The pro-domains of neurotrophins, including BDNF, are linked to Alzheimer's disease through a toxic synergy with Aβ

摘要: Brain-derived neurotrophic factor (BDNF) has a crucial role in learning and memory by promoting neuronal survival modulating synaptic connectivity. BDNF levels are lower the brains of individuals with Alzheimer's disease (AD), suggesting pathogenic involvement. The Drosophila orthologue is highly conserved Neurotrophin 1 (DNT1). DNT1 have same overall protein structure can be cleaved, resulting conversion full-length polypeptide into separate pro- mature-domains. While mature-domain neuroprotective, pro-domain less clear. In flies mammalian cells, we identified synergistic toxic interaction between amyloid-β peptide (Aβ1–42) pro-domains both BDNF. Specifically, show that acquires neurotoxic activity presence Aβ1–42. contrast, protective against Aβ1–42 toxicity. Likewise, SH-SY5Y cell culture, only Western blots indicate this likely results from Aβ1–42-induced upregulation receptor p75NTR. clinical relevance these findings underlined greater than thirty fold increase ratio to mature-domains AD. This unbalanced pro:mature-domain patients represents possible biomarker AD may offer target for therapeutic intervention.