TIMP-1, Secreted by a Distinct State of Reactive Astrocyte in Response to Aβ, Promotes Neuronal Survival and Improves Cognitive Functions in 5xFAD Mice
Journal Title: The 2nd Annual Meeting of International Center for Neuroscience Research - Year 2021, Vol 2, Issue 1
Abstract
Astrocytes that respond to any pathological stimulus in brain including in Alzheimer’s disease (AD), by undergoing extensive remodeling at the molecular, functional and morphological levels, are termed as reactive astrocytes. ‘Astrocyte reactivity’ encompasses multiple distinct states astrocytes adopt across any disease continuum. Reactive astrocyte states in AD are complex and their phenotypes are only partially understood. We observed that primary astrocytes upon Aβ1-42 (Amyloid-β, the toxic protein triggering AD) treatment adopted a unique neuroprotective reactive phenotype at 6h but showed neurotoxic behaviors at 16h and 24h. Tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) was detected as the major candidate in the 6h Aβ-treated astrocyteconditioned medium that promoted neuronal survival and neurite outgrowth against Aβ toxicity. TIMP-1 expression is significantly reduced in hippocampi of 5xFAD mice compared to age-matched wild-type mice. Intracerebroventricular TIMP-1 injection in 6-month 5xFAD mouse alleviated cognitive abnormalities assessed through behavioral tests and strongly improved synaptic functions quantified from pre-and post-synaptic protein expressions and spine density. In viable synaptosomal preparations from TIMP-1-treated 5xFAD mice, level of active GSK3β that induces LTD signaling and diminish synaptic plasticity, was significantly reduced. Further studies revealed that TIMP-1 triggered neuronal survival by phosphorylating Akt at Thr308 and Ser473 by binding to neuronal transmembrane receptor CD63. Upregulated phosphoAktThr308 level inhibited GSK3β activity. Moreover, phosphorylation at AktS473 corrected autophagy flux and inhibited the apoptotic pathway that were induced by Aβ. Thus, a specific Aβ-induced state of reactive astrocyte secretes TIMP-1 that mediates its neuroprotective role and is proposed as a therapeutic candidate.
Authors and Affiliations
Sukanya Sarkar*, Ramesh Kumar Paidi, Kusumika Gharami and Subhas Chandra Biswas
Keywords
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