Endocannabinoids and neuroprotection in an in vitro model of Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterised by the progressive deterioration of cognition and memory as a result of selective neuronal loss in the hippocampus and surrounding areas of the cerebral cortex. There is now substantial evidence to suggest that at least a subset of neurones in the AD brain die due to inappropriate apoptosis, triggered by β-amyloid (Aβ) toxicity. Under normal conditions lysosomes have the propensity to degrade Aβ peptides, but in the AD brain a gradual dysfunction of the lysosomal system is evident which results in an Aβ load. It has recently emerged that lysosomal membrane permeability plays a vital role in executing as well as initiating the apoptotic pathway, while disturbances in the lysosomal system are one of the earliest known intracellular manifestations of AD. Thus, understanding the molecular pathway underlying lysosomal membrane permeability could be key to preventing the neuronal cell loss that occurs in AD. The endocannabinoid system has emerged as a promising new area of research for the treatment of AD. Numerous studies have identified neuroprotective roles of endocannabinoids against excitotoxicity, oxidative stress and inflammation; all key pathological events in the AD brain. Moreover, the overlap between CB1 receptors and AD pathology suggests a role for this system in AD pathogenesis. Thus, the aims of this study were to establish (i) whether Aβ impacts on lysosomes to evoke lysosomal membrane permeability and cell death, (ii) to understand the molecular mechanisms that result in lysosomal membrane permeability, (iii) to investigate the proclivity of endocannabinoids to protect against Aβ toxicity.