Deregulated Cdk5 activity is involved in inducing Alzheimer's disease
Open accessAbstract
Alzheimer's disease (AD), the most devastating chronic neurodegenerative disease in adults, causes dementia and eventually, death of the affected individuals. Clinically, AD is characterized as late-onset, age-dependent cognitive decline due to loss of neurons in cortex and hippocampus. The pathologic corollary of these symptoms is the formation of senile plaques and neurofibrillary tangles. Senile plaques are formed due to accumulation of oligomeric amyloid beta (Aβ) forming plaques. This occurs due to the amyloidogenic processing of the amyloid precursor protein (APP) by various secretases. On the other hand, neurofibrillary tangles are formed due to hyperphosphorylation of cytoskeleton proteins like tau and neurofilament. Both are hyperphosphorylated by cyclin-dependent kinase-5 (Cdk5) and are part of the paired helical filament (PHF), an integral part of neurofibrillary tangles. Unlike other cyclin-dependent kinases, Cdk5 plays a very important role in the neuronal development. Cdk5 gets activated by its neuronal activators p35 and p39. Upon stress, p35 and p39 are cleaved by calpain resulting in truncated products as p25 and p29. Association of Cdk5/p25 is longer and uncontrolled causing aberrant hyperphosphorylation of various substrates of Cdk5 like APP, tau and neurofilament, leading to neurodegenerative pathology like AD. Additionally recent evidence has shown increased levels of p25, Aβ, hyperactivity of Cdk5, phosphorylated tau and neurofilament in human AD brains. This review briefly describes the above-mentioned aspects of involvement of Cdk5 in the pathology of AD and at the end summarizes the advances in Cdk5 as a therapeutic target.
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Elevated Ca2+ concentrations activate calpain, which cleaves p35 to p25.
“Elevated Ca 2ϩ concentrations activate calpain, which cleaves p35 to p25 (reviewed in Ref. 62).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [62]
Both p25 and calpain are elevated in AD brains, and Aβ can induce tau phosphorylation through deregulating Cdk5 activation.
“Both p25 and calpain are elevated in AD brains, and A can induce tau phosphorylation through deregulating Cdk5 activation (reviewed in Ref. 62).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [62]
In AD, levels of active CDK5 and p25 are increased in post-mortem brain tissue.
“For example, evidence from post-mortem tissue from the brains of patients with AD indicates that levels of active cyclin-dependent-like kinase 5 (CDK5) and cyclin-dependent kinase 5 activator 1, p25 — a truncated form of a CDK5 regulator — are increased in disease28.”
From Tau-targeting therapies for Alzheimer disease (2018) · cites this paper as [28]
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- Authors
- Shukla, V., Skuntz, S., & Pant, H. C.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Pant, Harish C.
- Venue
- Archives of Medical Research
- Publisher
- Elsevier BV
- Published
- 2012-11
- Volume
- 43
- Issue
- 8
- Pages
- 655-662
- ISSN
- 0066-6769 (ISSN-L)
- 0188-4409
- PMC
- PMC3532552
- OpenAlex
- W2028700140
- Cited by
- 185
- References
- 102
- Citations by year
- 2026: 5 · 2025: 19 · 2024: 17 · 2023: 17 · 2022: 5 · 2021: 13 · 2020: 15 · 2019: 17 · 2018: 7 · 2017: 11 · 2016: 17 · 2015: 16 · 2014: 20 · 2013: 6
- FWCI
- 1.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Archives of Medical Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99 NS999999)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, cyclin-dependent kinase 5, p25, p35, p39, calpain cleavage, amyloid-beta, amyloid precursor protein, tau hyperphosphorylation, neurofibrillary tangles, amyloid plaques, paired helical filaments, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Brain, Humans, Nerve Degeneration, Phosphorylation, Amyloid beta-Protein Precursor, Neurofibrillary Tangles, tau Proteins, Cyclin-Dependent Kinase 5, Plaque, Amyloid, Molecular Targeted Therapy
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