Medium-Dose Chronic Cannabidiol Treatment Reverses Object Recognition Memory Deficits of APP Swe /PS1ΔE9 Transgenic Female Mice.

Madilyn Coles,Tim Karl,Georgia Watt,Fabian Kreilaus

doi:10.3389/fphar.2020.587604

Madilyn Coles, Tim Karl + Show 2 more

Open Access

https://doi.org/10.3389/fphar.2020.587604

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Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease that causes behavioral and cognitive impairments. The phytocannabinoid cannabidiol (CBD) has anti-inflammatory, antioxidant, and neuroprotective properties, and in vitro and limited in vivo evidence suggests that CBD possesses therapeutic-like properties for the treatment of AD. Cannabinoids are known to have dose-dependent effects and the therapeutic potential of medium-dose CBD for AD transgenic mice has not been assessed in great detail yet. 12-month-old control and APP Swe /PS1ΔE9 (APPxPS1) transgenic female mice were treated daily via intraperitoneal injection with 5 mg/kg bodyweight CBD (or vehicle) commencing three weeks prior to the assessment of behavioral domains including anxiety, exploration, locomotion, motor functions, cognition, and sensorimotor gating. APPxPS1 mice exhibited a hyperlocomotive and anxiogenic-like phenotype and had wild type-like motor and spatial learning abilities, although AD transgenic mice took generally longer to complete the cheeseboard training (due to a lower locomotion speed). Furthermore spatial learning and reversal learning was delayed by one day in APPxPS1 mice compared to control mice. All mice displayed intact spatial memory and retrieval memory, but APPxPS1 mice showed reduced levels of perseverance in the cheeseboard probe trial. Importantly, vehicle-treated APPxPS1 mice were characterized by object recognition deficits and delayed spatial learning, which were reversed by CBD treatment. Finally, impairments in sensorimotor gating of APPxPS1 mice were not affected by CBD. In conclusion, medium-dose CBD appears to have therapeutic value for the treatment of particular behavioral impairments present in AD patients. Future research should consider the molecular mechanisms behind CBD’s beneficial properties for AD transgenic mice.

Highlights

Alzheimer’s disease (AD) is an insidious neurodegenerative disease that is caused by progressive damage to neuronal cells and results in irreversible cognitive and behavioral deficits including memory loss, spatial disorientation, and language impairments
This study demonstrated that chronic administration of a medium dose of 5 mg/kg CBD reversed novel object recognition deficits in 12-month-old female double transgenic APPxPS1 mice
Spatial learning and reversal learning was delayed in APPxPS1 mice by one day when considering performance across three daily trials compared to wild type-like littermates (WT) mice on a day-to-day basis the acoustic startle response (ASR) of all mice was similar but APPxPS1 transgenic mice showed a deficit in prepulse inhibition (PPI)

Summary

Introduction

Alzheimer’s disease (AD) is an insidious neurodegenerative disease that is caused by progressive damage to neuronal cells and results in irreversible cognitive and behavioral deficits including memory loss, spatial disorientation, and language impairments. Often a verified diagnosis of AD can only be made postmortem, with the two main pathological hallmarks of AD being (1) the extracellular accumulation of amyloid-beta (Aβ) protein fragments around the neurons in the brain, forming Aβ plaques, and (2) the intracellular accumulation of hyperphosphorylated microtubule-associated protein tau (MAPT), forming neurofibrillary tangles (NFT). Familial AD is estimated to represent less than 5% of all AD cases and results from the inheritance of an autosomal dominant mutation in the genes encoding amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2), the latter two being enzymes participating in the processing of APP. Mutations in APP, PS1, and PS2 result in the aberrant cleavage of APP into Aβ peptides of 40 residues (Aβ40) or of 42 residues (Aβ42), which are thought to form toxic Aβ plaques responsible for causing neuronal cell death in AD (Hardy and Higgins, 1992)

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