Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis
Open accessAbstract
The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD). The influence of apoE on amyloid β (Aβ) accumulation may be the major mechanism by which apoE affects AD. ApoE interacts with Aβ and facilitates Aβ fibrillogenesis in vitro. In addition, apoE is one of the protein components in plaques. We hypothesized that certain anti-apoE antibodies, similar to certain anti-Aβ antibodies, may have antiamyloidogenic effects by binding to apoE in the plaques and activating microglia-mediated amyloid clearance. To test this hypothesis, we developed several monoclonal anti-apoE antibodies. Among them, we administered HJ6.3 antibody intraperitoneally to 4-mo-old male APPswe/PS1ΔE9 mice weekly for 14 wk. HJ6.3 dramatically decreased amyloid deposition by 60–80% and significantly reduced insoluble Aβ40 and Aβ42 levels. Short-term treatment with HJ6.3 resulted in strong changes in microglial responses around Aβ plaques. Collectively, these results suggest that anti-apoE immunization may represent a novel AD therapeutic strategy and that other proteins involved in Aβ binding and aggregation might also be a target for immunotherapy. Our data also have important broader implications for other amyloidosis. Immunotherapy to proteins tightly associated with misfolded proteins might open up a new treatment option for many protein misfolding diseases.
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Written from the paper’s full text.
TL;DR
Weekly peripheral administration of monoclonal anti-apoE antibody HJ6.3 reduced amyloid plaque deposition and insoluble Aβ accumulation in APPswe/PS1ΔE9 mice. The treatment also recruited microglia around plaques and acutely decreased proinflammatory cytokines without altering plasma cholesterol, apoE levels, or body weight.
Key findings
- In 4-mo-old male APPswe/PS1ΔE9 mice treated weekly for 14 wk with HJ6.3 at 10 mg/kg, Aβ plaque load was reduced by 70–80% in cortex and hippocampus versus PBS controls; plaque number and X-34–positive fibrillar plaque load/number were also significantly decreased (n = 7 PBS; n = 18 HJ6.3).
- Insoluble Aβ40 and Aβ42 levels were significantly reduced in both cortex and hippocampus by Aβ end-specific ELISA after HJ6.3 treatment.
- Short-term HJ6.3 treatment (4 intraperitoneal injections every 3 d in 9-mo-old mice with preexisting plaques) significantly increased CD45+ microglia around plaques and significantly decreased cortical proinflammatory cytokines IFN-γ and IL-1α; IL-10 trended higher (PBS, 10.88 ± 1.061 pg/mg; HJ6.3, 13.65 ± 1.855 pg/mg; P = 0.21).
- No significant changes were observed in total plasma cholesterol (PBS, 151.0 ± 13.82 mg/dl; HJ6.3, 140.0 ± 12.45 mg/dl; P = 0.598), cortex apoE, plasma apoE, or body weight. Brain HJ6.3 level 24 h after a single injection was 0.096 ± 0.019% of plasma level.
Methods
- Monoclonal anti-apoE antibodies were generated by immunizing apoe KO mice with purified, astrocyte-secreted, lipidated apoE lipoprotein particles; approximately 2,000 hybridoma wells were screened, 36 clones were initially identified, and HJ6.3 was selected based on Western blotting, ELISA, immunohistochemistry, and immunoprecipitation performance.
- Long-term treatment: 4-mo-old male APPswe/PS1ΔE9 mice were intraperitoneally injected weekly for 14 wk with PBS or HJ6.3 at 10 mg/kg; brain tissues were collected 10 d after the last injection. Short-term treatment: 9-mo-old male APPswe/PS1ΔE9 mice were injected 4 times every 3 d, with brain tissues collected 24 h after the last injection.
- Analyses included anti-Aβ and X-34 histology with blinded quantification of 3 sections per mouse separated by 300 µm, Aβ and apoE ELISAs, CD45 staining, cytokine multi-analyte profiling, and total cholesterol assay; statistical significance was assessed with two-tailed Student’s t tests, with variance reported as SEM.
Limitations
- Stated: the long-term study began in 4-mo-old mice when amyloid deposition had just started, so it tested a preventative rather than treatment mode; the authors state that future studies are needed to determine whether anti-apoE antibodies are effective after significant amyloid deposition has occurred.
- Stated: in the 14-wk long-term treatment, HJ6.3 did not significantly change cytokine levels, which the authors suggest may be due to the 10-d delay between the last antibody injection and tissue collection.
- Evident from the text: findings are limited to male APPswe/PS1ΔE9 mice and one anti-apoE antibody clone, HJ6.3; proposed mechanisms such as microglial phagocytosis or interference with apoE–Aβ interactions are discussed but not definitively established.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
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Claims the paper makes
10 of 24 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Previous 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).”
Quote in the paperSubstantial claim1 of 3 sources checked- cites Ma et al., 1994
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Wisniewski et al., 1994
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Castano et al., 1995 source
- Premisecitation
A similar strategy preventing the interaction between apoE and Aβ has already been successfully used to attenuate Aβ toxicity and amyloid deposition.
“A similar strategy preventing the interaction between apoE and Aβ has already been successfully used to attenuate Aβ toxicity and amyloid deposition (Sadowski et al., 2006).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Sadowski et al., 2006 source
- Premisecitation
9-mo-old APPswe/PS1ΔE9 mice have preexisting fibrillar plaques.
“Because we used 9-mo-old APPswe/PS1ΔE9 mice with preexisting fibrillar plaques (Jankowsky et al., 2004), we calculated HJ6.3-induced microglial activation after normalizing with fibrillar plaque load.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Jankowsky et al., 2004 source
- Findingown data
HJ6.3-treated group had significantly less X-34-positive fibrillar plaque load in cortex and hippocampus.
“Consistent with the anti-Aβ antibody staining results (Fig. 2), the HJ6.3-treated group had significantly less X-34–positive fibrillar plaque load (Fig. 3, C and D) and a decrease in the number of fibrillar plaques per area (Fig. 3, E and F) in the cortex (Fig. 3, C and E) and hippocampus (Fig. 3, D and F).”
Quote in the paperSubstantial claim - Findingown data
HJ6.3 antibody did not give detectable signal with APP/PS1/apoe−/− tissues, validating its specificity to apoE in tissue sections.
“When HJ6.3 antibody was used as a primary antibody in the immunohistochemical staining, it did not give any detectable signal with the tissues from APP/PS1/apoe−/− mice, thereby validating the specificity of HJ6.3 antibody to apoE in tissue sections (Fig. 1 H).”
Quote in the paperSubstantial claim
- Findingown data
HJ6.3 treatment significantly decreased the number of plaques per area in cortex and hippocampus.
“HJ6.3 treatment also significantly decreased the number of plaques per area in the cortex (Fig. 2 E) and hippocampus (Fig. 2 F).”
Quote in the paperSubstantial claim - Findingown data
In 14-wk long-term treatment experiments, HJ6.3 treatment did not cause any significant change in cytokine levels.
“In the 14-wk long-term treatment experiments, HJ6.3 treatment did not cause any significant change in the cytokine levels (unpublished data).”
Quote in the paperNot a substantial claim - Findingown data
HJ6.3 treatment significantly reduced insoluble Aβ42 levels in cortex and hippocampus.
“Significant reductions in insoluble Aβ40 (Fig. 4, A and C) and Aβ42 (Fig. 4, B and D) levels were observed in the cortex (Fig. 4, A and B) and hippocampus (Fig. 4, C and D) of mice treated with HJ6.3 antibody.”
Quote in the paperSubstantial claim - Findingown data
HJ6.3-treated group had a decrease in the number of fibrillar plaques per area in cortex and hippocampus.
“Consistent with the anti-Aβ antibody staining results (Fig. 2), the HJ6.3-treated group had significantly less X-34–positive fibrillar plaque load (Fig. 3, C and D) and a decrease in the number of fibrillar plaques per area (Fig. 3, E and F) in the cortex (Fig. 3, C and E) and hippocampus (Fig. 3, D and F).”
Quote in the paperSubstantial claim - Findingown data
HJ6.3 antibody was the only antibody that recognized apoE associated with amyloid plaques and in astrocytes.
