Spatiotemporal characterization of tau pathology and dendritic atrophy in the human locus coeruleus

Abstract

AbstractBackgroundTau pathology of the noradrenergic locus coeruleus (LC) is a hallmark of several age‐related neurodegenerative disorders, including Alzheimer’s disease. However, comprehensive neuropathological examination of the LC is difficult due to its small size and rod‐like shape.MethodTo investigate the LC cytoarchitecture and tau cytoskeletal pathology in relation to possible propagation patterns of disease‐associated tau in a large‐scale and high resolution three‐dimensional view, we applied the state‐of‐the‐art volume immunostaining and optical clearing technology iDISCO+, 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 to 6.ResultWe demonstrate a high morphological complexity 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. 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. Moreover, already in the precortical Braak 0 stage, 3D analysis reveals clustering tendency and dendro‐dendritic close appositions of AT8+ LC neurons, AT8+ long axons of NFT‐bearing cells that join the ascending dorsal noradrenergic bundle after leaving the LC, as well as AT8+ processes of NFT‐bearing LC neurons that target the 4th ventricle wall.ConclusionOur study suggests that the unique cytoarchitecture, comprised of a densely packed and dendritically extensively interconnected neuronal network with long projections, makes the human LC to be an ideal anatomical template for early accumulation and trans‐neuronal spreading of hyperphosphorylated tau.