Rodriguez-Rodriguez Patricia, Wang Wei, Tsagkogianni Christina, Feng Irena, Morello-Megias Ana, Jain Kaahini, Alanko Vilma, Kahvecioglu Han-Ali, Mohammadi Elyas, Li Xiaofei, Flajolet Marc, Sandebring-Matton Anna, Maioli Silvia, Vidal Noemi, Milosevic Ana, Roussarie Jean-Pierre
Department of Neurobiology Care Sciences and Society, Karolinska Institute. Stockholm, Sweden.
Bioinformatics Resource Center, The Rockefeller University. New York, NY, USA.
bioRxiv. 2025 Feb 3:2024.12.31.630881. doi: 10.1101/2024.12.31.630881.
Neurons located in layer II of the entorhinal cortex (ECII) are the primary site of pathological tau accumulation and neurodegeneration at preclinical stages of Alzheimer's disease (AD). Exploring the alterations that underlie the early degeneration of these cells is essential to develop therapies that curb the disease before symptom onset. Here we performed cell-type specific profiling of human EC at the onset of AD neuropathology. We identify an early response to amyloid pathology by microglia and oligodendrocytes. Importantly, we provide the first insight into neuronal alterations that coincide with incipient tau pathology: the signaling pathway for Reelin, recently shown to be a major AD resilience gene is dysregulated in ECII neurons, while the secreted synaptic organizer molecules NPTX2 and CBLN4, emerging AD biomarkers, are downregulated in surrounding neurons. By uncovering the complex multicellular landscape of EC at these early AD stages, this study paves the way for detailed characterization of the mechanisms governing NFT formation and opens long-needed novel therapeutic avenues.
位于内嗅皮层第II层（ECII）的神经元是阿尔茨海默病（AD）临床前期病理性tau蛋白积累和神经退行性变的主要部位。探索这些细胞早期退化背后的改变对于开发在症状出现前抑制该疾病的疗法至关重要。在此，我们在AD神经病理学开始时对人类EC进行了细胞类型特异性分析。我们确定了小胶质细胞和少突胶质细胞对淀粉样蛋白病理学的早期反应。重要的是，我们首次深入了解了与初期tau蛋白病理学同时出现的神经元改变：最近被证明是主要AD抵抗基因的Reelin信号通路在ECII神经元中失调，而新兴的AD生物标志物分泌性突触组织者分子NPTX2和CBLN4在周围神经元中下调。通过揭示这些早期AD阶段EC的复杂多细胞格局，本研究为详细表征控制神经原纤维缠结形成的机制铺平了道路，并开辟了长期以来急需的新治疗途径。
