INVESTIGATING THE THERAPEUTIC POTENTIAL OF PSILOCYBIN IN A PRECLINICAL MODEL OF ALZHEIMER’S DISEASE

Alzheimer's disease (AD) is the most common form of neurodegenerative dementia, characterised by irreversible cognitive decline. Most AD patients also suffer from depression, but current antidepressants show limited therapeutic efficacy. Recently, the serotonergic psychedelic psilocybin has received considerable interest for its long-lasting antidepressant effects, even in non-responders to conventional treatments. Psilocybin is also associated with anti-inflammatory effects, increased brain-derived neurotrophic factor (BDNF), and improvement of cognitive performance. Since AD progression is marked by increased inflammation and decreased neurotrophic signalling, we hypothesise that in a model of AD psilocybin might alleviate depressive symptoms and improve cognition by modulating these pathways.
To test this hypothesis, we used female triple transgenic 3xTg-AD mice (APPSwe/TauP301L; PSEN1 M146V knock-in), which develop progressive AD pathology. 3xTg-AD mice received two injections of either saline or psilocybin (1mg/kg; day 1 and 7) and were tested in a battery of behavioural paradigms (days 8-20) assessing depressive-like behaviour and cognitive abilities. Performance was compared to wildtype controls receiving two saline injections. Two cohorts of 7- and 10-month-old mice were used to capture different disease stages. In a third cohort of 10-month-old mice, levels of plasma inflammatory markers and BDNF were quantified 2 hours or 3 days after a single saline or psilocybin injection via Meso Scale Discovery assays.
These experiments characterise the long-term effects of psilocybin on cognition and depressive-like behaviour in a preclinical model of AD. In parallel, measures of inflammatory and neurotrophic signalling provide insights into candidate pathways for psilocybin’s potential therapeutic effects in this disease model.