Taurodeoxycholate, a master key locking both priming and activation signal necessary for inflammasomal activation of microglia by Amyloid beta in Alzheimer’s diseases

Abstract

Abstract Alzheimer’s disease (AD) is an inflammatory neurodegenerative condition characterized by deposition of amyloid beta (Abeta) in the brain and origins dementia. Neuronal apoptosis following neuroinflammation by Abeta impairs cognition and memory. In this study we focused on Taurodeoxyxcholate (TDCA) is an active bile acid derivative with potent anti-inflammatory function. In 5× Familial Alzheimer’s disease (5xFAD) mice model, chronic administration of TDCA in 5xFAD mice improved learning and memory in different memory test compared with PBS group. TDCA treatment significantly decreased neuronal apoptosis, load of Abeta plaques, the number of activated GFAP+ astrocytes and Iba-1+ microglia in different brain region of 5xFAD mice. CD11bhiGr1intF4/80+ myeloid cells in brain and spleen increased significantly in TDCA-treated group compared to PBS-treated group when brain single cell were immune-stained. In vitro, TDCA increased phagocytosis of Abeta. TDCA suppressed NLRP3-ASC oligomerization and production of mature IL-1β/IL-18 in Microglia by Abeta. TDCA inhibited Ca++ influx incurred by ATP or BzATP (P2X7 agonists). Compared with wild type, Ca++ influx of macrophages from TGR5 KO mice was like that of P2X7 KO mice in response to BzATP, suggesting that TDCA might play role as an inverse agonist for TGR5 complexed with P2X7. TDCA activates adenylate cyclase and cAMP inhibit priming phase of inflammasomal activation and oligomerization of NLRP3-ASC complex, suggesting that TDCA suppresses both priming and activation phase of NLRP3 inflammasome. TDCA and its novel chemical derivatives could be better choice in ameliorating broad spectrum of neuroinflammation to improve cognition and memory in AD patients.