Differential protective effects of connective tissue growth factor against Aβ neurotoxicity on neurons and glia

Impaired clearance of amyloid-beta peptide (A beta) leads to abnormal extracellular accumulation of this neurotoxic protein that drives neurodegeneration in sporadic Alzheimer's disease (AD). Connective tissue growth factor (CTGF/CCN2) expression is elevated in plaque-surrounding astrocytes in AD patients. However, the role of CTGF in AD pathogenesis remains unclear. Here we characterized the neuroprotective activity of CTGF. We found that CTGF facilitated A beta uptake and subsequent degradation within primary glia and neuroblastoma cells. CTGF enhanced extracellular A beta degradation via membrane-bound matrix metalloproteinase-14 (MMP14) in glia and extracellular MMP13 in neurons. In the brain of a Drosophila AD model, glial-expression of CTGF reduced A beta deposits, improved locomotor function, and rescued memory deficits. Neuroprotective potential of CTGF against A beta 42-induced photoreceptor degeneration was disrupted through silencing MMPs. Therefore, CTGF may represent a node for potential AD therapeutics as it intervenes in glia-neuron communication via specific MMPs to alleviate A beta neurotoxicity in the central nervous system.