In Alzheimer’s disease (AD), the propagation and spreading of CNS tau pathology closely correlates with cognitive decline, positioning tau as an attractive therapeutic target. Amyloid beta (Aβ) has been strongly implicated in driving tau spread, whereas primary tauopathies such as primary age-related tauopathy (PART)—which lack Aβ pathology—exhibit limited tau spread and minimal-to-no cognitive decline. Emerging evidence converges on a trans-synaptic mechanism of tau spread, facilitated by the transfer of misfolded tau aggregates (e.g. soluble oligomers). However, it is unclear whether Aβ oligomers modulate the binding and internalization of tau oligomers in human synapses. Our translationally focused paradigms utilize post-mortem brain specimens from Control, PART, and AD patients. Synaptosomes isolated from the temporal cortex of all three groups were incubated with preformed recombinant tauO (rtauO), ± preformed recombinant AβO (rAβO), and oligomer binding/internalization was quantified via flow cytometry following proteinase K (PK) digestion of surface-bound oligomers. TauO-synapse interactions were visualized using EM immunogold. Brain-derived tau oligomers (BDTO) from AD and PART PBS-soluble hippocampal fractions were co-immunoprecipitated and analyzed via mass spectrometry to compare synaptic tauO interactomes in primary and secondary tauopathies, thereby inferring the role of Aβ. AD synaptosomes, enriched in endogenous Aβ pathology, exhibited increased rtauO internalization compared to PART synaptosomes. This observation was mirrored in Control synaptosomes, where recombinant rAβO significantly increased rtauO binding and internalization. PK pre-treatment abolished this effect, implicating synaptic membrane proteins in AβO-mediated tauO internalization. While both PART and AD BDTO were broadly enriched in synaptic proteins, AD BDTO exhibited differential enrichment of endocytic proteins across pre- and post-synaptic compartments, whereas PART BDTO showed no significant synaptic enrichment. This study demonstrates that Aβ oligomers enhance tau oligomer binding and drive its internalization through synaptic membrane proteins. These findings offer novel mechanistic insights underlying pathological tau spreading directly within human synapses and emphasize the therapeutic potential of targeting Aβ-tau interactions.

在阿尔茨海默病 （AD） 中，CNS tau 病理的传播和扩散与认知能力下降密切相关，使 tau 成为有吸引力的治疗靶点。β 淀粉样蛋白 （Aβ） 与驱动 tau 蛋白传播密切相关，而缺乏 Aβ 病理学的原发性 tau 蛋白病，如原发性年龄相关性 tau 蛋白病 （PART），表现出有限的 tau 蛋白扩散和轻微或没有认知能力下降。新出现的证据集中在 tau 扩散的跨突触机制上，由错误折叠的 tau 聚集体（例如可溶性寡聚体）的转移促进。然而，目前尚不清楚 Aβ 寡聚体是否调节人突触中 tau 寡聚体的结合和内化。我们以转化为重点的范式利用了来自对照、PART 和 AD 患者的死后脑标本。从所有三组颞叶皮层分离的突触体与预制重组 tauO （rtauO） ±预制重组 AβO （rAβO） 一起孵育，并在蛋白酶 K （PK） 消化表面结合的寡聚体后通过流式细胞术定量寡聚体结合/内化。使用 EM 免疫金可视化 TauO-突触相互作用。对来自 AD 和 PART PBS 可溶性海马组分的脑源性 tau 寡聚体 （BDTO） 进行共免疫沉淀，并通过质谱分析，以比较原发性和继发性 tau 蛋白病中的突触 tauO 相互作用组，从而推断 Aβ 的作用。与 PART 突触体相比，富含内源性 Aβ 病理学的 AD 突触体表现出增加的 rtauO 内化。这一观察结果在对照突触体中得到了反映，其中重组 rAβO 显着增加了 rtauO 结合和内化。PK 预处理消除了这种影响，表明突触膜蛋白参与 AβO 介导的 tauO 内化。 虽然 PART 和 AD BDTO 在突触蛋白中广泛富集，但 AD BDTO 在突触前和突触后区室中表现出内吞蛋白的差异富集，而 PART BDTO 没有显示显着的突触富集。本研究表明，Aβ 寡聚体增强 tau 寡聚体结合，并通过突触膜蛋白驱动其内化。这些发现为病理性 tau 直接在人类突触内传播提供了新的机制见解，并强调了靶向 Aβ-tau 相互作用的治疗潜力。