title: Autophagic and lysosomal defects in human tauopathies: analysis of post-mortem brain from patients with familial Alzheimer disease, corticobasal degeneration and progressive supranuclear palsy.
abstract: BACKGROUND
  The accumulation of insoluble proteins within neurons and glia cells is a pathological hallmark of several neurodegenerative diseases. Abnormal aggregation of the microtubule-associated protein tau characterizes the neuropathology of tauopathies, such as Alzheimer disease (AD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). An impairment of the lysosomal degradation pathway called macroautophagy, hereafter referred to as autophagy, could contribute to the accumulation of aggregated proteins. The role of autophagy in neurodegeneration has been intensively studied in the context of AD but there are few studies in other tauopathies and it is not known if defects in autophagy is a general feature of tauopathies. In the present study, we analysed autophagic and lysosomal markers in human post-mortem brain samples from patients with early-onset familial AD (FAD) with the APP Swedish mutation (APPswe), CBD and PSP and control individuals.
  
  
  RESULTS
  FAD, CBD and PSP patients displayed an increase in LC3-positive vesicles in frontal cortex, indicating an accumulation of autophagic vesicles. Moreover, using double-immunohistochemistry and in situ proximity ligation assay, we observed colocalization of hyperphosphorylated tau with the autophagy marker LC3 in FAD, CBD and PSP patients but not in control individuals. Increased levels of the lysosomal marker LAMP1 was detected in FAD and CBD, and in addition Cathepsin D was diffusely spread in the cytoplasm in all tauopathies suggesting an impaired lysosomal integrity.
  
  
  CONCLUSIONS
  Taken together, our results indicate an accumulation of autophagic and lysosomal markers in human brain tissue from patients with primary tauopathies (CBD and PSP) as well as FAD, suggesting a defect of the autophagosome-lysosome pathway that may contribute to the development of tau pathology.
authors.affiliation: Karolinska Institutet, Department NVS, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, SE-141 57, Huddinge, Sweden.
authors.forename: Antonio
authors.initials: A
authors.lastname: Piras
authors.affiliation: Roche Pharma Research and Early Development, NORD DTA, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Collin
authors.affiliation: Roche Pharma Research and Early Development, NORD DTA, Roche Innovation Center Basel, Basel, Switzerland.
authors.forename: Fiona
authors.initials: F
authors.lastname: Grüninger
authors.affiliation: Karolinska Institutet, Department NVS, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, SE-141 57, Huddinge, Sweden.|Department Geriatric Medicine, Genet. Unit, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
authors.affiliation: Karolinska Institutet, Department NVS, Center for Alzheimer Research, Division for Neurogeriatrics, Karolinska Institutet, SE-141 57, Huddinge, Sweden. annica.ronnback@ki.se.
authors.forename: Annica
authors.initials: A
authors.lastname: Rönnbäck
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D001343:Autophagy / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008247:Lysosomes / Q000473:pathology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000473:pathology*; D011180:Postmortem Changes; D000071456:Sequestosome-1 Protein; D013494:Supranuclear Palsy, Progressive / Q000473:pathology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D052118:Lysosomal-Associated Membrane Protein 1; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D016875:tau Proteins