TIMP-1 enhances Akt and BDNF signaling in neurons to reduce synaptic and cognitive deficits in 5xFAD mouse model of Alzheimer’s disease
Sukanya Sarkar, Kusumika Gharami, Ananya Mondal, Keerthana Padmanabhan, Ramesh Kumar Paidi, Bettadapura N. Srikumar, Subhas C. Biswas
Abstract
Glial-secreted molecules influence neuronal function in Alzheimer's disease (AD), but their mechanisms of action are partially understood. Anti-inflammatory cytokine tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is secreted by astrocytes early in response to amyloid-β and is suggested to have a neuroprotective function. We demonstrated that TIMP-1 levels are increased in 7-day-old 5xFAD versus wild-type mice but are drastically decreased from two months onwards. Administration of TIMP-1 protein in 5xFAD mice ameliorated AD-associated cognitive impairments. TIMP-1 regulated both neuronal apoptosis and autophagy by binding to CD63 receptors in an AD model. Synaptosomal and electrophysiological studies revealed that TIMP-1 reduces AD-related synaptic deficits, likely by promoting post-synaptic long-term potentiation in the hippocampus, independent of pre-synaptic activity. TIMP-1 induced brain-derived neurotrophic factor (BDNF) and BDNF-mediated post-synaptic signaling. These findings suggest that TIMP-1 functions as a multifunctional cytokine with protective and long-term benefits for neurons and may be a promising therapeutic candidate in AD.