CDK5 Targeting as a Therapy for Recovering Neurovascular Unit Integrity in Alzheimer’s Disease

Issue title: Translational Research and Drug Discovery for Neurodegeneration: Challenges for Latin America

Guest editors: K.S. Jagannatha Rao, Gabrielle B. Britton, Luisa Lilia Rocha Arrieta, Norberto Garcia-Cairasco, Alberto Lazarowski, Adrián Palacios, Antoni Camins Espuny and Ricardo B. Maccioni

Article type: Review Article

Authors: Posada-Duque, Rafael Andrés^{a; b} | Cardona-Gómez, Gloria Patricia^{a; *}

Affiliations: [a] Cellular and Molecular Neurobiology Area, Group of Neuroscience of Antioquia, SIU, University of Antioquia, Medellín, Colombia | [b] Institute of Biology, Faculty of Exact and Natural Sciences, University of Antioquia, Medellín, Colombia

Correspondence: [*] Correspondence to: Gloria Patricia Cardona-Gómez, Calle 62 # 52-59 Torre 1 lab 412, Grupo de Neurociencias, SIU, Universidad de Antioquia, Medellín, Colombia. E-mail: [email protected].

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.

Keywords: Alzheimer’s disease, astrocytes, CDK5, endothelium, neuroprotection, neurovascular unit

DOI: 10.3233/JAD-200730

Journal: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S141-S161, 2021