LAUSR

&NA; Impaired clearance of amyloid‐&bgr; peptide (A&bgr;) 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&bgr; uptake and subsequent degradation within primary glia and neuroblastoma cells. CTGF enhanced extracellular A&bgr; 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&bgr; deposits, improved locomotor function, and rescued memory deficits. Neuroprotective potential of CTGF against A&bgr;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&bgr; neurotoxicity in the central nervous system.