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Abstract Repetitive mild head injuries incurred while playing organized sports, during car accidents and falls, or in active military service are a major health problem. These head injuries induce cognitive, motor, and behavioral deficits that can last for months and even years with an increased risk of dementia, Parkinson’s disease, and chronic traumatic encephalopathy. There is no approved medical treatment for these types of head injuries. To this end, we tested the healing effects of the psychedelic psilocybin, as it is known to reduce neuroinflammation and enhance neuroplasticity. Using a model of mild repetitive head injury in adult female rats, we provide unprecedented data that psilocybin can reduce vasogenic edema, restore normal vascular reactivity and functional connectivity, reduce phosphorylated tau buildup, enhance levels of brain-derived neurotrophic factor and its receptor TrkB, and modulate lipid signaling molecules. 

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease that affects neurons in the brain and spinal cord, causing loss of muscle control, and eventually leads to death. Phosphorylated transactive response DNA binding protein‐43 (TDP‐43) is the major pathological protein in both sporadic and familial ALS, forming cytoplasmic aggregates in over 95% of cases. Of the 10–15% of ALS cases that are familial, mutations in TDP‐43 represent about 5% of those with a family history. We have developed anin vitrooverexpression model by introducing three familial ALS mutations (A315T, M337V, and S379P) in the TDP‐43 (TARDBP) gene which we define as 3X‐TDP‐43. This overexpression model TDP‐43 shows deficits in autophagy flux and colocalization of TDP‐43 with stress granules. We also observe a progressive shift of TDP‐43 to the cytoplasm in this model. This overexpression model shows a reduction in solubility of phosphorylated TDP‐43 from RIPA to urea soluble. Four glycolytic enzymes, phosphoglycerate kinase one (PGK1), aldolase A (ALDOA), enolase 1 (ENO1), and pyruvate dehydrogenase kinase 1 (PDK1) show significant time‐dependent decreases in 3X‐TDP‐43 expressing cells. Shotgun proteomic analysis shows global changes in the importin subunit alpha‐1 (KPNA2), heat shock 70 kDa protein 1A (HSPA1A), and protein disulfide‐isomerase A3 (PDIA3) expression levels and coimmunoprecipitation reveals that these proteins complex with TDP‐43. Overall, these results suggest that the 3X‐TDP‐43 model may provide new insights into pathophysiology and an avenue for drug screeningin vitrofor those suffering from ALS and related TDP‐43 proteinopathies.