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Targeting Cannabinoid Receptor Activation and BACE-1 Activity Counteracts TgAPP Mice Memory Impairment and Alzheimer’s Disease Lymphoblast Alterations

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Abstract

Alzheimer’s disease (AD), the leading cause of dementia in the elderly, is a neurodegenerative disorder marked by progressive impairment of cognitive ability. Patients with AD display neuropathological lesions including senile plaques, neurofibrillary tangles, and neuronal loss. There are no disease-modifying drugs currently available. With the number of affected individuals increasing dramatically throughout the world, there is obvious urgent need for effective treatment strategy for AD. The multifactorial nature of AD encouraged the development of multifunctional compounds, able to interact with several putative targets. Here, we have evaluated the effects of two in-house designed cannabinoid receptors (CB) agonists showing inhibitory actions on β-secretase-1 (BACE-1) (NP137) and BACE-1/butyrylcholinesterase (BuChE) (NP148), on cellular models of AD, including immortalized lymphocytes from late-onset AD patients. Furthermore, the performance of TgAPP mice in a spatial navigation task was investigated following chronic administration of NP137 and NP148. We report here that NP137 and NP148 showed neuroprotective effects in amyloid-β-treated primary cortical neurons, and NP137 in particular rescued the cognitive deficit of TgAPP mice. The latter compound was able to blunt the abnormal cell response to serum addition or withdrawal of lymphoblasts derived from AD patients. It is suggested that NP137 could be a good drug candidate for future treatment of AD.

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Acknowledgments

We thank G. Porras for technical assistance. The help of Sonia Diaz Pacheco in the management and treatment of TgAPP mice is acknowledged.

Authorship Contributions

Participated in research design: JAP, MLC, NEC, and A M-R

Conducted experiments: EN-B, PGN, AR-S, CP, FB, CA, and MLC

Contributed new cannabinoids: JAP and PGN

Performed data analysis: All authors contributed to data analysis

Wrote or contributed to the writing of the manuscript: MLC, NEC, and AM-R

Funding

This work has been supported by grants from Ministerio de Economía y Competitividad (CTQ2015-66313-R, and RTI2018-096100-B-I00) and CIBERNED to MLC.

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Author notes

  1. Emilio Nuñez-Borque and Pedro González-Naranjo contributed equally to this work.

Authors and Affiliations

  1. Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain

    Emilio Nuñez-Borque, Carolina Alquézar, Alejandro Reinares-Sebastián, Nuria E. Campillo & Ángeles Martín-Requero

  2. Instituto de Química Médica (CSIC), Madrid, Spain

    Pedro González-Naranjo, Concepción Pérez & Juan A. Páez

  3. Neurodegenerative Disorders Group, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain

    Fernando Bartolomé

  4. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    Fernando Bartolomé, Maria L. Ceballos & Ángeles Martín-Requero

  5. Department of Neurology, Memory and Aging Center, University of California, Box 1207, San Francisco, CA, 94158, USA

    Carolina Alquézar

  6. Insituto Cajal (CSIC), Madrid, Spain

    Maria L. Ceballos

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  1. Emilio Nuñez-Borque
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  2. Pedro González-Naranjo
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  10. Ángeles Martín-Requero
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Corresponding authors

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

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All study protocols were approved by the Hospital Doce de Octubre and the Spanish Council of Higher Research Institutional Review Board and are in accordance with National and European Union Guidelines. In all cases, peripheral blood samples were taken after written informed consent of the patients or their relatives.

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Nuñez-Borque, E., González-Naranjo, P., Bartolomé, F. et al. Targeting Cannabinoid Receptor Activation and BACE-1 Activity Counteracts TgAPP Mice Memory Impairment and Alzheimer’s Disease Lymphoblast Alterations. Mol Neurobiol 57, 1938–1951 (2020). https://doi.org/10.1007/s12035-019-01813-4

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