Drug Development

Area of Science:

• Neuroscience
• Pharmacology
• Alzheimer's Disease Research

Background:

• Chronic neuroinflammation is a key driver of Alzheimer's disease (AD) pathogenesis, leading to cognitive and mood decline.
• Current Alzheimer's therapies are limited in their ability to halt disease progression.
• Psilocybin, known for its efficacy in treating depression, demonstrates potential in reducing neuroinflammation and promoting hippocampal neurogenesis.

Purpose of the Study:

• To investigate the efficacy of psilocybin in mitigating cognitive decline in a 5x familial Alzheimer's disease (5xFAD) mouse model.
• To assess psilocybin's impact on neuroinflammation, neurogenesis, and synaptic function in the context of AD.

Main Methods:

• Monthly administration of psilocybin (0.5mg/Kg) or vehicle to 5xFAD mice for 4 months.
• Neurobehavioral testing to evaluate cognitive and mood functions post-treatment.
• Analysis of brain tissues for neuroinflammation markers, hippocampal neurogenesis, synapse loss, and amyloid-beta plaques; hippocampal proteomics was also performed.

Main Results:

• Psilocybin-treated mice showed enhanced cognitive functions, including pattern separation and associative recognition memory, and lacked anhedonia compared to vehicle-treated controls.
• Significant reductions in neuroinflammatory markers (NLRP3 inflammasome, p38 MAPK, cGAS-STING signaling) were observed in psilocybin-treated mice.
• Increased neurogenesis, improved BDNF-ERK-CREB signaling, and preserved synaptic proteins were noted, alongside proteomic evidence of upregulated proteins involved in neuroinflammation, mTOR signaling, and synaptic function.

Conclusions:

• Psilocybin treatment effectively maintained cognitive function in an AD mouse model without altering amyloid-beta plaque load.
• The observed cognitive benefits are attributed to psilocybin-induced reduction in neuroinflammation, enhanced hippocampal neurogenesis, and synaptic preservation.