Fig. 4

VPS35 co-localizes with specific disease-related AT8-positive tau lesions in post-mortem frontal cortices from major tauopathies. A Co-immunostaining of AD brain sections revealed a robust colocalization between VPS35 and phospho-tau (white arrowheads) in neuronal tau lesions, including pre-tangles (series 1), neurofibrillary tangles (NFTs) (series 2), and more mature NFTs (series 3). Co-localization between VPS35 and AT8 phospho-tau is common in NFT-burdened brain regions (series 4). B VPS35 is sequestered in APs in CBD brains (series 1–4). Individual APs in 4 are denoted by dashed circles. C VPS35 is sequestered in CBs in PSP brains (series 1–3, white arrowheads indicate co-localization). D Circumscribed neuronal PBs displayed VPS35 punctate staining within the cores of the tau inclusions (series 1), whereas in larger ‘horseshoe’ shaped neuronal PBs VPS35 puncta were more evenly distributed (series 2, white arrowheads indicate co-localization). In addition, in PiD we observed frequent occurrence of VPS35 thread structures (VTs) that colocalized with AT8 but were mostly AT8-negative (series 1–2, VTs insert). E VPS35 is sequestered in glial phospho-tau inclusions (GTs), including oligodendroglial (series 1, Crop GTs/VTs insert) and astrocytic [4,5,6] phospho-tau inclusions in PiD. Small clusters of VTs were sometimes observed in the vicinity of AT8 oligodendroglial inclusions (series 1, Crop GTs/VTs and Crop VTs inserts). Larger clusters of VTs varied in lengths (series 2). In dense areas of VTs some portion of them was AT8 positive (series 3). Grey matter Pick body inclusions were positive for VPS35 (series 7, white arrowheads), yet at the border of the white matter, smaller spherical inclusions were negative for VPS35. F Quantification of VPS35-positive phospho-tau lesions from n = 3 cases/tauopathy showing the relative area of overlap between AT8 and VPS35 in tauopathy lesions. Modified violin plots with data points show individual lesions plotted against relative overlap area. Lesions are categorized into co-localization categories based on their relative area of overlap. Red lines indicate median values. Pie charts underneath the violin plots illustrate the relative proportions of lesions with different degrees of co-localization. Abbreviations: VPS35, vacuolar protein sorting-associated protein 35; AD, Alzheimer’s disease; PiD, Pick’s disease; CBD, corticobasal degeneration; PSP, progressive supranuclear palsy; PTs, pre-tangles; NFTs, neurofibrillary tangles; TANCs, tangle-associated neuritic clusters; APs, astrocytic plaques; CBs, coiled bodies; PBs, Pick bodies; VTs, VPS35 threads; GT, glial tau; NTs, neuropil threads; NP, neuritic plaques; SPL, small phospho-tau lesions; TA, tufted astrocytes; GLO-NFT, globose NFTs; GM PB, grey matter Pick Body; WM PB, white matter PB