Astroglia-derived TIMP-1 alleviates cognitive deficits by restoring synaptic plasticity in Alzheimer's disease

The influence of astrocyte-secreted cytokines on neuronal health in Alzheimers disease (AD) is poorly understood, despite their increasing recognition as potential molecules for therapeutic targeting. Recently, we demonstrated that an anti-inflammatory cytokine, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is robustly secreted by astrocytes early in response to amyloid-{beta} (A{beta}) but is reduced in its prolonged presence. Here, we found strikingly diminished levels of TIMP-1 in the brain of six-month-old 5xFAD mice concomitant with high levels of A{beta}, versus wild-type mice. Intracerebroventricular injection of TIMP-1 in 5xFAD mice ameliorated their cognitive functions. TIMP-1 not only ensured neuronal viability against apoptosis and aberrant autophagy in the AD model by binding to neuronal CD63 receptors, but also conferred synapse-specific effects. Synaptosomal analysis revealed TIMP-1 elevates dendritic spine size and protein levels, likely by promoting post-synaptic long-term potentiation in hippocampus, independent of pre-synaptic activity. TIMP-1 induced brain-derived neurotrophic factor (BDNF) and BDNF-mediated post-synaptic signaling. Therefore, we identify TIMP-1 as a multifunctional cytokine with distinct protective mechanisms-of-action on neurons and propose it as a promising therapeutic candidate in AD. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/533245v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@187adadorg.highwire.dtl.DTLVardef@9b6ae1org.highwire.dtl.DTLVardef@185e352org.highwire.dtl.DTLVardef@10f2995_HPS_FORMAT_FIGEXP M_FIG C_FIG