C-terminal cleaved tau at D421 (∆D421-tau) accumulates in the brains of Alzheimer’s disease (AD) patients. However, it is unclear how tau truncation, an understudied tau post-translational modification, contributes to AD pathology and progression. Utilizing an adeno-associated virus (AAV) gene delivery-based approach, we overexpressed full-length tau (FL-tau) and ∆D421-tau in 4- and 12-month-old mice for 4 months to study the neuropathological impact of accumulation in young adult (8-month) and middle-aged (16-month) mice. Overall, we show that independent of the tau species, age was an important factor facilitating tau phosphorylation, oligomer formation, and deposition into silver-positive tangles. However, mice overexpressing ∆D421-tau exhibited a distinct phosphorylation profile to those overexpressing FL-tau and increased tau oligomerization in the middle-age group. Importantly, overexpression of ∆D421-tau, but not FL-tau in middle-aged mice, resulted in pronounced cognitive impairments and hippocampal long-term potentiation deficits. While both FL-tau and ∆D421-tau induced neuronal loss in mice with age, ∆D421-tau led to significant neuronal loss in the CA3 area of the hippocampus and medial entorhinal cortex compared to FL-tau. Based on our data, we conclude that age increases the susceptibility to neuronal degeneration associated with ΔD421-tau accumulation. Our findings suggest that ΔD421-tau accumulation contributes to synaptic plasticity and cognitive deficits, thus representing a potential target for tau-associated pathologies.

D421 (ΔD421-tau) 的 C 末端切割 tau 在阿尔茨海默病 (AD) 患者的大脑中积累。然而，目前尚不清楚 tau 截断（一种未被充分研究的 tau 翻译后修饰）如何促进 AD 病理学和进展。利用基于腺相关病毒 (AAV) 基因传递的方法，我们在 4 个月和 12 个月大的小鼠中过表达全长 tau (FL-tau) 和 ΔD421-tau 4 个月，以研究在年轻成年（8 个月）和中年（16 个月）小鼠中积累。总体而言，我们表明，独立于 tau 物种，年龄是促进 tau 磷酸化、低聚物形成和沉积成银阳性缠结的重要因素。然而，过表达ΔD421-tau的小鼠与过表达FL-tau的小鼠表现出明显的磷酸化特征，并且在中年组中tau寡聚化增加。重要的是，ΔD421-tau 的过度表达，但不是 FL-tau 在中年小鼠中的过度表达，导致明显的认知障碍和海马长期增强缺陷。虽然 FL-tau 和 ΔD421-tau 均会导致小鼠随着年龄增长而出现神经元丢失，但与 FL-tau 相比，ΔD421-tau 会导致海马 CA3 区域和内侧内嗅皮层的神经元显着丢失。根据我们的数据，我们得出结论，年龄增加了与 ΔD421-tau 积累相关的神经元变性的易感性。我们的研究结果表明，ΔD421-tau 积累有助于突触可塑性和认知缺陷，因此代表了 tau 相关病理的潜在目标。