“HJ6.3 antibody was the only antibody that recognized apoE associated with amyloid plaques and in astrocytes, which are the major producers of apoE in the brain (Kim et al., 2009a; Fig. 1 F).”
Quote in the paperSubstantial claim - Findingown data
Body weights of PBS and HJ6.3 groups were similar.
“Body weights of both groups were similar (PBS group, 45.57 ± 0.8226 g; HJ6.3 group, 45.26 ± 1.154 g; P = 0.8340; 95% confidence interval: −2.691–3.314).”
Quote in the paperNot a substantial claim - Findingown data
The level of HJ6.3 antibody detected in the brain 24 h after a single injection was 0.096 ± 0.019% of the level present in the plasma.
“The level of HJ6.3 antibody detected in the brain 24 h after a single injection was 0.096 ± 0.019% of the level present in the plasma.”
Quote in the paperNot a substantial claim - Findingown data
No significant difference in total cholesterol levels was observed between PBS-treated and HJ6.3-treated APP/PS1 mice after 14 wk.
“No significant difference in total cholesterol levels was observed between the PBS-treated and HJ6.3 antibody-treated groups (PBS group, 151.0 ± 13.82 mg/dl; HJ6.3 group, 140.0 ± 12.45 mg/dl; P = 0.598; 95% confidence interval, −34.16–56.23).”
Quote in the paperSubstantial claim - Findingown data
HJ6.3 treatment significantly reduced insoluble Aβ40 levels in cortex and hippocampus.
“Significant reductions in insoluble Aβ40 (Fig. 4, A and C) and Aβ42 (Fig. 4, B and D) levels were observed in the cortex (Fig. 4, A and B) and hippocampus (Fig. 4, C and D) of mice treated with HJ6.3 antibody.”
Quote in the paperSubstantial claim - Findingown data
No significant change in apoE levels was observed between PBS and HJ6.3 groups in cortex or plasma.
“there was no significant change in apoE levels between two groups (cortex apoE in PBS group, 6.026 ± 0.1783 ng/mg of wet brain weight; cortex apoE in HJ6.3 group, 6.507 ± 0.3107 ng/mg of wet brain weight; P = 0.25; 95% confidence interval, −1.340–0.3773; plasma apoE in PBS group, 207.1 ± 25.01 µg/ml; plasma apoE in HJ6.3 group, 192.3 ± 13.54 µg/ml; P = 0.58; 95% confidence interval: −39.21–68.90).”
Quote in the paperSubstantial claim - Findingown data
Levels of proinflammatory cytokines IFN-γ and IL-1α were significantly decreased by anti-apoE antibody treatment.
“Although the levels of proinflammatory cytokines (IFN-γ and IL-1α) were significantly decreased by anti-apoE antibody treatment (Fig. 5, D and E), the antiinflammatory cytokine IL-10 showed a trend toward increased level (PBS group, 10.88 ± 1.061 pg/mg of total protein; HJ6.3 group, 13.65 ± 1.855 pg/mg of total protein; P = 0.21).”
Quote in the paperSubstantial claim - Findingown data
All HJ6 antibodies also recognized lipid-free apoE.
“all of them also recognized lipid-free apoE (Fig. 1, A–C).”
Quote in the paperNot a substantial claim - Findingown data
Antiinflammatory cytokine IL-10 showed a trend toward increased level in HJ6.3-treated mice (P = 0.21).
“the antiinflammatory cytokine IL-10 showed a trend toward increased level (PBS group, 10.88 ± 1.061 pg/mg of total protein; HJ6.3 group, 13.65 ± 1.855 pg/mg of total protein; P = 0.21).”
Quote in the paperNot a substantial claim - Findingown data
HJ6.3 treatment reduced Aβ plaque load by 70-80% in cortex and hippocampus compared with PBS.
“Aβ plaque load in the cortex (Fig. 2 C) and hippocampus (Fig. 2 D) was markedly decreased by HJ6.3 antibody treatment, compared with the PBS-treated control group.”
- Also stated in: § Anti-apoE immunotherapy inhibits amyloid accumulation in the brain · boosted
“There was a strong 70–80% reduction in Aβ plaque load in the cortex (Fig. 2 C) and hippocampus (Fig. 2 D).”
Quote in the paperSubstantial claim - Also stated in: § Anti-apoE immunotherapy inhibits amyloid accumulation in the brain · boosted
- Premisecitation
Prevailing evidence suggests that apoE's effect on Aβ accumulation may be the major mechanism among proposed mechanisms for apoE effects on AD pathogenesis.
“Among several mechanisms proposed to explain the effects of apoE on AD pathogenesis, prevailing evidence suggests that apoE’s effect on Aβ accumulation may be the major mechanism (Kim et al., 2009a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kim et al., 2009a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Anti-apoE immunotherapy acutely modulates inflammatory response of microglia to amyloid plaques.
“Collectively, these data suggest that anti-apoE immunotherapy acutely modulates inflammatory response of microglia to amyloid plaques.”
Quote in the paperSubstantial claim - Interpretationown data
Anti-apoE antibody might modulate similar inflammatory responses, consistent with the effect of certain anti-Aβ antibodies.
“This finding suggests that anti-apoE antibody might modulate similar inflammatory responses, which is consistent with the effect of certain anti-Aβ antibodies (Bard et al., 2000; Wilcock et al., 2004).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationown data
Passive immunization against Aβ-associated protein apoE can be very effective in attenuating Aβ accumulation.
“We demonstrate that passive immunization against Aβ-associated protein, apoE, can be very effective in attenuating Aβ accumulation.”
Quote in the paperSubstantial claim - Interpretationown data
HJ6.3 treatment mediates recruitment of microglia around plaques.
“suggesting HJ6.3-mediated recruitment of microglia around plaques.”
Quote in the paperSubstantial claim - Premisecitation
Mice lacking apoE have faster Aβ clearance relative to apoE-expressing mice.
“This possibility is supported by the fact that mice lacking apoE have faster Aβ clearance, relative to apoE-expressing mice (DeMattos et al., 2004).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites DeMattos et al., 2004 source
- Premisecitation
Several studies demonstrated that apoE modulates Aβ clearance.
“Several studies demonstrated that apoE modulates Aβ clearance (Kim et al., 2009a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kim et al., 2009a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- May combine two claims. 9
- Classified as probably not a substantial claim. 12
- The quote only partly states this claim. 1
May combine two claims.
PremisecitationApoE 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).”
Quote in the paperSubstantial claim1 of 3 sources checked- cites Ma et al., 1994
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Wisniewski et al., 1994
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Castano et al., 1995 source
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 measured
Classified as probably not a substantial claim.
PremisecitationRecruitment and activation of microglia around plaques and subsequent Aβ degradation/clearance have been proposed as one of the mechanisms by which Aβ immunotherapy decreases amyloid levels.
“Recruitment and activation of microglia around plaques and subsequent Aβ degradation/clearance have been proposed as one of the mechanisms by which Aβ immunotherapy decreases amyloid levels (Bard et al., 2000; Koenigsknecht-Talboo et al., 2008; Wang et al., 2011).”
Quote in the paperSubstantial claim2 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFibrillar amyloid plaques are strongly associated with activation of microglia.
“Previous studies demonstrated that fibrillar amyloid plaques are strongly associated with the activation of microglia (Lucin and Wyss-Coray, 2009).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Lucin and Wyss-Coray, 2009 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationA variety of different anti-Aβ antibodies have been shown to inhibit Aβ accumulation in mouse models of Aβ amyloidosis, and they are considered promising disease-modifying therapies.
“Previously, a variety of different anti-Aβ antibodies have been shown to inhibit Aβ accumulation in mouse models of Aβ amyloidosis, and they are considered promising disease-modifying therapies (Brody and Holtzman, 2008; Golde et al., 2009).”
Quote in the paperNot a substantial claim1 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationAlong with other amyloid-associated proteins, apoE is found in amyloid plaques.
“Along with other amyloid-associated proteins, apoE is found in amyloid plaques (Namba et al., 1991; Wisniewski and Frangione, 1992).”
