Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis

Huynh, Tien-Phat V.; Liao, Fan; Francis, Caroline M.; Robinson, Grace O.; Serrano, Javier Remolina; Jiang, Hong; Roh, Joseph; Finn, Mary Beth; Sullivan, Patrick M.; Esparza, Thomas J.; Stewart, Floy R.; Mahan, Thomas E.; Ulrich, Jason D.; Cole, Tracy; Holtzman, David M.

doi:10.1016/j.neuron.2017.11.014

Cited by 209Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis

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Huynh, Tien-Phat V., Liao, Fan, Francis, Caroline M., Robinson, Grace O., Serrano, Javier Remolina, Jiang, Hong, Roh, Joseph, Finn, Mary Beth +7 more·2017·Neuron

DOI 10.1016/j.neuron.2017.11.014PMC PMC5728673

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Abstract

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease. Previous studies suggest that reduction of apoE levels through genetic manipulation can reduce Aβ pathology. However, it is not clear how reduction of apoE levels after birth would affect amyloid deposition. We utilize an antisense oligonucleotide (ASO) to reduce apoE expression in the brains of APP/PS1-21 mice homozygous for the APOE-ε4 or APOE-ε3 allele. ASO treatment starting after birth led to a significant decrease in Aβ pathology when assessed at 4 months. Interestingly, ASO treatment starting at the onset of amyloid deposition led to an increase in Aβ plaque size and a reduction in plaque-associated neuritic dystrophy with no change in overall plaque load. These results suggest that lowering apoE levels prior to plaque deposition can strongly affect the initiation of Aβ pathology while lowering apoE after Aβ seeding modulates plaque size and toxicity.

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Starting antisense oligonucleotide treatment before Aβ plaque deposition prevented Aβ plaque development, whereas animals treated after the onset of plaque deposition actually showed an increase in Aβ plaque size and plaque-associated dystrophic neurites.
“starting before Aβ plaque deposition prevented Aβ plaque development, whereas animals treated after the onset of plaque deposition actually showed an increase in Aβ plaque size and plaque-associated dystrophic neurites.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [124]
Split into 2 atoms — 0 confirmed, 0 partially supported, 2 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Reducing ApoE levels is generally protective in AD models.
“Reducing ApoE levels is generally protective in AD models1,4–6.”
From Decreased lipidated ApoE‐receptor interactions confer protection against pathogenicity of ApoE and its lipid cargoes in lysosomes (2025) · cites this paper as [5]
The Discussion reports that reducing apoE before amyloid deposition decreased Aβ pathology in the mouse models studied. It also reports that treatment begun at the onset of aggregation did not reduce overall amyloid burden, although it reduced neuritic dystrophy; the Abstract notes increased plaque size. Thus the paper supports protective effects under some conditions, but not an unqualified generalization across AD models or treatment times. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Antisense oligonucleotides against APOE4 have been effective in mouse models of both Aβ plaque deposition and tauopathy, although the timing of administration seems to be crucial for success.
“Another mechanism of decreasing APOE4 expression is using antisense oligonucleotides against APOE4 (Fig. 3d). This method has been effective in mouse models of both Aβ plaque deposition and tauopathy, although the timing of administration seems to be crucial for success124,206.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [124]
The Results and Discussion report that apoE-lowering antisense treatment reduced Aβ plaque pathology in mice when begun before deposition, while treatment begun at the onset of aggregation did not substantially reduce plaque burden. This supports the timing qualification. The paper does not report an antisense-treatment result in a tauopathy mouse model, so it does not support that part of the sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measured
ApoE is enriched in amyloid plaques as a major constituent and promotes Aβ aggregation.
“apoE is enriched in amyloid plaques as a major constituent and promotes Aβ aggregation”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Huynh et al 2017
The Introduction (page unavailable) says apoE co-localizes with amyloid plaques and promotes Aβ aggregation; the Discussion (page unavailable) also describes its role in initial plaque formation. But co-localization does not establish that apoE is enriched in plaques or is a major constituent, and the paper says plaques consist mostly of aggregated Aβ. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Using ASOs to reduce human apoE expression in the brains of APP/PS1-21 mice homozygous for human APOE ε2, ε3 or ε4 allele, apoE4 reduction prior to plaque deposition led to a significant decrease in Aβ pathology, and lowering apoE4 after Aβ seeding resulted in a reduction in plaque-associated neuritic dystrophy.
“apoE4 reduction prior to plaque deposition led to a significant decrease in Aβ pathology, and that lowering apoE4 after Aβ seeding resulted in a reduction in plaque-associated neuritic dystrophy”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Huynh et al 2017
Split into 3 atoms — 2 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured

