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Cited by 28Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Are apolipoprotein E fragments a promising new therapeutic target for Alzheimer’s disease?

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Vecchio, Filomena Lo, Bisceglia, Paola, Imbimbo, Bruno Pietro, Lozupone, Madia, Latino, Raffaela Rita, Resta, Emanuela, Leone, Maurizio, Solfrizzi, Vincenzo +5 more·2022·Therapeutic Advances in Chronic Disease
DOI 10.1177/20406223221081605PMC PMC8935560
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Abstract

Human apolipoprotein E (ApoE) is a 299-amino acid secreted glycoprotein that binds cholesterol and phospholipids. ApoE exists as three common isoforms (ApoE2, ApoE3, and ApoE4) and heterozygous carriers of the ε4 allele of the gene encoding ApoE ( APOE) have a fourfold greater risk of developing Alzheimer’s disease (AD). The enzymes thrombin, cathepsin D, α-chymotrypsin-like serine protease, and high-temperature requirement serine protease A1 are responsible for ApoE proteolytic processing resulting in bioactive C-terminal-truncated fragments that vary depending on ApoE isoforms, brain region, aging, and neural injury. The objectives of the present narrative review were to describe ApoE processing, discussing current hypotheses about the potential role of various ApoE fragments in AD pathophysiology, and reviewing the current development status of different anti-ApoE drugs. The exact mechanism by which APOE gene variants increase/decrease AD risk and the role of ApoE fragments in the deposition are not fully understood, but APOE is known to directly affect tau-mediated neurodegeneration. ApoE fragments co-localize with neurofibrillary tangles and amyloid β (Aβ) plaques, and may cause neurodegeneration. Among anti-ApoE approaches, a fascinating strategy may be to therapeutically overexpress ApoE2 in APOE ε4/ε4 carriers through vector administration or liposomal delivery systems. Another approach involves reducing ApoE4 expression by intracerebroventricular antisense oligonucleotides that significantly decreased Aβ pathology in transgenic mice. Differences in the proteolytic processing of distinct ApoE isoforms and the use of ApoE fragments as mimetic peptides in AD treatment are also under investigation. Treatment with peptides that mimic the structural and biological properties of native ApoE may reduce Aβ deposition, tau hyperphosphorylation, and glial activation in mouse models of Aβ pathology. Alternative strategies involve the use of ApoE4 structure correctors, passive immunization to target a certain form of ApoE, conversion of the ApoE4 aminoacid sequence into that of ApoE3 or ApoE2, and inhibition of the ApoE-Aβ interaction.

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  • Collagenase, MMP-9, neuron-specific α-chymotrypsin-like serine protease, cathepsin D and HtrA1 are proteases able to cleave ApoE4 into neurotoxic fragments.

    “Nevertheless, as previously mentioned in this review, some authors identified collagenase, MMP-9, neuron-specific α-chymotrypsin-like serine protease, cathepsin D and HtrA1 as some of the proteases that are able to cleave ApoE4 into neurotoxic fragments.”

    From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [21]

    The ‘ApoE-cutting enzymes’ section identifies cathepsin D, α-chymotrypsin-like serine protease and HtrA1 as ApoE-cutting enzymes, and says MMP-9 probably mediates fragmentation. It also says ApoE4 cleavage produces more neurotoxic fragments than ApoE3 cleavage. The copy does not identify collagenase as an ApoE-cutting enzyme or establish that each listed protease produces neurotoxic fragments. (LLM, conf=0.88)

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Cited by

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Authors
Vecchio, F. L., Bisceglia, P., Imbimbo, B. P., Lozupone, M., Latino, R. R., Resta, E., Leone, M., Solfrizzi, V., Greco, A., Daniele, A., Watling, M., Panza, F., & Seripa, D.
Affiliations
  • Casa Sollievo della Sofferenza (IT)
  • Chiesi (Italy) (IT)
  • University of Bari Aldo Moro (IT)
  • University of Foggia (IT)
  • Università Cattolica del Sacro Cuore (IT)
  • CNS & Pain Department, TranScrip Ltd, Reading, UK
Corresponding author
Panza, Francesco
ORCID
Venue
Therapeutic Advances in Chronic Disease
Publisher
SAGE Publications
Published
2022-01
Volume
13
Pages
20406223221081605-20406223221081605
ISSN
  • 2040-6223 (ISSN-L)
  • 2040-6231
DOI
10.1177/20406223221081605
PMC
PMC8935560
OpenAlex
W4220869344
Cited by
28
References
49
Citations by year
2026: 5 · 2025: 6 · 2024: 8 · 2023: 9
FWCI
0.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Therapeutic Advances in Chronic Disease (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, cc-by-nc)
Funders
Ministero della Salute
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 › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
apolipoprotein E, Alzheimer's disease, APOE isoforms, APOE ε4, proteolytic processing, thrombin, cathepsin D, amyloid-beta, tau hyperphosphorylation, neurofibrillary tangles, antisense oligonucleotides, liposomal drug delivery, passive immunization

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