Quote in the paperSubstantial claim1 of 2 sources checkedClassified as probably not a substantial claim. May combine two claims.
PremisecitationPrevious studies have demonstrated that anti-Aβ antibodies can effectively decrease amyloid accumulation when given preventatively, but they are less effective in a treatment mode.
“Previous studies have demonstrated that anti-Aβ antibodies can effectively decrease amyloid accumulation when they are given preventatively, but they are less effective in a treatment mode (Brody and Holtzman, 2008; Golde et al., 2009).”
Quote in the paperSubstantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataWhen membranes were overexposed, other HJ antibodies also recognized apoE.
“When the membranes were overexposed, other antibodies also recognized apoE (Fig. 1 B).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataHJ6.3 antibody was the only antibody able to bind apoE in cortical tissue lysates, resulting in successful immunoprecipitation.
“HJ6.3 antibody was the only antibody that was able to bind to apoE in cortical tissue lysates, resulting in successful immunoprecipitation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataAmong four HJ antibodies tested, HJ6.3 antibody gave the strongest signal in Western blotting.
“Among four HJ antibodies tested, HJ6.3 antibody (IgG2b isotype) gave the strongest signal in Western blotting (Fig. 1 A).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataAlthough all HJ6 antibodies recognized apoE in ELISA, HJ6.1 generated the strongest signals.
“Although all HJ6 antibodies recognized apoE in the ELISA, HJ6.1 antibody (IgG1 isotype) generated the strongest signals.”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataHJ6.3 significantly increased CD45 staining associated with amyloid plaques in 9-mo-old APP/PS1 mice.
“Quantitative analyses indicted that anti-apoE antibody HJ6.3 significantly increased CD-45 staining associated with amyloid plaques (Fig. 5 C), suggesting HJ6.3-mediated recruitment of microglia around plaques.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationThe ε4 allele of APOE is the strongest genetic risk factor for common late-onset AD, and the ε2 allele is protective.
“the ε4 allele of apolipoprotein E (APOE) gene is the strongest genetic risk factor for the common late-onset form of AD, and the ε2 allele is protective (Kim et al., 2009a).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kim et al., 2009a
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Interpretationown dataAnti-apoE antibody HJ6.3 treatment dramatically inhibits Aβ aggregation and amyloid accumulation in the brain.
“Collectively, our results clearly demonstrate that anti-apoE antibody HJ6.3 treatment dramatically inhibits Aβ aggregation and amyloid accumulation in the brain.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAnti-apoE immunotherapy with HJ6.3, when given weekly, does not influence brain apoE, peripheral cholesterol metabolism, and general health.
“Collectively, these data indicate that anti-apoE immunotherapy with HJ6.3, when given weekly, does not influence brain apoE, peripheral cholesterol metabolism, and general health.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataAnti-apoE antibodies may recruit microglia to apoE-containing plaques, triggering both direct phagocytosis and attenuation of proinflammatory cytokines, leading to reduction in amyloid accumulation.
“Anti-apoE antibodies may recruit microglia to apoE-containing plaques, triggering both direct phagocytosis and the attenuation of proinflammatory cytokines, leading to reduction in amyloid accumulation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningNo effect on cytokine is likely caused by an extended time delay (10 d) between the last antibody injection and tissue collection in the long-term treatment paradigm.
“No effect on cytokine is likely caused by an extended time delay (10 d) between the last antibody injection and tissue collection in the long term treatment paradigm.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll analyses were performed in a blinded manner.
“All analyses were performed in a blinded manner.”
- Also stated in: § MATERIALS AND METHODS · plain
“All analyses were performed in a blinded fashion after stained images were thresholded to minimize false-positive signals.”
Quote in the paperNot a substantial claim- Also stated in: § MATERIALS AND METHODS · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll animal experiments were approved by the animal study committee at Washington University in St. Louis.
“All animal experiments were approved by the animal study committee at Washington University in St. Louis.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Passive immunotherapy targeting other components of Aβ plaques, such as apoE, has not been previously considered.
“However, passive immunotherapy targeting other components of Aβ plaques, such as apoE, has not been previously considered.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Passive immunization of APP/PS1 mice before Aβ plaque onset resulted in a strong decrease of Aβ plaques and insoluble Aβ40 and Aβ42 levels.
“Recently, we found that passive immunization of APPswe/PS1⌬E9 (APP/PS1) mice before A plaque onset resulted in a strong decrease of A plaques and insoluble A 40 and A 42 levels (Kim et al., 2012).”
From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Kim et al., 2012
The Results and Discussion section reports a 70–80% reduction in Aβ plaque load and significant reductions in insoluble Aβ40 and Aβ42 in HJ6.3-treated APPswe/PS1ΔE9 mice (page unavailable). But it says treatment began when the mice had just started to develop amyloid deposition, not before plaque onset. (LLM, conf=0.88)
Experimental — accuracy not yet measured14 d short-term passive immunization with HJ6.3 increased reactive microglia.
“For apoE passive immunotherapy, we previously observed an increase of reactive microglia with a 14 d short-term passive immunization with HJ6.3 (Kim et al., 2012), suggesting the involvement of microglia in the antibody-mediated A removal.”
From Anti-ApoE Antibody Given after Plaque Onset Decreases Aβ Accumulation and Improves Brain Function in a Mouse Model of Aβ Amyloidosis (2014) · cites this paper as Kim et al., 2012
The Results and Discussion section reports that short-term HJ6.3 treatment significantly increased CD45 staining around amyloid plaques, a marker used to assess activated microglia. But Materials and Methods describes four injections every three days, with tissue collected 24 hours after the last injection—not a 14-day treatment. (LLM, conf=0.88)
Experimental — accuracy not yet measuredApoE antibodies can suppress amyloidosis progression, alleviate amyloid pathology and improve cognitive function through multiple mechanisms including modification of glia responses, regulation of proinflammatory cytokines, amendment of apoE4-induced apoER2 reduction, and improvement of cerebrovascular function.
“ApoE antibodies can suppress amyloidosis progression, alleviate amyloid pathology and improve cognitive function through multiple mechanisms including modification of glia responses”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Kim et al 2012
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredAβ accumulation in the brain of APPSW/PS1dE9 mice can be effectively reduced through targeting brain apoE with systemic anti-apoE passive immunization.
“Similarly, it has been shown that Aβ accumulation in the brain of APPSW/PS1dE9 mice can be effectively reduced through targeting brain apoE with systemic anti-apoE passive immunization [36].”
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 [36]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting buffers reported for immunoprecipitation
MinorThe Figure 1 caption says immunoprecipitation used RIPA lysates, whereas the results describe using 1% Triton X-100 cortical tissue lysates.
“Cerebral cortical tissues from wild-type mice were lysed with RIPA buffer, and the RIPA lysates were used for immunoprecipitation with each HJ antibody.”
“For immunoprecipitation application, each HJ antibody was first covalently conjugated to Sepharose beads and then incubated with 1% Triton X-100 cortical tissue lysates.”
Cites
Bard, F., Cannon, C., Barbour, R., Burke, R.-L., Games, D., Grajeda, H., Guido, T., Hu, K., Huang, J., Johnson-Wood, K., et al. (2000) · Nature Medicine · doi:10.1038/78682 · Cited by 2,012 · see citing works
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · cited 10× · see citing works
“Digital Commons@Becker Open Access Publications 2012 Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis Jungsu Kim Washington University School of Medicine in St. Louis Adam E M Eltorai Washington University School of Medicine in St. Louis Hong Jiang Washington Universi…”
BackgroundInfluentialSelf-citationJankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh019 · Cited by 1,575 · cited 3× · see citing works
“4-mo-old male APPswe/PS1 E9 mice (Jankowsky et al., 2004) were intraperitoneally injected weekly for 14 wk with PBS or anti-apoE antibody (HJ6.”
