Format

Send to

Choose Destination
Mol Neurobiol. 2020 Jan 3. doi: 10.1007/s12035-019-01813-4. [Epub ahead of print]

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

Author information

1
Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain.
2
Instituto de Química Médica (CSIC), Madrid, Spain.
3
Neurodegenerative Disorders Group, Instituto de Investigación Hospital 12 de Octubre, Madrid, Spain.
4
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
5
Department of Neurology, Memory and Aging Center, University of California, Box 1207, San Francisco, CA, 94158, USA.
6
Insituto Cajal (CSIC), Madrid, Spain.
7
Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain. nuria.campillo@cscic.es.
8
Centro de Investigaciones Biológicas (CSIC), Ramiro de Maeztu 9, 28040, Madrid, Spain. amrequero@cib.csic.es.
9
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. amrequero@cib.csic.es.

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.

KEYWORDS:

Alzheimer’s disease; Cannabinoids; Cell proliferation; Cell survival; Lymphoblasts; Memory; TgAPP mice

PMID:
31898159
DOI:
10.1007/s12035-019-01813-4

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center