Walkiewicz Grzegorz, Ronisz Alicja, Ospitalieri Simona, Tsaka Grigoria, Tomé Sandra O, Vandenberghe Rik, von Arnim Christine A F, Rousseau Frederic, Schymkowitz Joost, De Groef Lies, Thal Dietmar Rudolf
Laboratory of Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute, KU Leuven, Leuven, Belgium.
Switch Laboratory, VIB Center for Brain & Disease Research, VIB, Leuven, Belgium.
Acta Neuropathol Commun. 2024 Dec 20;12(1):194. doi: 10.1186/s40478-024-01907-8.
The accumulation of abnormal phosphorylated Tau protein (pTau) in neurons of the brain is a pathological hallmark of Alzheimer's disease (AD). PTau pathology also occurs in the retina of AD cases. Accordingly, questions arise whether retinal pTau can act as a potential seed for inducing cerebral pTau pathology and whether retinal pTau pathology causes degeneration of retinal neurons. To address these questions, we (1) characterized pTau pathology in the retina of TAU58 mice, (2) determined the impact of pTau pathology on retinal ganglion cell density, and (3) used this mouse model to test whether brain lysates from AD and/or non-AD control cases induce seeding in the retina and/or propagation into the brain. TAU58 mice developed retinal pTau pathology at 6 months of age, increasing in severity and extent with age. TAU58 mice showed reduced retinal ganglion cell density compared to wild-type mice, which declined with age and pTau pathology progression. Brain lysates from non-AD Braak neurofibrillary tangle (NFT) stage I controls increased retinal pTau pathology after subretinal injection compared to phosphate-buffered saline (PBS) but did not accelerate pTau pathology in the brain. In contrast, subretinally injected AD brain lysates accelerated pTau pathology in the retina and the contralateral superior colliculus. Subretinal injection of AD brain lysates, but not of non-AD brain, induced in this context a neuroinflammatory response in the retina and in the contralateral primary visual cortex. These results lead to the following conclusions: (1) Brain lysates from AD and non-AD sources can accelerate tauopathy within the retina. (2) The anterograde propagation of pTau pathology from the retina to the brain can be triggered by subretinal injections of AD brain lysates. (3) Such subretinal injections also provoke a neuroinflammatory response in both the retina and the visual cortex. (4) The accumulation of retinal pTau is associated with the degeneration of the involved ganglion cells, indicating that retinal tauopathy might contribute to vision impairment in the elderly and underscore the retina's potential role in spreading tau pathology to the brain.
大脑神经元中异常磷酸化 Tau 蛋白（pTau）的积累是阿尔茨海默病（AD）的一个病理标志。pTau 病理改变也出现在 AD 患者的视网膜中。因此，出现了这样的问题：视网膜 pTau 是否能作为诱导大脑 pTau 病理改变的潜在种子，以及视网膜 pTau 病理改变是否会导致视网膜神经元变性。为了解决这些问题，我们（1）对 TAU58 小鼠视网膜中的 pTau 病理改变进行了表征，（2）确定了 pTau 病理改变对视网膜神经节细胞密度的影响，（3）使用该小鼠模型来测试来自 AD 和/或非 AD 对照病例的脑裂解物是否会在视网膜中诱导种子形成和/或传播到大脑中。TAU58 小鼠在 6 个月大时出现视网膜 pTau 病理改变，并随着年龄的增长，其严重程度和范围不断增加。与野生型小鼠相比，TAU58 小鼠的视网膜神经节细胞密度降低，且随着年龄增长和 pTau 病理改变的进展而下降。与磷酸盐缓冲盐水（PBS）相比，视网膜下注射来自非 AD 布拉赫神经原纤维缠结（NFT）I 期对照的脑裂解物后，视网膜 pTau 病理改变增加，但并未加速大脑中的 pTau 病理改变。相比之下，视网膜下注射 AD 脑裂解物可加速视网膜和对侧上丘中的 pTau 病理改变。在这种情况下，视网膜下注射 AD 脑裂解物而非非 AD 脑裂解物会在视网膜和对侧初级视觉皮层中诱导神经炎症反应。这些结果得出以下结论：（1）来自 AD 和非 AD 来源的脑裂解物可加速视网膜内的 tau 蛋白病。（2）视网膜下注射 AD 脑裂解物可触发 pTau 病理改变从视网膜向大脑的顺行传播。（3）这种视网膜下注射还会在视网膜和视觉皮层中引发神经炎症反应。（4）视网膜 pTau 的积累与受累神经节细胞的变性有关，这表明视网膜 tau 蛋白病可能导致老年人视力受损，并强调了视网膜在将 tau 病理改变传播到大脑中的潜在作用。
