INTRA-HIPPOCAMPAL INJECTION OF ALPHA-SYNUCLEIN PRE-FORMED FIBRILS TRIGGERS COGNITIVE DEFECT AND CHANGES TRANSCRIPTOME PROFILES

Abstract Parkinson's disease (PD) constitutes a significant aspect of motor and non-motor symptoms, the latter includes cognitive defect and mood disorders. Clinically, abnormal aggregation of α-synuclein (α-Syn) was found in patient’ s brain, but the pathogenesis mechanism of synucleinopathy remains to be defined. In this study, we aimed to determine whether hippocampal synucleinopathy contributes to cognitive dysfunction and to investigate the molecular changes connecting hippocampal synucleinopathy to dementia. To understand synucleinopathy-induced dementia, mice were injected α-Syn preformed fibrils (PFFs) into the hippocampus bilaterally. After 8 months of PFF injection, there was a significant increase in amount of α-Syn/pSer129. In the behavioral test, mice displayed cognitive deficits in recognition memory, social memory, working memory, and long-term memory. In addition, RNA-sequencing analysis identified 2,585 differentially expressed genes (DEGs, p-value <0.05) in the PFF-treated mice compared to the PBS control, In particular, pathway of transforming growth factor beta (TGFβ) was enriched in the PFF-injected mice. The TGFβ-related genes were increased in the hippocampus during the progress of synucleinopathy, i.e. BMPR2, BMP2, BMP5, TGFβ1 and the downstream signals of Smad1/5/8 and Smad2. Furthermore, there is a time-dependent change in the expression of GFAP, Iba1, inflammasome and the complement system, with those gene expression decreased at 8 months, while increased at 12-13 months after PFF injection. Moreover, amount of AMPA1/pSer845 of glutamate receptor increased after post- PFF injection across both time intervals. Collectively, our findings demonstrate that hippocampal synucleinopathy effectively induces cognitive impairments associated with dementia. These effects parallel with the altered BMP/TGFβ pathways, immune responses, the complement system, and glutamate systems. These molecular changes may serve as valuable biomarkers and potential therapeutic targets that bridge the link between hippocampal synucleinopathy and dementia.