Administration of ASOs lowered ApoE levels in APOE ε4 homozygous mice, which prevented Aβ plaque formation or related toxicity in an age-dependent way.
“a previous study in APP/PS1 mice showed that administration of ASOs lowered ApoE levels in APOE ε4 homozygous mice, which prevented Aβ plaque formation or related toxicity in an age-dependent way [82].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [82]
The Results report that ASOs lowered apoE in APOE4/4 mice and that treatment begun at birth reduced Aβ plaque area by about 50%. Treatment begun at six weeks did not significantly reduce overall plaque load, although it reduced plaque-associated dystrophic neurites. The paper supports age-dependent reductions in pathology, not prevention of plaque formation or related toxicity. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Lowering ApoE levels prior to the formation of Aβ plaque in APP/PS1 mice reduces Aβ plaque pathology.
“lowering ApoE levels prior to the formation of A 𝛃 plaque in APP/PS1 mice reduces A 𝛃 plaque pathology (4).”
From Therapeutic Idol reduction ameliorates amyloidosis and improves cognitive function in APP/PS1 mice (2020) · cites this paper as [4]
Antisense oligonucleotide therapy in mice suggests that lowering APOE levels is less effective after plaque deposition than before plaque deposition.
“However, antisense oligonucleotide therapy in mice suggests that lowering APOE levels is less effective after plaque deposition than before plaque deposition124, which reinforces the idea that Aβ plaque deposition is a multistep process.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [124]
These results indicate that clinical trials with antisense oligonucleotide therapeutics should be carefully designed.
“These results indicate that clinical trials with these therapeutics should be carefully designed124.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [124]
ApoE deletion leads to impaired microglial cell response to plaques, the same phenotype observed with TREM2 deficiency.
“Corresponding to loose and enlarged plaques, ApoE deletion leads to impaired microglial cell response to plaques120, the same phenotype observed with TREM2 deficiency44,46.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [120]
ApoE ablation in APPSwePSEN1dE9 or APPPS1-21 mice results in enlarged plaques with wispy fibre-like structures projecting from loosely packed cores, similar to the plaques observed in TREM2-deficient amyloid-β-depositing mice.
“Interestingly, ApoE ablation in APPSwePSEN1dE9 [G] or APPPS1–21 [G] mice also results in enlarged plaques with wispy fibre-like structures projecting from loosely packed cores120, similar to the plaques observed in TREM2-deficient amyloid-β-depositing mice48,49.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [120]
ApoE is required for microglial association with plaques to perform plaque-trimming function similar to that of TREM2.
“This work demonstrates that ApoE is required for microglial association with plaques to perform plaque-trimming function similar to that of TREM2, supporting an ApoE-TREM2 axis in mediating microglial function.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [120]
There is an ApoE-TREM2 axis in mediating microglial function.
“This work demonstrates that ApoE is required for microglial association with plaques to perform plaque-trimming function similar to that of TREM2, supporting an ApoE-TREM2 axis in mediating microglial function.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [120]

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Authors: Huynh, T.-P. V., Liao, F., Francis, C. M., Robinson, G. O., Serrano, J. R., Jiang, H., Roh, J., Finn, M. B., Sullivan, P. M., Esparza, T. J., Stewart, F. R., Mahan, T. E., Ulrich, J. D., Cole, T., & Holtzman, D. M.
Affiliations: Washington University in St. Louis (US)
Veterans Health Administration (US)
Ionis Pharmaceuticals (United States) (US)
Corresponding author: Holtzman, David M.
ORCID: Huynh, Tien-Phat V.
Liao, Fan
Francis, Caroline M.
Serrano, Javier Remolina
Jiang, Hong
Roh, Joseph
Finn, Mary Beth
Sullivan, Patrick M.
Esparza, Thomas J.
Mahan, Thomas E.
Ulrich, Jason D.
Holtzman, David M.
Venue: Neuron
Publisher: Elsevier BV
Published: 2017-12
Volume: 96
Issue: 5
Pages: 1013-1023.e4
ISSN: 0896-6273 (ISSN-L)
DOI: 10.1016/j.neuron.2017.11.014
PMC: PMC5728673
OpenAlex: W2774482055
Cited by: 209
References: 37
Citations by year: 2026: 13 · 2025: 31 · 2024: 29 · 2023: 28 · 2022: 33 · 2021: 23 · 2020: 18 · 2019: 22 · 2018: 10 · 2017: 2
FWCI: 10.52
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 370 d)
Locations: Neuron (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: NIH (R01AG047644, R01NS034467)
JPB Foundation
Gilliam Fellowships for Advanced Study from the Howard Hughes Medical Institute
NIH MSTP (T32 GM07200)
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, antisense oligonucleotides, beta-amyloidosis, Alzheimer's disease, APP/PS1 mice, APOE ε4, APOE ε3, amyloid plaques, neuritic dystrophy, amyloid seeding, gene silencing
MeSH terms: Aging, Alleles, Alzheimer Disease, Amyloidosis, Animals, Apolipoproteins E, Humans, Male, Mice, Transgenic, Amyloid beta-Peptides, Oligonucleotides, Antisense, Amyloid beta-Protein Precursor, Mice, Apolipoprotein E3, Apolipoprotein E4, Plaque, Amyloid

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Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis

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