CDK5 Targeting as a Therapy for Recovering Neurovascular Unit Integrity in Alzheimer’s Disease
Abstract
The neurovascular unit (NVU) is responsible for synchronizing the energetic demand, vasodynamic changes, and neurochemical and electrical function of the brain through a closed and interdependent interaction of cell components conforming to brain tissue. In this review, we will focus on cyclin-dependent kinase 5 (CDK5) as a molecular pivot, which plays a crucial role in the healthy function of neurons, astrocytes, and the endothelium and is implicated in the cross-talk of cellular adhesion signaling, ion transmission, and cytoskeletal remodeling, thus allowing the individual and interconnected homeostasis of cerebral parenchyma. Then, we discuss how CDK5 overactivation affects the integrity of the NVU in Alzheimer’s disease (AD) and cognitive impairment; we emphasize how CDK5 is involved in the excitotoxicity spreading of glutamate and Ca2+ imbalance under acute and chronic injury. Additionally, we present pharmacological and gene therapy strategies for producing partial depletion of CDK5 activity on neurons, astrocytes, or endothelium to recover neuroplasticity and neurotransmission, suggesting that the NVU should be the targeted tissue unit in protective strategies. Finally, we conclude that CDK5 could be effective due to its intervention on astrocytes by its end feet on the endothelium and neurons, acting as an intermediary cell between systemic and central communication in the brain. This review provides integrated guidance regarding the pathogenesis of and potential repair strategies for AD.
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NVU integrity depends on endothelial cells, astrocytes, microglia, and mural cells, and its dysfunction contributes to AD pathogenesis.
“These mechanisms are closely linked to neurovascular unit (NVU) integrity, which depends on endothelial cells, astrocytes, microglia, and mural cells, and whose dysfunction contributes to AD pathogenesis. 9 , 10”
NVU dysfunction is a key regulator of brain-periphery communication and is implicated in AD pathogenesis.
“As NVU dysfunction, a key regulator of brain–periphery communication, is implicated in AD pathogenesis, biomarkers capturing early NVU alterations, including those from systemic or peripheral factors, are needed.”
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Molecular mechanisms of Alzheimer’s disease: From therapeutic targets to promising drugs
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Self-citation
- Authors
- Posada-Duque, R. A., & Cardona-Gómez, G. P.
- Affiliations
- Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, SIU, University of Antioquia, Medellín, Colombia
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2021-06-22
- Volume
- 82
- Issue
- s1
- Pages
- S141-S161
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W3091311627
- Cited by
- 14
- References
- 11
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 2
- FWCI
- 0.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- cyclin-dependent kinase 5, neurovascular unit
- MeSH terms
- Neurovascular Coupling, Animals, Astrocytes, Clinical Trials as Topic, Humans, Drug Delivery Systems, Gene Silencing, Protein Kinase Inhibitors, Cyclin-Dependent Kinase 5
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