arm preference above chance from −4.1 ± 9.4% in vehicle-injected mice to 18.7 ± 11.7% in A11-injected mice (P = 0.0007).
“A11 treatment improved performance of CK-p25 mice in the Y maze (Cruz et al., 2003; Fischer et al., 2005), increasing the novel arm preference above chance from −4.1 ± 9.4% in vehicle-injected mice to 18.7 ± 11.7% to in A11-injected mice (P = 0.0007; left panel of Fig. 4 i).”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Cruz et al., 2003
In CK-p25 mice, p25 expression is driven by the CaMKII-tTA (CK) promoter crossed to tetO-p25 mice in the absence of doxycycline, with CK mice as littermate controls.
“In CK-p25 mice, p25 expression is driven by the CaMKII-tTA (CK) promoter crossed to tetO-p25 mice (005706; JAX) in the absence of doxycycline, with CK mice as littermate controls.”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Cruz et al., 2003
p25 expression is suppressed by a constant 1 g/kg doxycycline diet and induced when mice are put on a regular diet.
“Therefore, p25 expression is suppressed by a constant 1 g/kg doxycycline diet (Bio-Rad, custom-made) and induced when mice are put on a regular diet (Teklad RMH 3000; Envigo).”
From A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation (2023) · cites this paper as Cruz et al., 2003
Coincident changes in both cluster B and cluster C module genes were characteristic of selected MAPT strains and were also seen in the CDK5-P25 mouse.
“Interestingly, coincident changes in both cluster B and cluster C module genes (Figure 4A, circles) were characteristic of selected MAPT strains and were also seen in the CDK5-P25 mouse, which similarly develops extensive tau pathology and brain atrophy (Cruz et al., 2003).”
From Meta-Analysis of the Alzheimer’s Disease Human Brain Transcriptome and Functional Dissection in Mouse Models (2020) · cites this paper as Cruz et al., 2003
Cyclin-dependent kinase 5 is another protein kinase highly implicated in tau phosphorylation.
“Another protein kinase highly implicated in tau phosphorylation is cyclin-dependent kinase 5 (CDK5).”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Cruz et al., 2003
Dysregulation of CDK5 signaling can contribute to neurodegeneration, excitotoxicity, and tau hyperphosphorylation.
“Dysregulation of CDK5 signaling can contribute to neurodegeneration, excitotoxicity, and tau hyperphosphorylation (Cruz et al., 2003).”
From Tauopathy and Epilepsy Comorbidities and Underlying Mechanisms (2022) · cites this paper as Cruz et al., 2003
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References 60 · Cited by 609
- Authors
- Cruz, J. C., Tseng, H.-C., Goldman, J. A., Shih, H., & Tsai, L.-H.
- Affiliations
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Cruz, Jonathan C.
- ORCID
- Tsai, Li-Huei
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2003-10
- Volume
- 40
- Issue
- 3
- Pages
- 471-483
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2063540863
- Cited by
- 609
- References
- 60
- Citations by year
- 2026: 14 · 2025: 25 · 2024: 18 · 2023: 23 · 2022: 21 · 2021: 25 · 2020: 24 · 2019: 21 · 2018: 18 · 2017: 28 · 2016: 22 · 2015: 22 · 2014: 38 · 2013: 31 · 2012: 36
- FWCI
- 15.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- cyclin-dependent kinase 5, p25, neurodegeneration, neurofibrillary tangles, tau hyperphosphorylation, tau aggregation, apoptosis, caspase-3, astrocyte activation, transgenic mouse model, hippocampus, cortex
- MeSH terms
- Animals, Brain, Cell Count, Cell Fractionation, Detergents, Humans, Immunohistochemistry, Leucine, Luminescent Proteins, Mice, Inbred C57BL, Mice, Transgenic, Microtubules, Models, Neurological, Nerve Degeneration, Nerve Tissue Proteins, Neurons, Phosphorylation, Proline, Sarcosine, Mass Spectrometry, Time Factors, Immunoblotting, Microscopy, Immunoelectron, Neurofibrillary Tangles, tau Proteins, Cyclin-Dependent Kinases, Caspases, Green Fluorescent Proteins, Cyclin-Dependent Kinase 5, Mice, Caspase 3
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