Elsevier

Experimental Neurology

Volume 158, Issue 2, August 1999, Pages 312-327
Experimental Neurology

Regular Article
Lysosomal Protease Inhibitors Induce Meganeurites and Tangle-like Structures in Entorhinohippocampal Regions Vulnerable to Alzheimer's Disease

https://doi.org/10.1006/exnr.1999.7087Get rights and content

Abstract

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 ∼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.

References (57)

  • A. Nieto et al.

    Characterization of tau protein present in microtubules and paired helical filaments of Alzheimer's disease patient's brain

    J. Neurosci.

    (1990)
  • H. Polet

    Effects of fibroblastic growth factor on protein degradation, the migration of nonhistone proteins to the nucleus and DNA synthesis in diploid fibroblasts

    Exp. Cell Res.

    (1987)
  • D.P. Purpura et al.

    Distortion of neuronal geometry and formation of aberrant synapses in neuronal storage disease

    Brain Res.

    (1976)
  • L. Stoppini et al.

    A simple method for organotypic cultures of nervous tissue

    J. Neurosci. Methods

    (1991)
  • J.H. Su et al.

    Plaque biogenesis in brain aging and Alzheimer's disease. I. Progressive changes in phosphorylation states of paired helical filaments and neurofilaments

    Brain Res.

    (1996)
  • J.H. Su et al.

    Transneuronal degeneration in the spread of Alzheimer's disease pathology: Immunohistochemical evidence for the transmission of tau hyperphosphorylation

    Neurobiol. Dis.

    (1997)
  • A.P. Yong et al.

    Lysosomal dysfunction results in lamina specific meganeurite formation in frontal cortex

    Exp. Neurol.

    (1999)
  • M. Baba et al.

    Two distinct pathways for targeting proteins from the cytoplasm to the vacuole/lysosome

    J. Cell Biol.

    (1997)
  • B. Bahr et al.

    Induction of β-amyloid containing polypeptides in hippocampus: Evidence for a concomitant loss of synaptic proteins and interactions with an excitotoxin

    Exp. Neurol.

    (1994)
  • B. Bahr et al.

    Amyloid beta-protein is selectively internalized by hippocampal field CA1 and causes neurons to accumulate amyloidogenic carboxyterminal fragments of the amyloid precursor protein

    J. Comp. Neurol.

    (1998)
  • J.D. Bancroft et al.

    Theory and Practice of Histological Techniques

    (1996)
  • M. Bannay-Schwartz et al.

    The distribution of cathepsin D activity in adult and aging human brain regions

    J. Neurochem.

    (1992)
  • E. Bednarski et al.

    Cytosolic proteolysis of tau by cathepsin D in hippocampus following suppression of cathepsins B and L

    J. Neurochem.

    (1996)
  • E. Bednarski et al.

    Selective suppression of cathepsin L results from elevations in lysosomal pH and is followed by proteolysis of tau protein

    NeuroReport

    (1998)
  • E. Bednarski et al.

    Suppression of cathepsins B and L causes a proliferation of lysosomes and the formation of meganeurites in hippocampus

    J. Neurosci.

    (1997)
  • E. Braak et al.

    A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads

    Acta Neuropathol.

    (1994)
  • H. Braak

    Architectonics as seen by lipofuscin stains

  • H. Braak et al.

    Pathology of Alzheimer's disease

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