PSILOCYBIN AT LOW DOSES AS PROSPECTIVE EARLY INTERVENTION IN AD - A PROMISING RESULTS FROM 3XTG-AD MODEL

Alzheimer’s disease (AD) is characterized by progressive cognitive decline, metabolic dysregulation, neuroinflammation, and impaired brain waste clearance. Here, we show that long-term, weekly psilocybin administration at low doses exerts multi-level protective effects in the 3xTg-AD mouse model. Psilocybin significantly extended survival and prevented early AD-associated body mass loss, preserving lean, fat, and fluid compartments in 3xTg-AD without affecting wild-type animals. Cognitively, treated 3xTg-AD mice displayed improved spatial learning, working memory, and object recognition, counteracting age-dependent deterioration. Dynamic contrast–enhanced MRI revealed that psilocybin normalized blood–brain contrast dynamics and facilitated Gadovist wash-out from the brain parenchyma, indicating improved brain cleansing mechanisms consistent with possibly restored glymphatic-related clearance. These functional changes occurred without alterations in hippocampal or white matter volume. Histologically, psilocybin reduced astrogliosis, microgliosis, phosphorylated Tau, and amyloid-β accumulation in the hippocampus, improving cognitive functions, despite no observed adult hippocampal neurogenesis. Transcriptomic profiling of AD cortex showed selective upregulation of genes linked to circadian rhythm and neuroendocrine regulation, including avp and pmch, alongside geness involved in hormone secretion, calcium signaling, and G-protein–coupled receptor activity. Peripherally, psilocybin prevented splenomegaly and reduced pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IFN-γ). Mechanistically, in vitro psilocin modulated SIM-A9 microglia function by reducing TLR2 surface expression, altering amyloid-β phagocytosis dynamics, and preserving dendritic spine density in SIM-A9 cortical neuron co-culture. Together, these preliminary findings identify psilocybin at low dose as prospective early AD intervention with possible effect on modulation of brain clearance, neuroinflammation, and circadian–neuroendocrine signaling. Funded by NCN52021/40/C/NZ4/00326.