Protease inhibitor coinfusion with amyloid β-protein results in enhanced deposition and toxicity in rat brain
Open accessAbstract
Amyloid β-protein, Aβ, is normally produced in brain and is cleared by unknown mechanisms. In Alzheimer’s disease (AD), Aβ accumulates in plaque-like deposits and is implicated genetically in neurodegeneration. Here we investigate mechanisms for Aβ degradation and Aβ toxicityin vivo, focusing on the effects of Aβ40, which is the peptide that accumulates in apolipoprotein E4-associated AD. Chronic intraventricular infusion of Aβ40 into rat brain resulted in limited deposition and toxicity. Coinfusion of Aβ40 with the cysteine protease inhibitor leupeptin resulted in increased extracellular and intracellular Aβ immunoreactivity. Analysis of gliosis and TUNEL in neuron layers of the frontal and entorhinal cortex suggested that leupeptin exacerbated Aβ40 toxicity. This was supported further by the neuronal staining of cathepsin B in endosomes or lysosomes, colocalizing with intracellular Aβ immunoreactivity in pyknotic cells. Leupeptin plus Aβ40 caused limited but significant neuronal phospho-tau immunostaining in the entorhinal cortex. Intriguingly, Aβ40 plus leupeptin induced intracellular accumulation of the more toxic Aβ, Aβ42, in a small group of septal neurons. Leupeptin infusion previously has been reported to interfere with lysosomal proteolysis and to result in the accumulation of lipofuscin, dystrophic neurites, tau- and ubiquitin-positive inclusions, and structures resembling paired helical filaments. Coinfusion of Aβ40 with the serine protease inhibitor aprotinin also increased diffuse extracellular deposition but reduced astrocytosis and TUNEL and was not associated with intracellular Aβ staining. Collectively, these data suggest that an age or Alzheimer’s-related defect in lysosomal/endosomal function could promote Aβ deposition and DNA fragmentation in neurons and glia similar to that found in Alzheimer’s disease.
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In the brains of human AD patients and transgenic AD mouse models, infiltration of activated astrocytes and microglia is seen in the area of Aβ plaques.
“In the brains of human AD patients and transgenic AD mouse models, infiltration of activated astrocytes and microglia are seen in the area of A plaques (Itagaki et al., 1989;Frautschy et al., 1998;Stalder et al., 1999;Bornemann et al., 2001;Matsuoka et al., 2001)”
From Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model (2008) · cites this paper as Frautschy et al., 1998
The significant decrease in activated microglia and astrocytes seen in ATRA-treated APP/PS1 mice can be attributed to its inhibition of Aβ accumulation.
“Given the central role of fibrillar A in the activation of microglia and astrocytes seen in AD brain (Rozemuller et al., 2005) and in AD animal models (Frautschy et al., 1998;Apelt and Schliebs, 2001;Matsuoka et al., 2001), the significant decrease in activated microglia and astrocytes seen in the ATRA-treated APP/PS1 mice can be attributed to its inhibition of A accumulation.”
From Retinoic Acid Attenuates β-Amyloid Deposition and Rescues Memory Deficits in an Alzheimer's Disease Transgenic Mouse Model (2008) · cites this paper as Frautschy et al., 1998
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- Authors
- Frautschy, S. A., Horn, D. L., Sigel, J. J., Harris-White, M. E., Mendoza, J. J., Yang, F., Saido, T. C., & Cole, G. M.
- Affiliations
- University of California, Los Angeles (US)
- RIKEN (JP)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 1998-10-15
- Volume
- 18
- Issue
- 20
- Pages
- 8311-8321
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- OpenAlex
- W4328001100
- Cited by
- 65
- References
- 64
- Citations by year
- 2023: 1 · 2020: 2 · 2019: 1 · 2017: 2 · 2016: 3 · 2013: 1 · 2012: 2
- FWCI
- 2.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, public-domain)
- Funders
- National Institute on Aging (AG1125, R01AG016793, R01AG010685, AG10685)
- National Cancer Institute (U01CA091343)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- amyloid-beta, Aβ40, amyloid-beta 42, leupeptin, aprotinin, cysteine protease inhibitors, serine protease inhibitors, lysosomal dysfunction, endosomal dysfunction, amyloid deposition, neurotoxicity, cathepsin B, tau phosphorylation, DNA fragmentation, astrocyte activation, gliosis, Alzheimer's disease, entorhinal cortex, septal neurons, intraventricular infusion
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