MethodInfluentialAlzheimer’s Disease: The Challenge of the Second Century
Holtzman, D. M., Morris, J. C., & Goate, A. M. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002369 · Cited by 1,424 · cited 8× · see citing works
“Digital Commons@Becker Open Access Publications 2012 Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis Jungsu Kim Washington University School of Medicine in St. Louis Adam E M Eltorai Washington University School of Medicine in St. Louis Hong Jiang Washington Universi…”
BackgroundInfluentialSelf-citationHuman ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,227 · cited 5× · see citing works
“Digital Commons@Becker Open Access Publications 2012 Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis Jungsu Kim Washington University School of Medicine in St. Louis Adam E M Eltorai Washington University School of Medicine in St. Louis Hong Jiang Washington Universi…”
BackgroundInfluentialSelf-citationNamba, Y., Tomonaga, M., Kawasaki, H., Otomo, E., & Ikeda, K. (1991) · Brain Research · doi:10.1016/0006-8993(91)91092-f · Cited by 1,157 · cited 5× · see citing works
“Digital Commons@Becker Open Access Publications 2012 Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of Aβ amyloidosis Jungsu Kim Washington University School of Medicine in St. Louis Adam E M Eltorai Washington University School of Medicine in St. Louis Hong Jiang Washington Universi…”
BackgroundInfluentialApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876 · cited 1× · see citing works
“It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker.”
BackgroundSelf-citationMa, J., Yee, A., Brewer, H. B., Das, S., & Potter, H. (1994) · Nature · doi:10.1038/372092a0 · Cited by 871 · cited 1× · see citing works
“ApoE appears to affect A accumulation by modulating both A 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).”
BackgroundApolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid
Wisniewski, T., & Frangione, B. (1992) · Neuroscience Letters · doi:10.1016/0304-3940(92)90444-c · Cited by 802 · cited 2× · see citing works
“Along with other amyloid-associated proteins, apoE is found in amyloid plaques (Namba et al., 1991; Wisniewski and Frangione, 1992).”
BackgroundapoE isoform–specific disruption of amyloid β peptide clearance from mouse brain
Deane, R., Sagare, A., Hamm, K., Parisi, M., Lane, S., Finn, M. B., Holtzman, D. M., & Zlokovic, B. V. (2008) · Journal of Clinical Investigation · doi:10.1172/jci36663 · Cited by 771 · cited 1× · see citing works
“ApoE appears to affect A accumulation by modulating both A 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).”
BackgroundSelf-citationImmune activation in brain aging and neurodegeneration: too much or too little?
Lucin, K. M., & Wyss-Coray, T. (2009) · Neuron · doi:10.1016/j.neuron.2009.08.039 · Cited by 679 · cited 1× · see citing works
“Previous studies demonstrated that fibrillar amyloid plaques are strongly associated with the activation of microglia (Lucin and Wyss-Coray, 2009).”
BackgroundApoE and Clusterin Cooperatively Suppress Aβ Levels and Deposition
DeMattos, R. B., Cirrito, J. R., Parsadanian, M., May, P. C., O'Dell, M. A., Taylor, J. W., Harmony, J. A. K., Aronow, B. J., Bales, K. R., Paul, S. M., et al. (2004) · Neuron · doi:10.1016/s0896-6273(03)00850-x · Cited by 459 · see citing works
Self-citationAcceleration of Alzheimer's fibril formation by apolipoprotein E in vitro.
(1994) · PubMed Central · Cited by 441 · see citing works
Anti-Aβ Therapeutics in Alzheimer's Disease: The Need for a Paradigm Shift
Golde, T. E., Schneider, L. S., & Koo, E. H. (2011) · Neuron · doi:10.1016/j.neuron.2011.01.002 · Cited by 382 · cited 2× · see citing works
“Therapeutic strategies to inhibit A accumulation, such as A immunotherapy, are currently being tested as disease-modifying therapies (Golde et al., 2011; Holtzman et al., 2011).”
BackgroundInfluentialKim, J., Castellano, J. M., Jiang, H., Basak, J. M., Parsadanian, M., Pham, V., Mason, S. M., Paul, S. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.11.013 · Cited by 274 · see citing works
Self-citationFibrillogenesis in Alzheimer's disease of amyloid <i>β</i> peptides and apolipoprotein E
Castano, E. M., Prelli, F., Wisniewski, T., Golabek, A., Kumar, R. A., Soto, C., & Frangione, B. (1995) · Biochemical Journal · doi:10.1042/bj3060599 · Cited by 267 · cited 2× · see citing works
“ApoE appears to affect A accumulation by modulating both A 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).”
BackgroundActive and passive immunotherapy for neurodegenerative disorders
Brody, D. L., & Holtzman, D. M. (2008) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.31.060407.125529 · Cited by 250 · cited 2× · see citing works
“…the small fraction of anti-apoE antibodies that enter the brain would bind to apoE in plaques and decrease A accumulation by activating microglia-mediated clearance of A aggregates, similar to what has been described for certain anti-A antibodies (Bard et al., 2000; Brody and Holtzman, 2008).”
Self-citationWilcock, D. M., Munireddy, S. K., Rosenthal, A., Ugen, K. E., Gordon, M. N., & Morgan, D. (2004) · Neurobiology of Disease · doi:10.1016/j.nbd.2003.09.015 · Cited by 202 · see citing works
Kim, J., Jiang, H., Park, S., Eltorai, A. E. M., Stewart, F. R., Yoon, H., Basak, J. M., Finn, M. B., & Holtzman, D. M. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.3773-11.2011 · Cited by 199 · see citing works
Self-citationBien-Ly, N., Gillespie, A. K., Walker, D., Yoon, S. Y., & Huang, Y. (2012) · The Journal of Neuroscience · doi:10.1523/jneurosci.0033-12.2012 · Cited by 170 · see citing works
Sadowski, M. J., Pankiewicz, J., Scholtzova, H., Mehta, P. D., Prelli, F., Quartermain, D., & Wisniewski, T. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604011103 · Cited by 167 · cited 2× · see citing works
“ApoE appears to affect A accumulation by modulating both A 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).”
BackgroundKoenigsknecht-Talboo, J., Meyer-Luehmann, M., Parsadanian, M., Garcia-Alloza, M., Finn, M. B., Hyman, B. T., Bacskai, B. J., & Holtzman, D. M. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.4147-08.2008 · Cited by 149 · cited 1× · see citing works
“Among them, recruitment and activation of microglia triggered by antibody in the brain appears to be one of main underlying mechanisms (Koenigsknecht-Talboo et al., 2008; Wang et al., 2011).”
BackgroundWang, A., Das, P., Switzer, R. C., Golde, T. E., & Jankowsky, J. L. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.5077-10.2011 · Cited by 118 · cited 1× · see citing works
“Among them, recruitment and activation of microglia triggered by antibody in the brain appears to be one of main underlying mechanisms (Koenigsknecht-Talboo et al., 2008; Wang et al., 2011).”
BackgroundQuantitative and Mechanistic Studies of A&#946; Immunotherapy
Golde, T., Das, P., & Levites, Y. (2009) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152709787601830 · Cited by 46 · cited 1× · see citing works
“Anti-apoE antibody treatment recruits microglia around plaques and decreases levels of proinflammatory cytokines Several mechanisms have been proposed to explain the beneficial effects of anti-A immunotherapy (Brody and Holtzman, 2008; Golde et al., 2009).”
BackgroundActive vaccination with ankyrin G reduces β-amyloid pathology in APP transgenic mice
Chadha, A. S., Merlini, M., Shetty, A., Tackenberg, C., Bali, J., Ferretti, M. T., McAfoose, J., Kulic, L., Bernreuther, C., Welt, T., et al. (2012) · Molecular Psychiatry · doi:10.1038/mp.2012.70 · Cited by 24 · see citing works
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Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204 · see citing works
“3 delivered peripherally to APP/PS1 mice either before or after plaque deposition resulted in reduced Aβ levels and fibrillary amyloid pathology, increased microglial activation, and improved spatial memory performance (Kim et al., 2012; Liao et al., 2014).”
Self-citationKrasemann, S., Madore, C., Cialic, R., Baufeld, C., Calcagno, N., El Fatimy, R., Beckers, L., O’Loughlin, E., Xu, Y., Fanek, Z., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.08.008 · Cited by 2,979 · see citing works
“APOE both accumulates in amyloid plaques and facilitates Ab aggregation (Kim et al., 2012).”
