Effects of Chronic 100 mg/kg Cannabidiol Treatment in Male Double Transgenic APPSwe/PS1∆E9 Mice

<b>Background/Objectives</b>: Alzheimer's disease (AD) is a neurodegenerative disease for which there are no highly effective treatments, which highlights the need for novel therapeutics. Cannabidiol (CBD) has demonstrated antioxidant, anti-inflammatory and neuroprotective properties. Chronic CBD treatment (20 mg/kg and 50 mg/kg) reverses social recognition memory deficits of <i>APP_Swe/PS1∆E9</i> (<i>APP/PS1</i>) transgenic mice; however, it does not produce effects on AD-relevant brain pathology. <b>Methods</b>: Here, we investigated whether chronic high-dose CBD treatment (i.e., 100 mg/kg intraperitoneally) in early symptomatic 7.5-month-old <i>APP/PS1</i> males would reverse cognitive deficits while also influencing neuropathological markers relevant to AD. Mice were assessed for anxiety, recognition memory, and social and aggressive behaviours before carrying out neuropathological analyses of collected brain tissue. <b>Results</b>: Vehicle-treated <i>APP/PS1</i> transgenic males demonstrated reduced aggressive behaviour and increased socio-positive behaviour. A moderate deficit in social recognition memory was restored by CBD. <i>APP/PS1</i> mice also exhibited elevated cortical proBDNF levels under vehicle treatment, and hippocampal levels of TNF-α and IL-1β were reduced in all <i>APP/PS1</i> mice. AD transgenic mice exhibited no changes in soluble or insoluble Aβ₄₂ levels or PPARγ isoforms. <b>Conclusions</b>: This study found that high-dose CBD restored a moderate social recognition memory deficit. However, CBD did not have marked effects on AD-relevant neuropathological markers assessed, most likely because the AD transgenic mice were evaluated at a disease stage too early to detect significant pathological changes. Thus, the underlying mechanisms for CBD's effect on social recognition memory require further investigation.