Lysosomal protease inhibitors induce meganeurites and tangle-like structures in entorhinohippocampal regions vulnerable to Alzheimer's disease.
Lysosomal protease inhibitors induce signs of human brain aging in rat hippocampal slices. The present studies tested if they (1) also cause neurofibrillary tangles and (2) reproduce regional patterns of pathology found in Alzheimer's disease (AD). Slices of hippocampus plus retrohippocampal cortex were prepared from rats at postnatal days 6-7 and maintained for 2-5 weeks. In agreement with earlier studies, 6- to 12-day infusions of selective (ZPAD) or generalized (chloroquine) inhibitors of lysosomal proteases generated meganeurites of the type found in aged human cortex. Surveys and quantitative analyses established that the meganeurites developed almost exclusively in AD vulnerable regions. Antibodies against the phosphorylated tau protein in neurofibrillary tangles labeled thick filaments running through neurons in the superficial layers of entorhinal cortex in 6-day ZPAD-treated slices. The general appearance of the stained structures resembled that of early stage tangles. More mature tangle-like profiles were found at a number of sites after longer incubations; these were threefold more frequent in the superficial (AD vulnerable) than in the deep layers of the entorhinal cortex. Immunoblots indicated that essentially all phosphorylated tau labeling in the slices involved approximately 29-kDa fragments of the native isoforms. These findings establish that lysosomal dysfunction triggers the parallel formation of meganeurites and tangles with the regional distribution of both effects reflecting that for AD vulnerability.
Bi
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Human Behavior, University of California, Irvine, California, 92697-3800, USA.
Zhou
J
J
Lynch
G
G
D000368:Aged; D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors; D002738:Chloroquine / Q000633:toxicity; D003546:Cysteine Endopeptidases; D003978:Diazomethane / Q000031:analogs & derivatives* / Q000633:toxicity; D010450:Endopeptidases; D018728:Entorhinal Cortex / Q000187:drug effects / Q000473:pathology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D016501:Neurites / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D016874:Neurofibrillary Tangles / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
D015842:Serine Proteinase Inhibitors; C024918:benzyloxycarbonylphenylalanylalanine diazomethyl ketone; D003978:Diazomethane; D002738:Chloroquine; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534280:Ctsl protein, rat