BackgroundSelf-citationApolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425 · see citing works
APOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic approaches
Serrano-Pozo, A., Das, S., & Hyman, B. T. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30412-9 · Cited by 1,037 · see citing works
ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756 · see citing works
“3, a monoclonal antibody specific against apoE, is effective in reducing amyloid deposition by modulating microglial responses and inflammatory cytokine levels [193].”
BackgroundThree dimensions of the amyloid hypothesis: time, space and 'wingmen'
Musiek, E. S., & Holtzman, D. M. (2015) · Nature Neuroscience · doi:10.1038/nn.4018 · Cited by 697 · see citing works
Self-citationApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?
Kanekiyo, T., Xu, H., & Bu, G. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.045 · Cited by 608 · see citing works
ApoE4: an emerging therapeutic target for Alzheimer’s disease
Safieh, M., Korczyn, A. D., & Michaelson, D. M. (2019) · BMC Medicine · doi:10.1186/s12916-019-1299-4 · Cited by 449 · see citing works
Apolipoprotein E in Alzheimer's Disease: An Update
Yu, J.-T., Tan, L., & Hardy, J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014300 · Cited by 394 · see citing works
“3, inhibits amyloid accumulation in APPswe/PS1 E9 mice, suggesting antiapoE immunotherapy may represent a novel AD therapeutic strategy (Kim et al. 2012).”
BackgroundApolipoprotein E, Receptors, and Modulation of Alzheimer’s Disease
Zhao, N., Liu, C.-C., Qiao, W., & Bu, G. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.03.003 · Cited by 370 · see citing works
APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeutics
Husain, M. A., Laurent, B., & Plourde, M. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.630502 · Cited by 353 · see citing works
“Anti-apoE antibodies in mouse models were shown to effectively prevent deposition of Aβ when added with pre-existing Aβ deposits (Kim et al., 2012).”
BackgroundAdvances in developing novel therapeutic strategies for Alzheimer’s disease
Cao, J., Hou, J., Ping, J., & Cai, D. (2018) · Molecular Neurodegeneration · doi:10.1186/s13024-018-0299-8 · Cited by 283 · see citing works
“Interestingly, ApoE immunotherapy can achieve similar effects on decreasing amyloid burden [113, 114].”
BackgroundInfluentialFernández-Calle, R., Konings, S. C., Frontiñán-Rubio, J., García-Revilla, J., Camprubí-Ferrer, L., Svensson, M., Martinson, I., Boza-Serrano, A., Venero, J. L., Nielsen, H. M., et al. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00566-4 · Cited by 278 · see citing works
Astrocytic LRP1 Mediates Brain Aβ Clearance and Impacts Amyloid Deposition
Liu, C.-C., Hu, J., Zhao, N., Wang, J., Wang, N., Cirrito, J. R., Kanekiyo, T., Holtzman, D. M., & Bu, G. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.3442-16.2017 · Cited by 267 · see citing works
“Furthermore, anti-apoE immunotherapy also ameliorates A accumulation in APP/PS1 mice (Kim et al., 2012).”
BackgroundSelf-citationAPOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease
Parhizkar, S., & Holtzman, D. M. (2022) · Seminars in Immunology · doi:10.1016/j.smim.2022.101594 · Cited by 255 · see citing works
Self-citationUddin, M. S., Kabir, M. T., Al Mamun, A., Abdel-Daim, M. M., Barreto, G. E., & Ashraf, G. M. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1237-z · Cited by 212 · see citing works
Meilandt, W. J., Ngu, H., Gogineni, A., Lalehzadeh, G., Lee, S.-H., Srinivasan, K., Imperio, J., Wu, T., Weber, M., Kruse, A. J., et al. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.1871-19.2019 · Cited by 210 · see citing works
“The studies used different ApoE monoclonal antibodies that likely interact with distinct epitopes or configurations of ApoE (Kim et al., 2012) and whose binding may be differentially impacted by variations in staining procedure.”
BackgroundApolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease
Najm, R., Jones, E. A., & Huang, Y. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0324-6 · Cited by 183 · see citing works
Cell type‐specific roles of APOE4 in Alzheimer disease
Blumenfeld, J., Yip, O., Kim, M. J., & Huang, Y. (2024) · Nature Reviews Neuroscience · doi:10.1038/s41583-023-00776-9 · Cited by 202 · see citing works
“In amyloidosis mouse models, such therapies efficiently inhibited the formation of amyloid plaques when initiated before the onset of pathology 196,197 .”
The Role of APOE and TREM2 in Alzheimer′s Disease—Current Understanding and Perspectives
Wolfe, C. M., Fitz, N. F., Nam, K. N., Lefterov, I. M., & Koldamova, R. P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms20010081 · Cited by 192 · see citing works
“Another therapeutic approach is the use of specific antibodies to alter the protein levels of APOE [160].”
Xiong, M., Jiang, H., Serrano, J. R., Gonzales, E. R., Wang, C., Gratuze, M., Hoyle, R., Bien-Ly, N., Silverman, A. P., Sullivan, P. M., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abd7522 · Cited by 179 · see citing works
Self-citationTargeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation
Liao, F., Li, A., Xiong, M., Bien-Ly, N., Jiang, H., Zhang, Y., Finn, M. B., Hoyle, R., Keyser, J., Lefton, K. B., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci96429 · Cited by 178 · see citing works
“3 reduced A plaque load in APPPS1 mice expressing murine apoE (10, 11).”
BackgroundMethodInfluentialSelf-citationTherapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease
Williams, T., Borchelt, D., & Chakrabarty, P. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-0358-9 · Cited by 166 · see citing works
“Indeed, in mouse models, anti-APOE antibodies can efficiently inhibit the formation of Aβ deposits when introduced before the onset of pathology [98].”
BackgroundInfluentialHong, W., Wang, Z., Liu, W., O’Malley, T. T., Jin, M., Willem, M., Haass, C., Frosch, M. P., & Walsh, D. M. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1846-7 · Cited by 166 · see citing works
“HJ2 Monoclonal Aβ terminating at Val40 1 Holtzman lab/[20]”
Liu, C.-C., Zhao, J., Fu, Y., Inoue, Y., Ren, Y., Chen, Y., Doss, S. V., Shue, F., Jeevaratnam, S., Bastea, L., et al. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01127-0 · Cited by 168 · see citing works
Yamazaki, Y., Painter, M. M., Bu, G., & Kanekiyo, T. (2016) · CNS Drugs · doi:10.1007/s40263-016-0361-4 · Cited by 166 · see citing works
“The intraperitoneal administration of an anti-apoE antibody has also been shown to improve spatial learning performance by reducing brain soluble apoE levels and slowing brain Ab plaque formation in an amyloid mouse model without evident side effects [131, 132].”
BackgroundApolipoprotein E and Alzheimer's disease
Troutwine, B., Hamid, L., Lysaker, C. R., Strope, T. A., & Wilkins, H. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.10.002 · Cited by 164 · see citing works
Zhang, J., Guo, J., Zhao, X., Chen, Z., Wang, G., Liu, A., Wang, Q., Zhou, W., Xu, Y., & Wang, C. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.05.017 · Cited by 152 · see citing works
Feng, W., Zhang, Y., Wang, Z., Xu, H., Wu, T., Marshall, C., Gao, J., & Xiao, M. (2020) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00688-1 · Cited by 150 · see citing works
Fibrillar Aβ triggers microglial proteome alterations and dysfunction in Alzheimer mouse models
Sebastian Monasor, L., Müller, S. A., Colombo, A. V., Tanrioever, G., König, J., Roth, S., Liesz, A., Berghofer, A., Piechotta, A., Prestel, M., et al. (2020) · eLife · doi:10.7554/elife.54083 · Cited by 147 · see citing works
“3, 1:100, [Kim et al., 2012]), 3552 (1:5000, [Yamasaki et al., 2006]) and pE3-Ab (J8, 1:500, [Hartlage-Rübsamen et al., 2018]). pE3-Ab immunostaining required heat antigen retrieval (25 min at 95˚C) in citrate buffer (10 mM, pH 6.0) prior blocking.”
