Progress Toward Identification of Protease Activity Involved in Proteolysis of Apolipoprotein E in Human Brain

Marques, Marcos A.; Owens, Phillip A.; Crutcher, Keith A.

doi:10.1385/jmn:24:1:073

Cited by 29Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchProtease and Inhibitor Mechanisms

Progress Toward Identification of Protease Activity Involved in Proteolysis of Apolipoprotein E in Human Brain

Marques, Marcos A., Owens, Phillip A., Crutcher, Keith A.·2004·Journal of Molecular Neuroscience

DOI 10.1385/jmn:24:1:073

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Abstract

Apolipoprotein E (apoE) genotype is the single most important genetic risk factor for the most common (sporadic) form of Alzheimer's disease (AD). Increasing evidence supports the hypothesis that the presence of the E4 isoform of this cholesterol-binding protein contributes directly to disease risk, age of onset, and severity of the neuropathology. For example, studies in transgenic mice demonstrate that apoE is necessary for the formation of plaques with neuritic pathology. The precise mechanism by which apoE contributes to the disease remains unknown. However, several lines of investigation from a number of laboratories now point to a role for proteolytic fragments of apoE in the formation of both plaques and tangles, the two pathological hallmarks of the disease. In particular, the C-terminal portion of apoE has been implicated in binding to amyloid and is localized to plaques. The N-terminal domain, on the other hand, is neurotoxic in culture and has been localized to, and implicated in the formation of, neurofibrillary tangles. These results suggest that inhibition of apoE proteolysis is a potential therapeutic strategy for AD. Using human brain homogenates, we have determined that proteolysis of apoE is greatest at acidic pH and can be inhibited by compounds targeting aspartic proteases. The feasibility of screening candidate inhibitors is supported by both ELISA and immunoblotting methods. Future studies will use a combination of in vitro and in vivo assays to test the…

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“It has also been recognized that co-deposition of apoE in Aβ plaques promotes focal neurodegeneration in humans and in AD Tg mice [22,29,35].”
From Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice (2014) · cites this paper as [35]

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Authors: Marques, M. A., Owens, P. A., & Crutcher, K. A.
Affiliations: University of Cincinnati (US)
Corresponding author: Crutcher, Keith A.
ORCID: Crutcher, Keith A.
Venue: Journal of Molecular Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2004
Volume: 24
Issue: 1
Pages: 073-080
ISSN: 0895-8696 (ISSN-L)
DOI: 10.1385/jmn:24:1:073
OpenAlex: W2021255192
Cited by: 29
References: 74
Citations by year: 2022: 1 · 2021: 1 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 3 · 2015: 2 · 2014: 3 · 2013: 2 · 2012: 2
FWCI: 0.61
Type: journal article
Language: en
Open access: closed
Locations: Journal of Molecular Neuroscience (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Keywords: apolipoprotein E, Alzheimer's disease, aspartic protease, protease inhibitors, APOE ε4, amyloid plaques, neurofibrillary tangles, human brain, inhibitor screening, transgenic mouse model
MeSH terms: Alzheimer Disease, Animals, Apolipoproteins E, Brain, Drug Evaluation, Preclinical, Enzyme Inhibitors, Humans, Peptide Fragments, Peptide Hydrolases, Neurofibrillary Tangles, Plaque, Amyloid

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Progress Toward Identification of Protease Activity Involved in Proteolysis of Apolipoprotein E in Human Brain

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