Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 64, Issue 3, Pages 957-971Publisher
IOS PRESS
DOI: 10.3233/JAD-180142
Keywords
Alzheimer's disease; amyloid-beta degradation; angiotensin converting enzyme; type 2-cannabinoid receptors; insulin-degrading enzyme
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Funding
- National Nature Scientific Fund of China [81671262]
- Selfinnovation fund of HUST
- Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College, HUST
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Alzheimer's disease (AD) is characterized by neuritic plaques and neurofibrillary tangles. It is reported that enzymatic degradation of amyloid-beta (A beta) plays a pivotal role in A beta accumulation and type-2 cannabinoid receptor (CB2R) participates in A beta processing in the brain; however, the underlying mechanisms remain unclear. We determined that A beta degradation-related proteins are significantly different between CB2R(-/-) mice and wild-type (WT) mice via proteomic analysis. Moreover, the data demonstrated that the angiotensin converting enzyme (ACE) and insulin-degrading enzyme (IDE) levels are substantially attenuated, and the A beta level is significantly enhanced in CB2R(-/-)-A beta(1-42) mice compared with that of WT-A beta(1-42) mice. Furthermore, A beta-mediated synaptic dysfunction, the loss of memory associated proteins, and the suppression of glutamatergic transmission are more severe in CB2R(-/-)-A beta(1-42) mice than that in WT-A beta(1-42) mice. CB2R activation could decrease A beta(1-40) and A beta(1-42) levels and enhance ACE and IDE levels with its selective agonist JWH133; however, AM630 (CB2R antagonist) abrogates all changes induced by JWH133 in N2a cells with A beta PP overexpression. Taken together, our study demonstrated that the deletion of CB2R reduces exogenous A beta degradation and aggravates the toxicity of A beta via the reduction of ACE and IDE, which suggests that CB2R is involved in the onset of AD and a potential therapeutic target for AD.
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