InfluentialGarai, K., Verghese, P. B., Baban, B., Holtzman, D. M., & Frieden, C. (2014) · Biochemistry · doi:10.1021/bi5008172 · Cited by 145 · see citing works
Self-citationHaass, C., & Selkoe, D. (2022) · PLOS Biology · doi:10.1371/journal.pbio.3001694 · Cited by 145 · see citing works
“damage by Aβ accumulating in blood vessels [62].”
BackgroundKim, J., Yoon, H., Basak, J., & Kim, J. (2014) · Molecules and Cells · doi:10.14348/molcells.2014.0248 · Cited by 141 · see citing works
“…several modes of apoE modulation, such as altering its expression level or status of its lipidation, are pursed as promising therapeutic targets (Bien-Ly et al., 2012; Castellano et al., 2011; Cramer et al., 2012; Kim et al., 2009b; 2011; 2012a; 2012b; Liao et al., 2014; Wahrle et al., 2008;).”
BackgroundSelf-citationShi, Y., Andhey, P. S., Ising, C., Wang, K., Snipes, L. L., Boyer, K., Lawson, S., Yamada, K., Qin, W., Manis, M., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.05.034 · Cited by 135 · see citing works
Self-citationIn vivo measurement of apolipoprotein E from the brain interstitial fluid using microdialysis
Ulrich, J. D., Burchett, J. M., Restivo, J. L., Schuler, D. R., Verghese, P. B., Mahan, T. E., Landreth, G. E., Castellano, J. M., Jiang, H., Cirrito, J. R., et al. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-13 · Cited by 128 · see citing works
“Given recent interest in apoE as a therapeutic target for AD, there is a critical need to develop methods to dynamically assess the levels, lipidation, and effects of apoE within the brain in vivo [8,9].”
BackgroundMethodSelf-citationMicroglia-Mediated Neuroprotection, TREM2, and Alzheimer’s Disease: Evidence From Optical Imaging
Condello, C., Yuan, P., & Grutzendler, J. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.007 · Cited by 131 · see citing works
“Anti-APOE immunotherapy has been shown to increase microglial recruitment around plaques in mice (127).”
Götzl, J. K., Brendel, M., Werner, G., Parhizkar, S., Monasor, L. S., Kleinberger, G., Colombo, A.-V., Deußing, M., Wagner, M., Winkelmann, J., et al. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201809711 · Cited by 124 · see citing works
“3, 1/700), kindly provided by David E. Holtzman (Kim et al, 2012), CD68 (Abcam, ab125212, 1/1,000), and IBA1 (GeneTex, GTX100042, 1/1,000) were used.”
Liao, F., Hori, Y., Hudry, E., Bauer, A. Q., Jiang, H., Mahan, T. E., Lefton, K. B., Zhang, T. J., Dearborn, J. T., Kim, J., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.0646-14.2014 · Cited by 128 · see citing works
“DOI:10.1523/JNEUROSCI.0646-14.2014 Copyright © 2014 the authors 0270-6474/14/347281-12$15.00/0 that passive immunization of APPswe/PS1 E9 (APP/PS1) mice before A plaque onset resulted in a strong decrease of A plaques and insoluble A 40 and A 42 levels (Kim et al., 2012).”
BackgroundMethodInfluentialSelf-citationAPOE-amyloid interaction: Therapeutic targets
Wısnıewskı, T., & Drummond, E. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104784 · Cited by 125 · see citing works
“3) significantly reduced Aβ pathology in an AD transgenic mouse model (Kim et al., 2012;Liao et al., 2014).”
Leveraging preclinical models for the development of Alzheimer disease therapeutics
Scearce-Levie, K. A., Sanchez, P. E., & Lewcock, J. W. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0065-9 · Cited by 118 · see citing works
Tong, B., Ba, Y., Li, Z., Yang, C., Su, K., Qi, H., Zhang, D., Liu, X., Wu, Y., Chen, Y., et al. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106505 · Cited by 117 · see citing works
Panza, F., Solfrizzi, V., Imbimbo, B. P., Tortelli, R., Santamato, A., & Logroscino, G. (2014) · Expert Review of Clinical Immunology · doi:10.1586/1744666x.2014.883921 · Cited by 97 · see citing works
Is there still any hope for amyloid-based immunotherapy for Alzheimer's disease?
Panza, F., Logroscino, G., Imbimbo, B. P., & Solfrizzi, V. (2014) · Current Opinion in Psychiatry · doi:10.1097/yco.0000000000000041 · Cited by 98 · see citing works
The role of APOE4 in Alzheimer’s disease: strategies for future therapeutic interventions
Hunsberger, H. C., Pinky, P. D., Smith, W., Suppiramaniam, V., & Reed, M. N. (2019) · Neuronal Signaling · doi:10.1042/ns20180203 · Cited by 94 · see citing works
Hou, J., Zhou, Y., Cai, Z., Terekhova, M., Swain, A., Andhey, P. S., Guimaraes, R. M., Ulezko Antonova, A., Qiu, T., Sviben, S., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112293 · Cited by 85 · see citing works
Apolipoprotein E gene polymorphism and Alzheimer's disease in Chinese population: a meta-analysis
Liu, M., Bian, C., Zhang, J., & Wen, F. (2014) · Scientific Reports · doi:10.1038/srep04383 · Cited by 83 · see citing works
Apolipoprotein E in Alzheimer’s disease: molecular insights and therapeutic opportunities
Belaidi, A. A., Bush, A. I., & Ayton, S. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00843-y · Cited by 91 · see citing works
Apolipoprotein E 2 genotype delays onset of dementia with Lewy bodies in a Norwegian cohort
Berge, G., Sando, S. B., Rongve, A., Aarsland, D., & White, L. R. (2014) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2013-307228 · Cited by 79 · see citing works
Liao, F., Zhang, T. J., Jiang, H., Lefton, K. B., Robinson, G. O., Vassar, R., Sullivan, P. M., & Holtzman, D. M. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0250-y · Cited by 77 · see citing works
Self-citationPanza, F., Solfrizzi, V., Imbimbo, B. P., & Logroscino, G. (2014) · Expert Opinion on Biological Therapy · doi:10.1517/14712598.2014.935332 · Cited by 75 · see citing works
“Antiamyloidogenic effects have been showed also by anti-APOE antibodies, binding to APOE in the SPs and activating microglia-mediated amyloid clearance [65].”
BackgroundFu, Y., Zhao, J., Atagi, Y., Nielsen, H. M., Liu, C., Zheng, H., Shinohara, M., Kanekiyo, T., & Bu, G. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0099-y · Cited by 71 · see citing works
Cashikar, A. G., Toral-Rios, D., Timm, D., Romero, J., Strickland, M., Long, J. M., Han, X., Holtzman, D. M., & Paul, S. M. (2023) · Journal of Lipid Research · doi:10.1016/j.jlr.2023.100350 · Cited by 72 · see citing works
Self-citationDonald, J. M. M., O’Malley, T. T., Liu, W., Mably, A. J., Brinkmalm, G., Portelius, E., Wittbold, W. M., Frosch, M. P., & Walsh, D. M. (2015) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2015.01.005 · Cited by 71 · see citing works
“/[36] 21F12 Monoclonal Ab terminating at Ile42 – 1 mg/ml 1 mg/ml Elan/[31] HJ7.”
Lewandowski, C. T., Maldonado Weng, J., & LaDu, M. J. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104811 · Cited by 72 · see citing works
“Efficacy of several apoE-targeting antibodies has been reported, with one recently described that preferentially binds non-lipidated and aggregated forms of apoE3 and apoE4 to reduce Aβ pathology in APP/PS1/APOE4-TR mice (Kim et al., 2012; Liao et al., 2014; Liao et al., 2018).”
