protein

CDK5

Entity Detail — Knowledge Graph Node

Understanding Entity Pages

This page aggregates everything SciDEX knows about CDK5: its mechanistic relationships (Knowledge Graph edges), hypotheses targeting it, analyses mentioning it, and supporting scientific papers. The interactive graph below shows its immediate neighbors. All content is AI-synthesized from peer-reviewed literature.

796Connections

6Hypotheses

15Analyses

50Outgoing

50Incoming

0Experiments

20Debates

Summary

Cyclin-Dependent Kinase 5 (CDK5) is a unique member of the CDK family that lacks a role in cell cycle regulation and is not activated by cyclins. Instead, CDK5 is activated by neuron-specific partners p35 and p39, which are expressed primarily in post-mitotic neurons. CDK5 phosphorylates numerous substrates including tau, APP, presenilins, and NMDA receptors, making it a critical regulator of neuronal function. In Alzheimer's disease and other neurodegenerative conditions, dysregulation of CDK5 occurs due to calpain-mediated cleavage of p35 to p25, leading to hyperactivation of CDK5 and hyperphosphorylation of tau at multiple AD-relevant epitopes. CDK5-mediated tau phosphorylation contributes to neurofibrillary tangle formation and granulovacuolar degeneration, both hallmarks of AD pathology. CDK5 also plays roles in synaptic plasticity, learning and memory, and motor neuron survival. While CDK5 inhibitors have been explored therapeutically, their lack of specificity and neural toxicity have been significant obstacles.

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🔬 Protein Info

Gene Symbol	CDK5
Protein Family	CMGC kinase group, CDK family
Protein Type	Serine/Threonine Kinase
Function	Cdk5 knockout mice die at birth with severe cortical layering defects due to failed neuronal migration.
Primary Expression	Cytoplasm, nucleus, synapses, growth cones, perinuclear region
Amino Acids	291 aa
Pathways	Apoptosis, Autophagy, Checkpoint Inhibitor, Immune Checkpoint, Immune Response
GeneCards	CDK5
Human Protein Atlas	CDK5
Associated Diseases	Aging, Als, Alzheimer, Alzheimer's disease, Ataxia
Known Drugs/Compounds	metformin, METFORMIN, N-ACETYLCYSTEINE, Protopanaxatriol, RESVERATROL
Interactions	ABETA, ACHE, Actin, AD, AGING, AKT
SciDEX Hypotheses	CDK5 Inhibition at Presynaptic Terminals Prevents CDK5 Inhibition Blocks Activity-Dependent Tau Prop
KG Connections	772 knowledge graph edges
Databases	GeneCards UniProt NCBI Gene HPA STRING

Wiki Pages (10)

Knowledge base pages for this entity

Canonical Page

Pathway Diagram

graph TD
    CDK5["CDK5"] -.->|"inhibits"| BECN1["BECN1"]
    CDK5["CDK5"] -->|"interacts"| Ms["Ms"]
    CDK5["CDK5"] -->|"activates"| Als["Als"]
    CDK5["CDK5"] -->|"therapeutic target"| Alzheimer["Alzheimer"]
    CDK5["CDK5"] -.->|"inhibits"| Neurodegeneration["Neurodegeneration"]
    CDK5["CDK5"] -->|"activates"| Ms_1["Ms"]
    DCX["DCX"] -->|"interacts"| CDK5["CDK5"]
    PAFAH1B1["PAFAH1B1"] -->|"interacts"| CDK5["CDK5"]
    DAB1["DAB1"] -->|"interacts"| CDK5["CDK5"]
    LIS1["LIS1"] -->|"interacts"| CDK5["CDK5"]
    style CDK5 fill:#006494,stroke:#4fc3f7,stroke-width:2px,color:#e0e0e0

Outgoing (545)

