Type-1 Cannabinoid Receptor Activity During Alzheimer's Disease Progression

Abstract

The activity of CB1 cannabinoid receptors was studied in postmortem brain samples of Alzheimer's disease (AD) patients during clinical deterioration. CB1 activity was higher at earlier AD stages in limited hippocampal areas and internal layers of frontal cortex, but a decrease was observed at the advanced stages. The pattern of modification appears to indicate initial hyperactivity of the endocannabinoid system in brain areas that lack classical histopathological markers at earlier stages of AD, indicating an attempt to compensate for the initial synaptic impairment, which is then surpassed by disease progression. These results suggest that initial CB1 stimulation might have therapeutic relevance.

Genetic deletion of CB1 cannabinoid receptors exacerbates the Alzheimer-like symptoms in a transgenic animal model

“…Interestingly, a similar reduction in CB1 levels was observed in both human and animal models brains at advanced stages of the AD, in contrast with the increase in CB1 expression during the asymptomatic stages (Aso et al, 2012a;Manuel et al, 2014). These findings suggest an attempt of CB1 receptor to compensate for the initial synaptic impairment occurring at the early asymptomatic stages of AD and reinforce the hypothesis that targeting the CB1 receptor could offer a strategy against AD.…”

“…AD is the most common form of dementia, histologically characterized by the dysfunctional accumulation of amyloid-β peptide (Aβ) and tau hyper-phosphorylation in major brain regions contributing to memory and cognition (Ferrer, 2012;Selkoe, 2012). Alterations in the expression or functionality of CB1 receptors have been described both in AD patients' brains (Ramírez et al, 2005;Solas et al, 2013;Manuel et al, 2014) and AD animal models (Kalifa et al, 2011;Aso et al, 2012a).…”

[18F]FMPEP-d2 PET imaging shows age- and genotype-dependent impairments in the availability of cannabinoid receptor 1 in a mouse model of Alzheimer's disease

“…6). Consequently, our results suggest the need to monitor CB 1 R-associated pathology also in younger AD Our results are in line with a previous study in which postmortem brain samples from AD patients exhibited impaired CB 1 R function in the HIPPO and FC, followed by decreased CB 1 R density at advanced stages of AD (Manuel et al, 2014). Altered CB 1 R activity was not a consequence of reductions in receptor density, as seen in another report (Oddi et al, 2011) and in the present study.…”

Endocannabinoids

“…These alterations have been interpreted in two ways. On the one hand, the loss of neuronal CB 1 receptors and the elevation of FAAH may contribute to the progression of AD pathogenesis by enhancing the vulnerability of specific groups of cortical and subcortical neurons to different neurotoxic stimuli (D'Addario et al 2012;Manuel et al 2014). On the other hand, the increase in 2-AG and the upregulation of microglial CB 2 receptors may protect against β-amyloid-induced neuroinflammation and neuronal injury (Benito et al 2003;Ramírez et al 2005).…”