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Spatiotemporal char...
Spatiotemporal characterization of cellular tau pathology in the human locus coeruleus–pericoerulear complex by three-dimensional imaging
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Gilvesy, A. (author)
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Husen, E. (author)
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Magloczky, Z. (author)
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Mihaly, O. (author)
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Hortobágyi, T. (author)
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- Kanatani, S. (author)
- Karolinska Institutet
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Heinsen, H. (author)
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Renier, N. (author)
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- Hökfelt, T. (author)
- Karolinska Institutet
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- Mulder, J. (author)
- Karolinska Institutet
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- Uhlén, Mathias (author)
- KTH,Science for Life Laboratory, SciLifeLab
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Kovacs, G. G. (author)
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Adori, C. (author)
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(creator_code:org_t)
- 2022-08-30
- 2022
- English.
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In: Acta Neuropathologica. - : Springer Nature. - 0001-6322 .- 1432-0533. ; 144:4, s. 651-676
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
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- 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 the cerebellum and medulla. 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. Our 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
Keyword
- Alzheimer’s disease
- Locus coeruleus
- Tau pathology
- Three-dimensional
- iDISCO
- light sheet fluorescence microscopy
- tau protein
- tyrosine 3 monooxygenase
- Alzheimer disease
- animal experiment
- animal model
- Article
- brain region
- cell body
- cell heterogeneity
- cell maturation
- cell structure
- cell surface
- controlled study
- cytoarchitecture
- dorsal noradrenergic bundle
- forebrain
- human
- human cell
- human tissue
- image reconstruction
- image segmentation
- immunohistochemistry
- light-sheet microscopy
- limit of quantitation
- locus ceruleus
- mouse
- neurofibrillary tangle
- neuropathology
- nonhuman
- practice guideline
- protein degradation
- spatiotemporal analysis
- three-dimensional imaging
- metabolism
- pathology
- Humans
- Imaging
- Three-Dimensional
- Neurofibrillary Tangles
- tau Proteins
Publication and Content Type
- ref (subject category)
- art (subject category)
Find in a library
To the university's database
- By the author/editor
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Gilvesy, A.
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Husen, E.
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Magloczky, Z.
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Mihaly, O.
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Hortobágyi, T.
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Kanatani, S.
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show more...
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Heinsen, H.
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Renier, N.
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Hökfelt, T.
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Mulder, J.
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Uhlén, Mathias
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Kovacs, G. G.
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Adori, C.
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Neurology
- Articles in the publication
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Acta Neuropathol ...
- By the university
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Royal Institute of Technology
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Karolinska Institutet