The Down-Expression of ACE and IDE Exacerbates Exogenous Amyloid-β Neurotoxicity in CB2R –/– Mice

Abstract

Alzheimer’s disease (AD) is characterized by neuritic plaques and neurofibrillary tangles. It is reported that enzymatic degradation of amyloid-β (Aβ) plays a pivotal role in Aβ accumulation and type-2 cannabinoid receptor (CB2R) participates in Aβ processing in the brain; however, the underlying mechanisms remain unclear. We determined that Aβ 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 Aβ level is significantly enhanced in CB2R^–/–-Aβ_1 - 42 mice compared with that of WT-Aβ_1 - 42 mice. Furthermore, Aβ-mediated synaptic dysfunction, the loss of memory associated proteins, and the suppression of glutamatergic transmission are more severe in CB2R^–/–-Aβ_1 - 42 mice than that in WT-Aβ_1 - 42 mice. CB2R activation could decrease Aβ_1 - 40 and Aβ_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 AβPP overexpression. Taken together, our study demonstrated that the deletion of CB2R reduces exogenous Aβ degradation and aggravates the toxicity of Aβ 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.