Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, United States of America.
Department of Neurology, Laboratory for Computational Neurochemistry and Drug Discovery, Veterans Affairs Health Care System and Department of Neurology, University of California-San Francisco, San Francisco, CA 94121, United States of America.
Neurobiol Dis. 2022 Jan;162:105563. doi: 10.1016/j.nbd.2021.105563. Epub 2021 Nov 24.
Degeneration of basal forebrain cholinergic neurons (BFCNs) in the nucleus basalis of Meynert (NBM) and vertical diagonal band (VDB) along with their connections is a key pathological event leading to memory impairment in Alzheimer's disease (AD). Aberrant neurotrophin signaling via Trks and the p75 neurotrophin receptor (p75) contributes importantly to BFCN dystrophy. While NGF/TrkA signaling has received the most attention in this regard, TrkB and TrkC signaling also provide trophic support to BFCNs and these receptors may be well located to preserve BFCN connectivity. We previously identified a small molecule TrkB/TrkC ligand, LM22B-10, that promotes cell survival and neurite outgrowth in vitro and activates TrkB/TrkC signaling in the hippocampus of aged mice when given intranasally, but shows poor oral bioavailability. An LM22B-10 derivative, PTX-BD10-2, with improved oral bioavailability has been developed and this study examined its effects on BFCN atrophy in the hAPP (APP) AD mouse model. Oral delivery of PTX-BD10-2 was started after appreciable amyloid and cholinergic pathology was present to parallel the clinical context, as most AD patients start treatment at advanced pathological stages. PTX-BD10-2 restored cholinergic neurite integrity in the NBM and VDB, and reduced NBM neuronal atrophy in symptomatic APP mice. Dystrophy of cholinergic neurites in BF target regions, including the cortex, hippocampus, and amygdala, was also reduced with treatment. Finally, PTX-BD10-2 reduced NBM tau pathology and improved the survival of cholinergic neurons derived from human induced pluripotent stem cells (iPSCs) after amyloid-β exposure. These data provide evidence that targeting TrkB and TrkC signaling with PTX-BD10-2 may be an effective disease-modifying strategy for combating cholinergic dysfunction in AD. The potential for clinical translation is further supported by the compound's reduction of AD-related degenerative processes that have progressed beyond early stages and its neuroprotective effects in human iPSC-derived cholinergic neurons.
基底前脑胆碱能神经元（BFCN）在梅内尔特核（NBM）和垂直对角带（VDB）中的退化以及它们的连接是导致阿尔茨海默病（AD）记忆损伤的关键病理事件。异常的神经营养因子信号通过 Trks 和 p75 神经营养因子受体（p75）对 BFCN 营养不良有重要贡献。虽然 NGF/TrkA 信号在这方面受到了最多的关注，但 TrkB 和 TrkC 信号也为 BFCNs 提供营养支持，这些受体可能很好地位于保留 BFCN 连接。我们之前鉴定了一种小分子 TrkB/TrkC 配体 LM22B-10，它在体外促进细胞存活和神经突生长，并在给予鼻腔内时激活老龄小鼠海马中的 TrkB/TrkC 信号，但口服生物利用度差。已经开发出一种具有改善口服生物利用度的 LM22B-10 衍生物 PTX-BD10-2，本研究检查了其对 hAPP（APP）AD 小鼠模型中 BFCN 萎缩的影响。在出现明显的淀粉样蛋白和胆碱能病理学后开始口服给予 PTX-BD10-2 给药，以平行于临床情况，因为大多数 AD 患者在晚期病理阶段开始治疗。PTX-BD10-2 恢复了 NBM 和 VDB 中的胆碱能神经突完整性，并减少了有症状的 APP 小鼠的 NBM 神经元萎缩。BF 靶区（包括皮质、海马和杏仁核）中的胆碱能神经突的营养不良也随着治疗而减少。最后，PTX-BD10-2 减少了 NBM tau 病理学，并改善了暴露于淀粉样蛋白-β后源自人诱导多能干细胞（iPSC）的胆碱能神经元的存活。这些数据提供了证据，表明用 PTX-BD10-2 靶向 TrkB 和 TrkC 信号可能是一种有效的疾病修饰策略，用于对抗 AD 中的胆碱能功能障碍。该化合物还减少了已经进展到早期阶段之外的 AD 相关退行性过程，并对源自人 iPSC 的胆碱能神经元具有神经保护作用，进一步支持了其临床转化的潜力。
