Department of Pharmacology, University of Navarra, Pamplona, Spain; Department of Cellular and Molecular Neuropharmacology, Division of Neuroscience, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.
Department of Cellular and Molecular Neuropharmacology, Division of Neuroscience, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Biochim Biophys Acta Mol Basis Dis. 2017 Apr;1863(4):991-1001. doi: 10.1016/j.bbadis.2017.01.023. Epub 2017 Jan 26.
Brain-derived neurotrophic factor (BDNF) plays pivotal roles in neuronal function. The cleaved - mature - form of BDNF (mBDNF), predominantly expressed in adult brains, critically determines its effects. However, insufficient proteolytic processing under pathology may lead to the precursor form of BDNF (proBDNF) and thereby increased neuronal apoptosis and synaptic weakening. Previous findings in our lab showed that cognitive stimulation (CS) delayed memory decline in Tg2576 mouse model of Alzheimer's disease (AD), an effect that was tightly associated with augmented levels of mBDNF. In view of this association, the present study explored whether altered cleavage of BDNF could be involved in AD-related traits triggered by excessive amyloid-β (Aβ) pathology and whether this process could be therapeutically targeted. Aβ pathology, both in AD patient samples and experimental models, triggered the upregulation of plasminogen-activator inhibitor-1 (PAI-1) via JNK/c-Jun. This led to inhibition of plasmin-regulated conversion of mBDNF. Pharmacological inhibition of PAI-1 with PAI-039 sufficiently reverted Aβ-induced tau hyperphosphorylation and neurotoxicity. Chronic treatment of 15 old-month Tg2576 mice with oral administration of PAI-039 resulted in improved BDNF maturation and cognitive function without inducing significant changes in amyloid burden. In conclusion, upregulation of PAI-1 may be a critical mechanism underlying insufficient neurotrophic support and increased neurodegeneration associated with AD. Thus, targeting BDNF maturation through pharmacological inhibition of PAI-1 might become a potential treatment for AD.
脑源性神经营养因子（BDNF）在神经元功能中发挥着关键作用。成熟形式的 BDNF（mBDNF）在成人脑中表达，对其作用至关重要。然而，在病理条件下，BDNF 的蛋白水解处理不足可能导致前体形式的 BDNF（proBDNF）增加，从而增加神经元凋亡和突触减弱。我们实验室的先前研究表明，认知刺激（CS）可延缓阿尔茨海默病（AD）Tg2576 小鼠模型的记忆衰退，这种作用与 mBDNF 水平的增加密切相关。鉴于这种关联，本研究探讨了过度淀粉样蛋白-β（Aβ）病理引发的 AD 相关特征是否涉及 BDNF 的切割变化，以及该过程是否可以作为治疗靶点。AD 患者样本和实验模型中的 Aβ 病理通过 JNK/c-Jun 触发纤溶酶原激活物抑制剂-1（PAI-1）的上调。这导致 mBDNF 的纤溶调节转化受到抑制。用 PAI-039 抑制 PAI-1 可充分逆转 Aβ诱导的 tau 过度磷酸化和神经毒性。15 个月大的 Tg2576 小鼠口服 PAI-039 进行慢性治疗可改善 BDNF 的成熟和认知功能，而不会引起淀粉样蛋白负荷的显著变化。总之，PAI-1 的上调可能是与 AD 相关的神经营养支持不足和神经退行性变增加的关键机制。因此，通过抑制 PAI-1 来促进 BDNF 的成熟可能成为 AD 的一种潜在治疗方法。
