TY - JOUR
T1 - Cannabinoid receptor 1 deficiency in a mouse model of Alzheimer's disease leads to enhanced cognitive impairment despite of a reduction in amyloid deposition
AU - Stumm, Christoph
AU - Hiebel, Christof
AU - Hanstein, Regina
AU - Purrio, Martin
AU - Nagel, Heike
AU - Conrad, Andrea
AU - Lutz, Beat
AU - Behl, Christian
AU - Clement, Angela B.
PY - 2013/11
Y1 - 2013/11
N2 - 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.
AB - 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.
KW - APP processing
KW - APP23
KW - Alzheimer's disease
KW - CB1
KW - Endocannbinoid system
KW - Learning and memory
UR - http://www.scopus.com/inward/record.url?scp=84881542568&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84881542568&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2013.05.027
DO - 10.1016/j.neurobiolaging.2013.05.027
M3 - Article
C2 - 23838176
AN - SCOPUS:84881542568
SN - 0197-4580
VL - 34
SP - 2574
EP - 2584
JO - Neurobiology of Aging
JF - Neurobiology of Aging
IS - 11
ER -