Target	Relation	Type	Str
benchmark_ot_ad_answer_key:CDK5	data_in	dataset_row	0.00
benchmark_ot_ad_answer_key:CDK5	data_in	dataset_row	0.00
ds-83b31ef18d49	provides_data_for	dataset	1.00
tau packaging into exosomes	regulates	process	0.90
TAU hyperphosphorylation	causes	process	0.90
NR2B	phosphorylates	protein	0.90
Tau aggregation	mediates	process	0.90
glutamate_signaling	regulates	process	0.90
NMDA_receptor_internalization	phosphorylates	protein	0.90
PSD-95	phosphorylates	protein	0.90
Synapsin-1	phosphorylates	protein	0.90
Alzheimer's disease	involved_in	disease	0.85
NEURONAL MIGRATION	regulates	entity	0.85
Hyperthyroidism	associated_with	disease	0.85
mitochondrial_division	induces	process	0.80
cell cycle	regulates	process	0.80
p25	activates	protein	0.80
Neurodegeneration	associated_with	disease	0.80
Als	activates	disease	0.75
Alzheimer	therapeutic_target	disease	0.75
Als	expressed_in	disease	0.75
PARKINSON'S DISEASE	associated_with	disease	0.75
Nucleokinesis	involved_in	process	0.75
PSEN1	expresses	gene	0.70
TNF	activates	gene	0.70
TREM2	activates	gene	0.70
GFAP	regulates	gene	0.70
CREB	activates	gene	0.70
TAU	expresses	gene	0.70
UNFOLDED PROTEIN RESPONSE	activates	pathway	0.70
GSK3B	inhibits	gene	0.70
NEURONS	expresses	cell_type	0.70
CREB	inhibits	gene	0.70
PSEN2	associated_with	gene	0.70
ENDOTHELIAL	activates	cell_type	0.70
SV2A phosphorylation	activates	mechanism	0.70
tau hyperphosphorylation	regulates	mechanism	0.70
memory consolidation	regulates	process	0.70
tau phosphorylation	causes	process	0.70
tau pathology	activates	mechanism	0.70
TAU Aggregation	activates	phenotype	0.70
tau phosphorylation at Ser202/Thr231	causes	mechanism	0.70
synaptophysin phosphorylation	activates	mechanism	0.70
GSK3	associated_with	gene	0.70
NEURODEGENERATION	associated_with	phenotype	0.70
GSK3	activates	gene	0.70
tau	phosphorylates	protein	0.70
Wnt signaling	participates_in	pathway	0.70
tau hyperphosphorylation	causes	mechanism	0.70
BECN1	inhibits	protein	0.70

Incoming (251)

Source	Relation	Type	Str
amyloid_plaques	activates	pathological_structure	0.00
entities-overview	associated_with	wiki	0.00
benchmark_ot_ad_answer_key:CDK5	data_in	dataset_row	0.00
benchmark_ot_ad_answer_key:CDK5	data_in	dataset_row	0.00
ds-83b31ef18d49	data_in	dataset	1.00
Protopanaxatriol	inhibits	compound	0.90
10588725	associated with and was activated by	paper	0.90
10588725	is a functional homologue of	paper	0.90
10588725	associates with and is activated by	paper	0.90
10588725	is activated by	paper	0.90
Hyperthyroidism	upregulates	disease	0.85
E2F1	regulates	gene	0.80
ABETA	activates	protein	0.80
RESVERATROL	modulates	drug	0.75
BDNF	expressed_in	gene	0.70
AMYOTROPHIC LATERAL SCLEROSIS	activates	disease	0.70
AMPK	inhibits	gene	0.70
BDNF	associated_with	gene	0.70
APP	causes	gene	0.70
ACHE	inhibits	gene	0.70
APP	expresses	gene	0.70
ADAM10	expresses	gene	0.70
neuroinflammation	activates	process	0.70
amyloid-beta	activates	protein	0.70
Aβ deposition	activates	pathology	0.70
TAU	associated_with	protein	0.70
TAU	activates	protein	0.70
NEURONS	inhibits	cell_type	0.65
NEURONS	causes	cell_type	0.65
APOPTOSIS	treats	phenotype	0.65
NEURONS	regulates	cell_type	0.65
BDNF	co_discussed	gene	0.65
METFORMIN	inhibits	drug	0.65
GABA	interacts_with	phenotype	0.65
SOD1	treats	gene	0.65
N-ACETYLCYSTEINE	inhibits	drug	0.65
CALCIUM SIGNALING	regulates	pathway	0.65
AMPK	phosphorylates	gene	0.65
AMPK	causes	gene	0.65
AMPK	activates	gene	0.65
AMPK	regulates	gene	0.65
BACE1	expressed_in	gene	0.65
N-ACETYLCYSTEINE	treats	drug	0.65
AKT	expressed_in	gene	0.65
N-ACETYLCYSTEINE	activates	drug	0.65
OXIDATIVE STRESS	activates	phenotype	0.65
ALZHEIMER'S DISEASE	associated_with	disease	0.64
GENES	associated_with	gene	0.60
INS	associated_with	gene	0.60
AD	interacts_with	gene	0.60

