神经退行性病

    Propagation of TDP-43 proteinopathy in neurodegenerative disorders
  • Figure 1 (A) Information from layer II neurons in the entorhinal cortex (ERC) travels to the granule cells of the dentate gyrus (DG) via the perforant pathway (Geula, 1998). Mossy fiber axons from the DG granule cells then carry information to CA3, and Schaffer axon collaterals project to the CA1 (Jamshidi et al., 2020). Finally, information from CA1 travels to the subiculum. (B) Hippocampal distribution of TDP-43 mature inclusions and pre-inclusions. (B1) Granule cells of the dentate gyrus show a high density of both mature inclusions (arrows) and pre-inclusions (arrowheads). (B2) CA3 pyramidal cells demonstrate a high abundance of pre-inclusions (arrows) but scarce mature inclusions. (B3) The CA2 subfield shows relatively fewer pre-inclusions compared to the CA3 subfield and a similar absence of mature inclusions. (B4) In the CA1 subfield, pre-inclusions and mature inclusions are virtually absent. Photomicrographs were acquired using 40 μm hippocampal sections stained with a human phosphorylated TDP-43 antibody and counterstained for Nissl using Cresyl violet. Scale bar: 100 μm.

    The hippocampus is a medial temporal lobe structure primarily involved in learning and memory; it has been highly studied in the context of normal human cognition as well as neurodegenerative diseases, and consequently its circuitry has been charted in great detail (Geula, 1998). Briefly, the hippocampus is comprised of the dentate gyrus (DG), the Ammon’s horn, and the subiculum (Figure 1). 

    In our study (Jamshidi et al., 2020), we quantified TDP-43 pre-inclusions and mature inclusions using unbiased stereological counting methods in the granule cell layer of the DG and pyramidal cell layer of CA1-3. Hippocampal sections were cut at a thickness of 40 μm, stained with an antibody recognizing human TDP-43 phosphorylated (p) at Ser409/410, and counterstained for Nissl using Cresyl violet. TDP-43 pre-inclusions were identified by the appearance of smooth, granular, or fibrillary accumulation of phosphorylated TDP-43 protein in the cytoplasm or nucleus, and mature inclusions were identified as neuronal intranuclear inclusions, neuronal cytoplasmic inclusions, or dystrophic neurites, all showing  pSer409/410 immunoreactivity (Kim et al., 2019). All participants in our study (Jamshidi et al., 2020) carried clinical diagnoses of PPA (n = 5) or bvFTD (n = 2) and were found to have TDP-43 pathology at autopsy (n = 4 type A and n = 3 type B). Our findings revealed that the density of mature TDP-43 inclusions was significantly higher in the DG, bilaterally, relative to other hippocampal subregions (Figure 1B). Both the DG and CA3 had higher densities of pre-inclusions than CA1 and CA2, and within CA3, the density of pre-inclusions was significantly higher than the density of mature inclusions (Figure 1B). Moreover, across the CA subfields, we observed mostly TDP-43 pre-inclusions and very few mature inclusions (Figure 1B).


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  • 发布日期: 2022-01-12  浏览: 368
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