Braak Heiko, Mayer Benjamin, Feldengut Simone, Schön Michael, Del Tredici Kelly
Department of Neurology, Center for Biomedical Research, Clinical Neuroanatomy, University of Ulm, Helmholtzstrasse 8/1, 89081, Ulm, Germany.
Institute of Epidemiology and Medical Biometry, University of Ulm, 89075, Ulm, Germany.
Acta Neuropathol. 2025 May 23;149(1):50. doi: 10.1007/s00401-025-02862-x.
Sporadic Alzheimer's disease (AD) involves specific neuronal types and progresses in a systematic manner, permitting subdivision into six neuropathological stages. Neurofibrillary tangle (NFT) stages I-III display abnormal tau inclusions confined to subcortical nuclei and temporal allocortical regions, frequently without amyloid β (Aβ) deposition. We previously suggested a sequence of neuronal involvement in AD that could proceed from entorhinal pre-α cells to hippocampal prosubicular pyramidal cells and the CA1/CA2 sectors, from there to the thorny excrescences on mossy cells in CA3/CA4, and, finally, from the mossy cells to dentate fascia (Fd) granular cells. Here, we aimed to see if associations existed between the early NFT stages I-III, when Aβ deposits are frequently absent, and the following four categories: (1) anatomical regions and abnormal morphological tau changes in region-specific layers, (2) nerve cell loss, (3) APOE genotype, and (4) the trajectory (directionality) of tau progression in the hippocampal formation. To do so, we examined the transentorhinal/entorhinal regions and hippocampal formation using AT8-immunohistochemistry in 100 µm sections from N = 308 brains with tau inclusions lacking Aβ deposits between NFT stages I and III (average age at death 66.7 years for females, 66.4 years for males). Our results indicated a significantly (p < 0.001) ordered progression of abnormal tau in a direction opposite to currently known unidirectional intrahippocampal connections, thereby indirectly supporting the idea of transneuronal abnormal tau spreading, i.e., anterogradely, through the hippocampal formation. Tau-related neuronal loss was also significant (p < 0.001 for the transentorhinal/entorhinal regions and for sectors CA1/CA2 and p = 0.003 for CA3/CA4/Fd). These findings challenge the amyloid cascade and the PART hypotheses, corroborating the concept that early AD-related tau inclusions and tau-related neuronal loss occur independently of Aβ deposition.
散发性阿尔茨海默病（AD）累及特定的神经元类型，并以一种系统性的方式进展，可细分为六个神经病理学阶段。神经原纤维缠结（NFT）的I-III期表现为异常的tau包涵体，局限于皮质下核团和颞叶原皮质区域，通常无淀粉样β蛋白（Aβ）沉积。我们之前提出了AD中神经元受累的顺序，可能从内嗅前α细胞发展到海马旁下托锥体细胞和CA1/CA2区，从那里到CA3/CA4区苔藓细胞上的棘状突起，最后从苔藓细胞到齿状回颗粒细胞。在此，我们旨在探究在Aβ沉积通常缺失的早期NFT的I-III期与以下四类情况之间是否存在关联：（1）解剖区域及区域特异性层中异常的形态学tau变化，（2）神经细胞丢失，（3）APOE基因型，以及（4）海马结构中tau进展的轨迹（方向性）。为此，我们使用AT8免疫组织化学方法，对来自N = 308例大脑的100μm切片中的跨内嗅/内嗅区域和海马结构进行了检查，这些大脑在NFT的I期和III期之间存在缺乏Aβ沉积的tau包涵体（女性平均死亡年龄66.7岁，男性平均死亡年龄66.4岁）。我们的结果表明，异常tau呈显著（p < 0.001）有序进展，其方向与目前已知的海马内单向连接方向相反，从而间接支持了跨神经元异常tau传播的观点，即通过海马结构顺行传播。tau相关的神经元丢失也很显著（跨内嗅/内嗅区域以及CA1/CA2区p < 0.001，CA3/CA4/齿状回p = 0.003）。这些发现对淀粉样蛋白级联假说和PART假说提出了挑战，证实了早期AD相关的tau包涵体和tau相关的神经元丢失独立于Aβ沉积而发生的概念。
