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Activation of the Cannabinoid Type 2 Receptor by a Novel Indazole Derivative Normalizes the Survival Pattern of Lymphoblasts from Patients with Late-Onset Alzheimer’s Disease

Abstract

Background

Alzheimer’s disease is a multifactorial disorder for which there is no disease-modifying treatment yet. CB2 receptors have emerged as a promising therapeutic target for Alzheimer’s disease because they are expressed in neuronal and glial cells and their activation has no psychoactive effects.

Objective

The aim of this study was to investigate whether activation of the CB2 receptor would restore the aberrant enhanced proliferative activity characteristic of immortalized lymphocytes from patients with late-onset Alzheimer’s disease. It is assumed that cell-cycle dysfunction occurs in both peripheral cells and neurons in patients with Alzheimer’s disease, contributing to the instigation of the disease.

Methods

Lymphoblastoid cell lines from patients with Alzheimer’s disease and age-matched control individuals were treated with a new, in-house-designed dual drug PGN33, which behaves as a CB2 agonist and butyrylcholinesterase inhibitor. We analyzed the effects of this compound on the rate of cell proliferation and levels of key regulatory proteins. In addition, we investigated the potential neuroprotective action of PGN33 in β-amyloid-treated neuronal cells.

Results

We report here that PGN33 normalized the increased proliferative activity of Alzheimer’s disease lymphoblasts. The compound blunted the calmodulin-dependent overactivation of the PI3K/Akt pathway, by restoring the cyclin-dependent kinase inhibitor p27 levels, which in turn reduced the activity of the cyclin-dependent kinase/pRb cascade. Moreover, this CB2 agonist prevented β-amyloid-induced cell death in neuronal cells.

Conclusion

Our results suggest that the activation of CB2 receptors could be considered a useful therapeutic approach for Alzheimer’s disease.

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Correspondence to Nuria E. Campillo or Ángeles Martín-Requero.

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Funding

This work has been supported by a Grant from Ministerio de Economía y Competitividad (CTQ2015-66313-R). FB is supported by a Sara Borrell fellowship from the Spanish Instituto de Salud Carlos III.

Conflict of interest

Patricia del Cerro, Carolina Alquézar, Fernando Bartolomé, Pedro González-Naranjo, Concepción Pérez, Eva Carro, Juan A. Páez, Nuria E. Campillo, and Ángeles Martín-Requero have no conflicts of interest directly relevant to the content of this article.

Ethics Approval

All study protocols were approved by the Hospital Doce de Octubre de Madrid and the Spanish Council of Higher Research Institutional Advisory Board, and were in accordance with national and European Union guidelines.

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In all cases, peripheral blood samples were taken after written informed consent was obtained from patients or their relatives.

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del Cerro, P., Alquézar, C., Bartolomé, F. et al. Activation of the Cannabinoid Type 2 Receptor by a Novel Indazole Derivative Normalizes the Survival Pattern of Lymphoblasts from Patients with Late-Onset Alzheimer’s Disease. CNS Drugs 32, 579–591 (2018). https://doi.org/10.1007/s40263-018-0515-7

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