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Free keywords:
Age Factors
Alzheimer Disease/*complications/*genetics/pathology
Amyloid beta-Peptides/*metabolism
Amyloid beta-Protein Precursor/genetics
Animals
Body Weight/genetics
Brain/*metabolism/pathology
Cell Line, Tumor
Cognition Disorders/*etiology
Disease Models, Animal
Gene Expression Regulation/genetics
Humans
Maze Learning/physiology
Mice
Mice, Transgenic
Microglia/metabolism/pathology
Mutation/genetics
Peptide Fragments/*metabolism
Receptor, Cannabinoid, CB1/*deficiency
APP processing
App23
Alzheimer's disease
Cb1
Endocannbinoid system
Learning and memory
Abstract:
Alzheimer's disease (AD) is characterized by amyloid-beta 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 in vitro. 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.
