Cannabinoid receptor 1 deficiency in a mouse model of Alzheimer's disease leads to enhanced cognitive impairment despite of a reduction in amyloid deposition

Christoph Stumm, Christof Hiebel, Regina Hanstein, Martin Purrio, Heike Nagel, Andrea Conrad, Beat Lutz, Christian Behl, Angela B. Clement

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Alzheimer's disease (AD) is characterized by amyloid-β deposition in amyloid plaques, neurofibrillary tangles, inflammation, neuronal loss, and cognitive deficits. Cannabinoids display neuromodulatory and neuroprotective effects and affect memory acquisition. Here, we studied the impact of cannabinoid receptor type 1 (CB1) deficiency on the development of AD pathology by breeding amyloid precursor protein (APP) Swedish mutant mice (APP23), an AD animal model, with CB1-deficient mice. In addition to the lower body weight of APP23/CB1-/- mice, most of these mice died at an age before typical AD-associated changes become apparent. The surviving mice showed a reduced amount of APP and its fragments suggesting a regulatory influence of CB1 on APP processing, which was confirmed by modulating CB1 expression invitro. Reduced APP levels were accompanied by a reduced plaque load and less inflammation in APP23/CB1-/- mice. Nevertheless, compared to APP23 mice with an intact CB1, APP23/CB1-/- mice showed impaired learning and memory deficits. These data argue against a direct correlation of amyloid plaque load with cognitive abilities in this AD mouse model lacking CB1. Furthermore, the findings indicate that CB1 deficiency can worsen AD-related cognitive deficits and support a potential role of CB1 as a pharmacologic target.

Original languageEnglish (US)
Pages (from-to)2574-2584
Number of pages11
JournalNeurobiology of Aging
Volume34
Issue number11
DOIs
StatePublished - Nov 1 2013

Keywords

  • APP processing
  • APP23
  • Alzheimer's disease
  • CB1
  • Endocannbinoid system
  • Learning and memory

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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