Targeting Hypotheses (6)

Hypotheses where this entity is a therapeutic target

Hypothesis	Score	Disease	Analysis
Gamma entrainment enhances TREM2-mediated microglial clearan	0.678	alzheimers	Gamma entrainment therapy to restore hip
CDK5 Inhibition at Presynaptic Terminals Prevents Activity-D	0.640	neurodegeneration	Investigate prion-like spreading of tau
CDK5 Inhibition Blocks Activity-Dependent Tau Propagation	0.620	neurodegeneration	Test Preregistration Analysis
Aβ42 oligomers drive TDP-43 phosphorylation at s409/410 thro	0.595	neurodegeneration	What mechanisms drive TDP-43 pathology s
A post-trigger CDK5-dominant kinase feedback loop maintains	0.590	neurodegeneration	Does tau dendritic missorting persist in

Cdk5/p25-PSD-95 Phosphorylation Disrupts Synaptic Scaffoldin	0.455	neurodegeneration	Quantitative proteomics of the aging syn

Mentioning Analyses (15)

Scientific analyses that reference this entity

Experiments (0)

Experimental studies targeting or related to this entity

Experiment	Type	Disease	Score	Feasibility	Model	Status	Est. Cost
No experiments found

Related Papers (0)

Scientific publications cited in analyses involving this entity

Title & PMID	Authors	Journal	Year	Citations
No papers found

Debates (20)

Multi-agent debates referencing this entity

Related Research

Hypotheses and analyses mentioning CDK5 in their description or question text

Cdk5/p25-PSD-95 Phosphorylation Disrupts Synaptic Scaffolding and Shifts APP Pro

Score: 0.455 · neurodegeneration · 2026-04-27

Age-dependent p35-to-p25 cleavage activates Cdk5, which phosphorylates PSD-95 S561, disrupting AMPA/NMDA receptor anchor

CDK5

Understanding Entity Pages

Summary

Wiki Pages (10)

Cdk5 (Cyclin-Dependent Kinase 5)

CDK5 Protein

CDK5R1 Gene

Cyclin-Dependent Kinase 5 (CDK5)

CDK5R1 (p35/p25, CDK5 Activator 1)

CDK5 Inhibitors for Neurodegeneration

CDK5R2 Protein

CDK5R2 Gene

CDK5 Gene

CDK5 Protein (Cyclin-Dependent Kinase 5)

Pathway Diagram

Outgoing (545)

Incoming (251)

Targeting Hypotheses (6)

Mentioning Analyses (15)

Test Preregistration Analysis

Can CSF p-tau217 normalization serve as a reliable surrogate endpoint for determ

Does tau dendritic missorting persist independently after Aβ clearance, maintain

What molecular mechanisms enable Gal3 to enhance tau fibrillation upon binding t

Does tau aggregation specifically cause PS externalization in vesicles independe

What evidence supports Cdk5 activation as THE primary cause of AD versus other e

What molecular mechanisms determine the conformational diversity and strain-like

Quantitative proteomics of the aging synapse in early Alzheimer disease

Epigenetic reprogramming in aging neurons

Investigate prion-like spreading of tau pathology through connected brain region

Tau propagation mechanisms and therapeutic interception points

Gene expression changes in aging mouse brain predicting neurodegenerative vulner

Circuit-level neural dynamics in neurodegeneration

APOE4 structural biology and therapeutic targeting strategies

4R-tau strain-specific spreading patterns in PSP vs CBD

Experiments (0)

Related Papers (0)

Debates (20)

Test question for preregistration

Extended debate: Closed-loop transcranial focused ultrasound with 40Hz gamma ent

Extended debate: Closed-loop tACS targeting EC-II SST interneurons to block tau

Debate: Closed-loop transcranial focused ultrasound targeting entorhinal PV inte

Debate: Chromatin Remodeling-Mediated Nutrient Sensing Restoration

Debate: Closed-loop tACS targeting EC-II SST interneurons to block tau propagati

Debate: Closed-loop transcranial focused ultrasound to restore hippocampal gamma

Debate: Closed-loop tACS targeting EC-II PV interneurons to suppress burst firin

Debate: Closed-loop tACS targeting EC-II somatostatin interneurons to restore de

Debate: Closed-loop transcranial focused ultrasound with real-time gamma feedbac

Related Research

Cdk5/p25-PSD-95 Phosphorylation Disrupts Synaptic Scaffolding and Shifts APP Pro