BackgroundThe VCAM1–ApoE pathway directs microglial chemotaxis and alleviates Alzheimer’s disease pathology
Lau, S.-F., Wu, W., Wong, H. Y., Ouyang, L., Qiao, Y., Xu, J., Lau, J. H.-Y., Wong, C., Jiang, Y., Holtzman, D. M., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00491-1 · Cited by 70 · see citing works
Self-citationDinkins, M. B., Dasgupta, S., Wang, G., Zhu, G., He, Q., Kong, J. N., & Bieberich, E. (2015) · Journal of Alzheimer s Disease · doi:10.3233/jad-150088 · Cited by 68 · see citing works
“Two recent reports show that passive immunization of AD-model mice against ApoE before [32] and after plaque accumulation [33] resulted in reduced A deposition, microglial response, and improvement in behavioral deficits.”
BackgroundAgadjanyan, M. G., Petrovsky, N., & Ghochikyan, A. (2015) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2015.06.1884 · Cited by 65 · see citing works
Chernick, D., Ortiz-Valle, S., Jeong, A., Qu, W., & Li, L. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2019.134306 · Cited by 54 · see citing works
ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease
Li, Y., Macyczko, J. R., Liu, C.-C., & Bu, G. (2022) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2022.03.011 · Cited by 61 · see citing works
Current thinking on the mechanistic basis of Alzheimer's and implications for drug development
Ising, C., Stanley, M., & Holtzman, D. (2015) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.200 · Cited by 59 · see citing works
“Following up on its interaction with Ab in plaques, recent research in the past years on immunotherapeutic approaches targeting apoE has shown beneficial effects on Ab plaque burden in APP transgenic mice.(4) Three different alleles of the APOE gene–E2, E3 and E4–exist.”
BackgroundSelf-citationDias, D., Portugal, C. C., Relvas, J. B., & Socodato, R. (2025) · Cells · doi:10.3390/cells14040243 · Cited by 66 · see citing works
“Monoclonal antibodies that activate TREM2 enhance microglial phagocytosis, reduce amyloid plaques, and decrease neurofibrillary tangles [62,85–87].”
Emerging drugs to reduce abnormal β-amyloid protein in Alzheimer’s disease patients
Panza, F., Seripa, D., Solfrizzi, V., Imbimbo, B. P., Lozupone, M., Leo, A., Sardone, R., Gagliardi, G., Lofano, L., Creanza, B. C., et al. (2016) · Expert Opinion on Emerging Drugs · doi:10.1080/14728214.2016.1241232 · Cited by 59 · see citing works
“Anti-APOE antibodies were shown to activate microglia-mediated amyloid clearance [129].”
BackgroundRAB10: an Alzheimer’s disease resilience locus and potential drug target
Tavana, J. P., Rosene, M. J., Jensen, N. O., Ridge, P. G., Kauwe, J. S. K., & Karch, C. M. M. (2018) · Clinical Interventions in Aging · doi:10.2147/cia.s159148 · Cited by 60 · see citing works
Pankiewicz, J. E., Guridi, M., Kim, J., Asuni, A. A., Sanchez, S., Sullivan, P. M., Holtzman, D. M., & Sadowski, M. J. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0075-0 · Cited by 57 · see citing works
Self-citationBilousova, T. V., Melnik, M., Miyoshi, E., Gonzalez, B. L., Poon, W. W., Vinters, H. V., Miller, C. A., Corrada, M. M., Kawas, C. H., Hatami, A., et al. (2019) · American Journal Of Pathology · doi:10.1016/j.ajpath.2019.04.010 · Cited by 54 · see citing works
Molecular Insight into the Therapeutic Promise of TargetingAPOE4for Alzheimer’s Disease
Mamun, A. A., Uddin, M. S., Bashar, M. F. B., Zaman, S., Begum, Y., Bulbul, I. J., Islam, M. S., Sarwar, M. S., Mathew, B., Amran, M. S., et al. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/5086250 · Cited by 53 · see citing works
“It is evident that the intraperitoneal injection of an anti-APOE antibody has also been exposed to enhance spatial learning ability by decreasing the quantity of soluble APOE in the brain and slowing the accumulation of Aβ in the brain in an amyloid animal model with no obvious side effects [101, 102].”
BackgroundInfluentialIn Vivo Chimeric Alzheimer’s Disease Modeling of Apolipoprotein E4 Toxicity in Human Neurons
Najm, R., Zalocusky, K. A., Zilberter, M., Yoon, S. Y., Hao, Y., Koutsodendris, N., Nelson, M., Rao, A., Taubes, A., Jones, E. A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107962 · Cited by 52 · see citing works
Chernick, D., Ortiz‐Valle, S., Jeong, A., Swaminathan, S. K., Kandimalla, K. K., Rebeck, G. W., & Li, L. (2018) · Journal of Neurochemistry · doi:10.1111/jnc.14554 · Cited by 53 · see citing works
“Furthermore, immunotherapy against apoEwas associatedwith reducedAb deposition inAD mice (Kim et al. 2012), an effect that has recently been recapitulated using an antibody targeting only non-lipidated forms of apoE (Liao et al. 2018).”
BackgroundChoi, J., Gao, J., Kim, J., Hong, C., Kim, J., & Tontonoz, P. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aad1904 · Cited by 49 · see citing works
Self-citationYang, A., Kantor, B., & Chiba‐Falek, O. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22031244 · Cited by 50 · see citing works
“These results suggested that treatment with anti-ApoE may activate microglia-mediated clearance of the Aβ aggregates [9,10].”
BackgroundStatus and future directions of clinical trials in Alzheimer's disease
Plascencia‐Villa, G., & Perry, G. L. (2020) · International review of neurobiology · doi:10.1016/bs.irn.2020.03.022 · Cited by 48 · see citing works
Disease-associated microglia in neurodegenerative diseases: Friend or foe?
Cheng, Y.-H., & Ho, M. S.-C. (2025) · PLoS Biology · doi:10.1371/journal.pbio.3003426 · Cited by 54 · see citing works
“While levels of Apoe expression correlates with neuronal loss [54], the protein also accumulates in amyloid plaques, stimulates amyloid precursor protein (APP) transcription, and facilitates A β aggregation in AD mouse models [20,55,56].”
Recent advancements toward therapeutic vaccines against Alzheimer’s disease
Herline, K., Drummond, E., & Wısnıewskı, T. (2018) · Expert Review of Vaccines · doi:10.1080/14760584.2018.1500905 · Cited by 44 · see citing works
Neuronal ApoE4 in Alzheimer’s disease and potential therapeutic targets
Zhang, L., Xia, Y., & Gui, Y. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1199434 · Cited by 41 · see citing works
Multi-functional role of apolipoprotein E in neurodegenerative diseases
Islam, S., Noorani, A., Sun, Y., Michikawa, M., & Zou, K. (2025) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2025.1535280 · Cited by 30 · see citing works
Immunotherapies in Alzheimer’s disease: Too much, too little, too late or off-target?
St‐Amour, I., Cicchetti, F., & Calon, F. (2015) · Acta Neuropathologica · doi:10.1007/s00401-015-1518-9 · Cited by 39 · see citing works
“As a major genetic risk factor, apoE has also been proposed as a suitable target for immunotherapy [69, 84].”
BackgroundLessons from Anti-Amyloid-β Immunotherapies in Alzheimer Disease: Aiming at a Moving Target
Wang, Y., Yan, T., Lu, H., Yin, W., Lin, B., Fan, W., Zhang, X., & Fernández-Fúnez, P. (2017) · Neurodegenerative Diseases · doi:10.1159/000478741 · Cited by 38 · see citing works
Concerning the structure of apoE
Frieden, C., & Garai, K. (2013) · Protein Science · doi:10.1002/pro.2379 · Cited by 39 · see citing works
Apolipoprotein E isoform-dependent effects on the processing of Alzheimer's amyloid-β
Chai, A. B., Lam, H. H. J., Kockx, M., & Gelissen, I. C. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2021.158980 · Cited by 39 · see citing works
Desai, G. S., Zheng, C., Geetha, T., Mathews, S. T., White, B. D., Huggins, K. W., Zizza, C. A., Broderick, T. L., & Babu, J. R. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-140018 · Cited by 36 · see citing works
Therapeutic Targeting Strategies for Early- to Late-Staged Alzheimer’s Disease
Kang, Y. J., Diep, Y. N., Tran, M., & Cho, H. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249591 · Cited by 36 · see citing works
“Antibodies that rescued the loss of TREM2 signal were developed and proved their therapeutic efficacy that can decrease the pro-inflammatory cytokines and abrogate survival defects [57].”
