Fibrillogenesis in Alzheimer's disease of amyloid β peptides and apolipoprotein E
Open accessAbstract
A central event in Alzheimer's disease is the conformational change from normally circulating soluble amyloid beta peptides (A beta) and tau proteins into amyloid fibrils, in the form of senile plaques and neurofibrillary tangles respectively. The apolipoprotein E (apoE) gene locus has recently been associated with late-onset Alzheimer's disease. It is not know whether apoE plays a direct role in the pathogenesis of the disease. In the present work we have investigated whether apoE can affect the known spontaneous in vitro formation of amyloid-like fibrils by synthetic A beta analogues using a thioflavine-T assay for fibril formation, electron microscopy and Congo Red staining. Our results show that, under the conditions used, apoE directly promotes amyloid fibril formation, increasing both the rate of fibrillogenesis and the total amount of amyloid formed. ApoE accelerated fibril formation of both wild-type A beta-(1-40) and A beta-(1-40A), an analogue created by the replacement of valine with alanine at residue 18, which alone produces few amyloid-like fibrils. However, apoE produced only a minimal effect on A beta-(1-40Q), found in the Dutch variant of Alzheimer's disease. When recombinant apoE isoforms were used, apoE4 was more efficient than apoE3 at enhancing amyloid formation. These in vitro observations support the hypothesis that apoE acts as a pathological chaperone, promoting the beta-pleated-sheet conformation of soluble A beta into amyloid fibres, and provide a possible explanation for the association of the apoE4 genetic isoform with Alzheimer's disease.
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Several groups have reported that all three apoE isoforms increase Aβ fibrillogenesis, with the effect being most exacerbated with ApoE4 and the least with ApoE2.
“While there are a few conflicting reports (Kim et al., 2009a), several groups have reported that all three apoE isoforms increase Aβ fibrillogenesis, with the effect being most exacerbated with ApoE4 and the least with ApoE2 (Ma et al., 1994; Wisniewski et al., 1994; Castano et al., 1995).”
From Haploinsufficiency of Human APOE Reduces Amyloid Deposition in a Mouse Model of Amyloid-β Amyloidosis (2011) · cites this paper as Castano et al., 1995
The Results and Table 2 show that apoE4 enhanced Aβ amyloid formation more than apoE3 in vitro; apoE3 also increased the fluorescence measure at the 10:1 peptide-to-apoE ratio. The paper did not test apoE2, so it cannot support the claim that all three isoforms increase fibrillogenesis or that apoE2 has the least effect. Page numbers are not available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredApoE appears to affect Aβ accumulation by modulating both Aβ aggregation and clearance.
“ApoE appears to affect Aβ accumulation by modulating both Aβ aggregation and clearance (Ma et al., 1994; Wisniewski et al., 1994; Castano et al., 1995; Sadowski et al., 2006; Deane et al., 2008; Jiang et al., 2008; Castellano et al., 2011).”
From Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis (2012) · cites this paper as Castano et al., 1995
The Results report more rapid Aβ(1–40) aggregation in the presence of apoE, and the Discussion describes apoE as promoting fibril assembly in vitro. Our copy does not address whether apoE modulates Aβ clearance, so it supports only the aggregation part of the claim (searched: clearance, removal, degradation and transport). (LLM, conf=0.91)
Experimental — accuracy not yet measuredThe major role of APOE in Aβ pathology is direct promotion of Aβ fibrillization.
“the major role is direct promotion of Aβ fibrillization (Castano et al, 1995; Ma et al, 1994; Wisniewski et al, 1994)”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Castano et al, 1995
The Introduction reports that apoE accelerated Aβ fibril formation in vitro, and the Discussion says apoE may promote Aβ assembly. But the Discussion also describes apoE as one of several possible contributors whose importance varies among cases of Alzheimer’s disease; it does not establish direct fibrillization as APOE’s major role in Aβ pathology. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPrevious studies have demonstrated that apoE increases Aβ fibrillogenesis under certain in vitro Aβ aggregation conditions.
“Previous studies have demonstrated that apoE increases Aβ fibrillogenesis under certain in vitro Aβ aggregation conditions (Ma et al., 1994; Wisniewski et al., 1994; Castano et al., 1995).”
From Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis (2012) · cites this paper as Castano et al., 1995
Others found that apoE4 was more efficient than apoE3 at increasing Aβ40 aggregation.
“Subsequently, others also found that apoE4 was more efficient than apoE3 at increasing Aβ40 aggregation (Castano et al., 1995; Wisniewski et al., 1994).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Castano et al., 1995
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- Authors
- Castano, E. M., Prelli, F., Wisniewski, T., Golabek, A., Kumar, R. A., Soto, C., & Frangione, B.
- Affiliations
- Departments of Pathology, New York University Medical Center, 550 First Avenue, Room TH 427, New York, NY 10016, U.S.A.
- NYU Langone Health (US)
- Venue
- Biochemical Journal
- Publisher
- Portland Press Ltd.
- Published
- 1995-03-01
- Volume
- 306
- Issue
- 2
- Pages
- 599-604
- ISSN
- 0264-6021 (ISSN-L)
- 1470-8728
- PMC
- PMC1136559
- OpenAlex
- W1858469465
- Cited by
- 267
- References
- 5
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 12 · 2022: 9 · 2021: 9 · 2020: 8 · 2019: 3 · 2018: 3 · 2017: 7 · 2016: 3 · 2015: 3 · 2014: 7 · 2013: 4 · 2012: 9
- FWCI
- 12.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Biochemical Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r35ag010953-07)
- National Institute on Aging (AG00542, AG10953, AG05891)
- 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
- Alzheimer's disease, amyloid-beta, apolipoprotein E, fibril formation, amyloid fibrils, APOE ε4, APOE3, Congo red staining, late-onset Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Amino Acid Sequence, Apolipoproteins E, Congo Red, Humans, Microscopy, Electron, Molecular Sequence Data, Protein Conformation, Recombinant Proteins, Staining and Labeling, Amyloid beta-Peptides, Neurofibrillary Tangles
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