The past decade has brought tremendous progress in unraveling the pathophysiology of Alzheimer's disease (AD). While increasingly sophisticated immunotherapy targeting soluble and aggregated brain amyloid-beta (Aβ) continues to dominate clinical research in AD, a deeper understanding of Aβ physiology has led to the recognition of distinct neuronal signaling pathways linking Aβ to synaptotoxicity and neurodegeneration and to new targets for therapeutic intervention. Identifying specific signaling pathways involving Aβ has allowed for the development of more precise therapeutic interventions targeting the most relevant molecular mechanisms leading to AD. In this review, I highlight the discovery of cellular prion protein as a high-affinity receptor for Aβ oligomers, and the downstream signaling pathway elucidated to date, converging on nonreceptor tyrosine kinase Fyn. I discuss preclinical studies targeting Fyn as a therapeutic intervention in AD and our recent experience with the safety, tolerability, and cerebrospinal fluid penetration of the Src family kinase inhibitor saracatinib in patients with AD. Fyn is an attractive target for AD therapeutics, not only based on its activation by Aβ via cellular prion protein but also due to its known interaction with tau, uniquely linking the two key pathologies in AD. Fyn is also a challenging target, with broad expression throughout the body and significant homology with other members of the Src family kinases, which may lead to unintended off-target effects. A phase 2a proof-of-concept clinical trial in patients with AD is currently under way, providing critical first data on the potential effectiveness of targeting Fyn in AD.

中文翻译：

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在阿尔茨海默病中靶向 Fyn 激酶

过去十年在解开阿尔茨海默病 (AD) 的病理生理学方面取得了巨大进展。虽然针对可溶性和聚集的脑淀粉样蛋白 (Aβ) 的日益复杂的免疫疗法继续主导 AD 的临床研究，但对 Aβ 生理学的更深入了解已导致人们认识到将 Aβ 与突触毒性和神经退行性联系起来的不同神经元信号通路以及新靶点治疗干预。识别涉及 Aβ 的特定信号通路允许开发针对导致 AD 的最相关分子机制的更精确的治疗干预措施。在这篇综述中，我重点介绍了细胞朊病毒蛋白作为 Aβ 寡聚体的高亲和力受体的发现，以及迄今为止阐明的下游信号通路，收敛于非受体酪氨酸激酶 Fyn。我讨论了针对 Fyn 作为 AD 治疗干预措施的临床前研究，以及我们最近在 AD 患者中 Src 家族激酶抑制剂萨拉卡替尼的安全性、耐受性和脑脊液渗透方面的经验。Fyn 是 AD 治疗的一个有吸引力的目标，不仅基于它通过细胞朊病毒蛋白被 Aβ 激活，而且还由于它与 tau 的已知相互作用，独特地将 AD 中的两个关键病理联系起来。Fyn 也是一个具有挑战性的目标，在全身广泛表达，并且与 Src 家族激酶的其他成员具有显着的同源性，这可能会导致意外的脱靶效应。目前正在进行 AD 患者的 2a 期概念验证临床试验，