Spatiotemporal characterization of cellular tau pathology in the human locus coeruleus–pericoerulear complex by three-dimensional imaging

作者：Abris Gilvesy, Evelina Husén, Zsófia Maglóczky, Orsolya Salamonné Mihály, Tibor Hortobágyi, Shigeaki Kanatani, Helmut Heinsen, Nicolas Renier, Tomas Hökfelt, Jan Mulder, Mathias Uhlén, Gábor G. Kovács, Csaba Ádori · 发表于：Acta Neuropathologica · 年份：2022 · DOI：10.1007/s00401-022-02477-6 · 被引用次数：68 · 研究领域：Alzheimer's disease research and treatments、Neuroinflammation and Neurodegeneration Mechanisms、Neuroscience and Neuropharmacology Research

Abstract Tau pathology of the noradrenergic locus coeruleus (LC) is a hallmark of several age-related neurodegenerative disorders, including Alzheimer’s disease. However, a comprehensive neuropathological examination of the LC is difficult due to its small size and rod-like shape. To investigate the LC cytoarchitecture and tau cytoskeletal pathology in relation to possible propagation patterns of disease-associated tau in an unprecedented large-scale three-dimensional view, we utilized volume immunostaining and optical clearing technology combined with light sheet fluorescence microscopy. We examined AT8 + pathological tau in the LC/pericoerulear region of 20 brains from Braak neurofibrillary tangle (NFT) stage 0–6. We demonstrate an intriguing morphological complexity and heterogeneity of AT8 + cellular structures in the LC, representing various intracellular stages of NFT maturation and their diverse transition forms. We describe novel morphologies of neuronal tau pathology such as AT8 + cells with fine filamentous somatic protrusions or with disintegrating soma. We show that gradual dendritic atrophy is the first morphological sign of the degeneration of tangle-bearing neurons, even preceding axonal lesions. Interestingly, irrespective of the Braak NFT stage, tau pathology is more advanced in the dorsal LC that preferentially projects to vulnerable forebrain regions in Alzheimer’s disease, like the hippocampus or neocortical areas, compared to the ventral LC projecting to ...