In Alzheimer's disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, and synaptic transmission and plasticity. Using cerebrospinal fluid and postmortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as a function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aβ in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential to be a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD.

中文翻译：

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在阿尔茨海默病中，一个小的 TAT-TrkB 肽可防止 BDNF 受体裂解并恢复突触生理学


在阿尔茨海默病 （AD） 中，淀粉样蛋白 β （Aβ） 触发的 TrkB-FL 切割损害脑源性神经营养因子 （BDNF） 信号传导，从而损害神经元存活、分化、突触传递和可塑性。使用脑脊液和死后人脑样本，我们表明 TrkB-FL 切割发生在疾病的早期阶段，并随着病理严重程度的增加而增加。为了探索这种疾病机制的治疗潜力，我们设计了小的 TAT 融合肽并筛选了它们防止 TrkB-FL 受体裂解的能力。其中，具有赖氨酸-赖氨酸接头的 TAT-TrkB 肽在体外和 体内阻止了 TrkB-FL 裂解 ，并挽救了海马切片中寡聚 Aβ 诱导的突触缺陷。此外，这种 TAT-TrkB 肽改善了 AD 的 5XFAD 小鼠模型中的认知能力，改善了突触可塑性缺陷，并阻止了体内 Tau 病理进展 。我们为这种治疗策略的有效性和安全性提供了概念验证证据，并预计这种 TAT-TrkB 肽有可能成为一种疾病缓解药物，可以预防和/或逆转 AD 患者的认知缺陷。