BackgroundMethodJablonski, A. M., Warren, L., Usenovic, M., Zhou, H. H., Sugam, J. A., Parmentier‐Batteur, S., & Voleti, B. (2021) · Scientific Reports · doi:10.1038/s41598-021-82901-1 · Cited by 35 · see citing works
Extracellular Proteolysis of Apolipoprotein E (apoE) by Secreted Serine Neuronal Protease
Tamboli, I. Y., Heo, D., & Rebeck, G. W. (2014) · PLoS ONE · doi:10.1371/journal.pone.0093120 · Cited by 35 · see citing works
Yang, Y. J., Cudaback, E., Jorstad, N. L., Hemingway, J. F., Hagan, C. E., Melief, E. J., Li, X., Yoo, T., Khademi, S. B., Montine, K. S., et al. (2013) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.05.009 · Cited by 36 · see citing works
Discontinued disease-modifying therapies for Alzheimer’s disease: status and future perspectives
Imbimbo, B. P., Lozupone, M., Watling, M., & Panza, F. (2020) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2020.1795127 · Cited by 31 · see citing works
Nemergut, M., Marques, S. M., Uhrik, L., Vanova, T., Nezvedova, M., Gadara, D. C., Jha, D., Tulis, J., Novakova, V., Planas-Iglesias, J., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00620-9 · Cited by 30 · see citing works
Kantor, B., O’Donovan, B., & Chiba‐Falek, O. (2025) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2025.102635 · Cited by 36 · see citing works
Molecular Pathogenesis and Interventional Strategies for Alzheimer’s Disease: Promises and Pitfalls
Bhute, S., Sarmah, D., Datta, A., Rane, P., Shard, A., Goswami, A., Borah, A., Kalia, K., Dave, K. R., & Bhattacharya, P. (2020) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.9b00104 · Cited by 30 · see citing works
Microglia and its Genetics in Alzheimer's Disease
Liang, X., Wu, H., Colt, M., Guo, X., Pluimer, B. R., Zeng, J., Dong, S., & Zhao, Z. (2021) · Current Alzheimer Research · doi:10.2174/1567205018666211105140732 · Cited by 31 · see citing works
Froestl, W., Pfeifer, A., & Muhs, A. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-121729 · Cited by 27 · see citing works
Are apolipoprotein E fragments a promising new therapeutic target for Alzheimer’s disease?
Vecchio, F. L., Bisceglia, P., Imbimbo, B. P., Lozupone, M., Latino, R. R., Resta, E., Leone, M., Solfrizzi, V., Greco, A., Daniele, A., et al. (2022) · Therapeutic Advances in Chronic Disease · doi:10.1177/20406223221081605 · Cited by 28 · see citing works
“Mouse J20 line of hAPPFAD and overexpressing APOE 272-299 ApoE4 (1-271)1 (N-terminal) Decreases Aβ clearance and increases Aβ deposition In vivo/ In vitro Full-length ApoE3 and ApoE4 expressing mice were able to stimulate Aβ clearance Bien-Ly et al.”
BackgroundKim, B., Dabin, L. C., Tate, M. D., Karahan, H., Sharify, A. D., Acri, D. J., Al-Amin, M. M., Philtjens, S., Smith, D. C., Wijeratne, H. R. S., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48484-x · Cited by 28 · see citing works
Self-citationLozupone, M., Imbimbo, B. P., Balducci, C., Vecchio, F. L., Bisceglia, P., Latino, R. R., Leone, M. A., Dibello, V., Solfrizzi, V., Greco, A., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12728 · Cited by 26 · see citing works
Alzheimer’s Disease Immunotherapy: Current Strategies and Future Prospects
Aljassabi, A., Zieneldien, T., Kim, J., Regmi, D., & Cao, C. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-231163 · Cited by 25 · see citing works
“3 monoclonal antibody against apoE, administered before plaque onset, significantly reduced A (cid:2) accumulation in mouse models (60–80% reduction) and improved brain function [141].”
Self-citationResearch progress of the CXCR4 mechanism in Alzheimer's disease
Wang, Q., Fang, C., Huang, X., & Xue, L. (2022) · Ibrain · doi:10.1002/ibra.12026 · Cited by 24 · see citing works
Cross interactions between Apolipoprotein E and amyloid proteins in neurodegenerative diseases
Loch, R. A., Wang, H., Perálvarez‐Marín, A., Berger, P., Nielsen, H. M., Chroni, A., & Luo, J. (2023) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2023.01.022 · Cited by 25 · see citing works
“However, this controversy has not prevented the use of ApoE-derived peptides and ApoE/Aβ antibodies as therapeutic agents for AD treatment [76,77].”
BackgroundImpact of Age on the Cerebrovascular Proteomes of Wild-Type and Tg-SwDI Mice
Searcy, J. L., Bihan, T. L., Salvadores, N., McCulloch, J., & Horsburgh, K. J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0089970 · Cited by 24 · see citing works
“Recent work undertaken using specific antibodies to APOE suggests that APOE might compete with clearance mechanisms for Ab at the BBB, and suggests potential novel targets for therapeutic intervention to reduce amyloidosis [66], [67].”
BackgroundCognitive Impairment in Neurological Diseases: Lessons from Apolipoprotein E
Shi, J., Han, P., & Kuniyoshi, S. M. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-130623 · Cited by 22 · see citing works
Nuytemans, K., Vasquez, M. L., Wang, L., Booven, D. V., Griswold, A. J., Rajabli, F., Celis, K., Oron, O., Hofmann, N. K., Rolati, S., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.12534 · Cited by 22 · see citing works
Apolipoprotein E in Alzheimer’s Disease: Focus on Synaptic Function and Therapeutic Strategy
Qu, L., Xu, S., Lan, Z., Fang, S., Xu, Y., & Zhu, X. (2024) · Molecular Neurobiology · doi:10.1007/s12035-024-04449-1 · Cited by 22 · see citing works
“Anti-APOE antibodies can inhibit the amyloidogenic process by binding to APOE in plaques, similar to the action of anti-Aβ antibodies [106, 107].”
- Authors
- Kim, J., Eltorai, A. E. M., Jiang, H., Liao, F., Verghese, P. B., Kim, J., Stewart, F. R., Basak, J. M., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2012-11-05
- Volume
- 209
- Issue
- 12
- Pages
- 2149-2156
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC3501350
- OpenAlex
- W2103139149
- Semantic Scholar
- 6e19a559e20bcb90676471900af5a3a80348d4d3
- Cited by
- 160
- References
- 25
- Citations by year
- 2026: 5 · 2025: 19 · 2024: 14 · 2023: 11 · 2022: 15 · 2021: 12 · 2020: 18 · 2019: 11 · 2018: 10 · 2017: 7 · 2016: 5 · 2015: 10 · 2014: 16 · 2013: 7
- FWCI
- 6.22
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Europe PMC (PubMed Central) (submittedVersion, cc-by-nc-sa)
- PubMed Central (submittedVersion, cc-by-nc-sa)
- Funders
- Cure Alzheimer's Fund
- National Institutes of Health (5p30ns069329-02, AG13956, NS057105)
- National Institute on Aging (R01 AG013956, R37AG013956, AG13956)
- National Institute of Neurological Disorders and Stroke (P30-NS069329, P30 NS057105)
- 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
- apolipoprotein E, Alzheimer's disease, amyloid-beta deposition, APOE ε4, microglial activation, amyloid plaque clearance, proteinopathies, amyloidosis
- MeSH terms
- Amyloidosis, Animals, Antibodies, Monoclonal, Apolipoproteins E, Brain Diseases, Enzyme-Linked Immunosorbent Assay, Immunotherapy, Male, Mice, Transgenic, Immunoblotting, Amyloid beta-Peptides, Statistics, Nonparametric, Immunoprecipitation, Mice
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