[¹²⁵I]SD-7015 reveals fine modalities of CB₁ cannabinoid receptor density in the prefrontal cortex during progression of Alzheimer's disease

Abstract

The cannabinoid type-1 receptor (CB₁R) is one of the most abundant members of the G protein-coupled receptor family in the central nervous system. Once activated by their cognate ligands, endocannabinoids, CB₁Rs generally limit the timing of neurotransmitter release at many cortical synapses. Prior studies have indicated the involvement of CB₁R in neurodegeneration and in various neuronal insults, with an emphasis on their neuroprotective role. In the present study we used a novel selective CB₁R radioligand to investigate regional variations in CB₁R ligand binding as a factor of progressive Braak tau pathology in the frontal cortex of Alzheimer's disease (AD) patients. The frontal cortex was chosen for this study due to the high density of CB₁Rs and their well-characterized involvement in the progression of AD. Post-mortem prefrontal cortex samples from AD patients from Braak stages I to VI and controls were subjected to CB₁R autoradiography with [¹²⁵I]SD-7015 as radioligand. Regional concentration of [¹²⁵I]SD-7015, corresponding to, and thereby representing, regional CB₁R densities, were expressed in fM/g_tissue. The results show that CB₁R density inversely correlates with Braak tau pathology with the following tendency: controls <AD Braak stage V-VI <AD Braak stage III-IV <AD Braak stage I-II. Differences were significant between control and AD Braak stage I-II groups, as well as between controls and the AD group comprising all Braak stages. These findings indicate an up-regulation of the tissue binding of the selective CB₁R radioligand [¹²⁵I]SD7015 in human brains, allowing the detection of fine modalities of receptor expression and radioligand binding during the progression of AD.

Fig. 1

Characteristic CB₁R autoradiographs of prefrontal cortex samples obtained with [¹²⁵I]-SD-7015 as radioligand. The scale bar is 10 mm. In the fourth column the specific binding images (shown in the third column as grey-scale images) are red weighted. Red arrow = white matter, black arrow = cortex.

Fig. 2

Age-ranges (horizontal lines) and CB₁R density ranges, expressed by the specific binding values of [¹²⁵I]SD7015, (vertical lines) for the four groups investigated in the present study (red: control, blue: Braak I–II, orange: Braak III– IV, green: Braak V–VI).