Intranasal Administration of Ganoderma Lucidum-derived Exosome-like Nanovesicles Ameliorates Cognitive Impairment by Reducing Inflammation in a Mouse Model of Alzheimer's Disease

Xue Mi^1,2Xing-Lin Ruan³Ren-Yi Lin⁴Shu-Xin Huang⁵Ping Cai⁵Xiao-Chun Chen^2,3Jiangfeng Liao^6*Xiao-Man Dai^2,3*

• ¹Public Technology Service Center, Fujian Medical University., Fuzhou, China
• ²Fujian Key Laboratory of Molecular Neurology, Institute of Neuroscience, Fujian Medical University, Fuzhou, China
• ³Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, China
• ⁴School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, China
• ⁵School of Public Health, Fujian Medical University, Fuzhou, Fujian Province, China
• ⁶Department of Neurology, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China

Background/Objectives: Although Alzheimer's disease (AD) is the most prevalent dementia in late life, with amyloid beta (Aβ) deposition and neuroinflammation are recognized among its primary pathological featuresits main pathological features. Currently, there is currently still a lack of effective therapeutic drugs for AD. Ganoderma lucidum (G. lucidum) is abundant in a variety of active ingredients that harbor anti-inflammatory properties in both central nervous system and the periphery. We attempted to determine whether G. lucidum contained exosome-like nanovesicles (GLENVs) and whether these GLENVsit can alleviate cognitive impairment. Methods: We extracted GLENVs by the differential ultracentrifugation method and identified the components by liquid chromatography-mass spectrometry (LC-MS). The 5×FAD mice underwent a 3-month intranasal administration of GLENVs and their behavioral and pathological changes of 5×FAD mice were evaluated after three months of intranasal administration of GLENVs. Results: GLENVs were successfully extracted and identified to contain multiple ganoderic acids; intranasal administration allowed GLENVs to penetrate the blood-brain barrier and enter the brain to exert their effects directly. The 3-month GLENVs treatment effectively ameliorated the impairment in the memory and learning of the 5×FAD mice. The administration of GLENVs treatment also reduced Aβ deposition in the cortex and hippocampus of 5×FAD mice, overactivated microglia, reactive astrocytes, and downregulated pro-inflammatory factors, reduced overactivated microglia and reactive astrocytes, and inhibited the Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) signaling pathway. Moreover, GLENVs exerted no adverse effects on liver and kidney function. Conclusions: GLENVs may be a promising candidate for AD treatment.