Balducci Claudia, Orsini Franca, Cerovic Milica, Beeg Marten, Rocutto Beatrice, Dacomo Letizia, Masone Antonio, Busani Eleonora, Raimondi Ilaria, Lavigna Giada, Chen Po-Tao, Leva Susanna, Colombo Laura, Zucchelli Chiara, Musco Giovanna, Kanaan Nicholas M, Gobbi Marco, Chiesa Roberto, Fioriti Luana, Forloni Gianluigi
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy.
Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy.
Acta Neuropathol Commun. 2025 Jan 27;13(1):17. doi: 10.1186/s40478-025-01930-3.
Deposition of abnormally phosphorylated tau aggregates is a central event leading to neuronal dysfunction and death in Alzheimer's disease (AD) and other tauopathies. Among tau aggregates, oligomers (TauOs) are considered the most toxic. AD brains show significant increase in TauOs compared to healthy controls, their concentration correlating with the severity of cognitive deficits and disease progression. In vitro and in vivo neuronal TauO exposure leads to synaptic and cognitive dysfunction, but their mechanisms of action are unclear. Evidence suggests that the cellular prion protein (PrP) may act as a mediator of TauO neurotoxicity, as previously proposed for β-amyloid and α-synuclein oligomers. To investigate whether PrP mediates TauO detrimental activities, we compared their effects on memory and synaptic plasticity in wild type (WT) and PrP knockout (Prnp) mice. Intracerebroventricular injection of TauOs significantly impaired recognition memory in WT but not in Prnp mice. Similarly, TauOs inhibited long-term potentiation in acute hippocampal slices from WT but not Prnp mice. Surface plasmon resonance indicated a high-affinity binding between TauOs and PrP with a K of 20-50 nM. Immunofluorescence analysis of naïve and PrP-overexpressing HEK293 cells exposed to TauOs showed a PrP dose-dependent association of TauOs with cells over time, and their co-localization with PrP on the plasma membrane and in intracellular compartments, suggesting PrP-may play a role in TauO internalization. These findings support the concept that PrP mediates the detrimental activities of TauOs through a direct interaction, suggesting that targeting this interaction might be a promising therapeutic strategy for AD and other tauopathies.
异常磷酸化的tau聚集体沉积是导致阿尔茨海默病（AD）和其他tau蛋白病中神经元功能障碍和死亡的核心事件。在tau聚集体中，寡聚体（TauOs）被认为毒性最强。与健康对照相比，AD患者大脑中的TauOs显著增加，其浓度与认知缺陷的严重程度和疾病进展相关。体外和体内神经元暴露于TauO会导致突触和认知功能障碍，但其作用机制尚不清楚。有证据表明，细胞朊蛋白（PrP）可能作为TauO神经毒性的介质，正如之前对β-淀粉样蛋白和α-突触核蛋白寡聚体所提出的那样。为了研究PrP是否介导TauO的有害活性，我们比较了它们对野生型（WT）和PrP基因敲除（Prnp）小鼠记忆和突触可塑性的影响。脑室内注射TauOs显著损害了WT小鼠的识别记忆，但对Prnp小鼠没有影响。同样，TauOs抑制了WT小鼠急性海马切片中的长时程增强，但对Prnp小鼠没有影响。表面等离子体共振表明TauOs与PrP之间存在高亲和力结合，解离常数K为20 - 50 nM。对未处理和过表达PrP的HEK293细胞暴露于TauOs后的免疫荧光分析显示，随着时间的推移，TauOs与细胞的结合呈PrP剂量依赖性，并且它们与PrP在质膜和细胞内区室中共定位，表明PrP可能在TauO内化中起作用。这些发现支持了PrP通过直接相互作用介导TauOs有害活性的概念，表明针对这种相互作用可能是AD和其他tau蛋白病的一种有前景的治疗策略。
