The DOI matches its Crossref record; 45 of the 45 references it cites were found in a registry or an index; 2 of the 42 sources its claims cite were checked for support.
BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 are implicated in tau pathology
Open accessPublished version of a preprint
Abstract
Background: Identified as an Alzheimer’s disease (AD) susceptibility gene by genome wide-association studies, BIN1 has 10 isoforms that are expressed in the Central Nervous System (CNS). The distribution of these isoforms in different cell types, as well as their role in AD pathology still remains unclear. Methods: Utilizing antibodies targeting specific BIN1 epitopes in human post-mortem tissue and analyzing mRNA expression data from purified microglia, we identified three isoforms expressed in neurons and astrocytes (isoforms 1, 2 and 3) and four isoforms expressed in microglia (isoforms 6, 9, 10 and 12). The abundance of selected peptides, which correspond to groups of BIN1 protein isoforms, was measured in dorsolateral prefrontal cortex, and their relation to neuropathological features of AD was assessed. Results: Peptides contained in exon 7 of BIN1’s N-BAR domain were found to be significantly associated with AD-related traits and, particularly, tau tangles. Decreased expression of BIN1 isoforms containing exon 7 is associated with greater accumulation of tangles and subsequent cognitive decline, with astrocytic rather than neuronal BIN1 being the more likely culprit. These effects are independent of the BIN1 AD risk variant. Conclusions: Exploring the molecular mechanisms of specific BIN1 isoforms expressed by astrocytes may open new avenues for modulating the accumulation of Tau pathology in AD.
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Written from the paper’s full text.
TL;DR
BIN1 protein isoforms show cell-type-specific expression in human CNS: isoforms 1–3 in neurons and astrocytes, and isoforms 6, 9, 10, and 12 in microglia. Reduced exon 7-containing BIN1 peptides in dorsolateral prefrontal cortex are associated with greater tau tangle burden and cognitive decline, with astrocytic BIN1 implicated as the more likely culprit.
Key findings
- BIN1 isoforms 1, 2, and 3 (exon 7-containing) were detected in neurons and astrocytes; isoforms 6, 9, 10, and 12 were expressed in purified human microglia, with isoform 10 most highly expressed in microglia RNA-seq.
- In DLPFC SRM proteomics (n = 1377), only peptides containing exon 7 were associated with AD-related traits, including AD dementia diagnosis, cognitive decline, residual cognition, amyloid, and tau pathology; as pathology burden increased, exon 7 peptide expression decreased.
- The peptide LQAHLVAQTNLLR explained 1.48% of variance in cognitive decline (p = 4.63×10⁻⁵), while tangles explained 20% (p = 7.59×10⁻⁶⁷); jointly, the peptide effect fell to 0.49% and tangles remained at 19.7%, suggesting BIN1’s cognitive effect is largely not independent of tangles.
- In post-mortem tissue, BIN1 exon 7+ neurons did not differ between AD and non-AD subjects (9,735 neurons assessed), but BIN1 exon 7+ astrocytes were significantly decreased in AD versus non-AD subjects (14,643 astrocytes evaluated), implicating astrocytes.
Methods
- Generated and validated exon-specific anti-BIN1 antibodies against exons 7, 11, 13, and 16, then used immunofluorescence co-staining with NeuN, ALDH1L1, and CD45 in human post-mortem brain tissue.
- Analyzed RNA-seq from human DLPFC (n = 508 ROSMAP subjects) and FACS-purified microglia (n = 21), plus LC-MS/MS shotgun proteomics from purified microglia and SRM proteomics for 7 BIN1 peptides in DLPFC (n = 1377).
- Used linear regression models adjusted for age, sex, cohort, and technical covariates; mediation and conditional analyses assessed relationships among BIN1 peptides, tau tangles, amyloid, APOEε4, and cognitive decline.
Limitations
- The paper states that the antibody may not detect epitopes present at very low expression levels, that reverse causation cannot be excluded (increased tangle burden might decrease exon 7 inclusion), and that larger microglia-specific datasets are needed.
- The paper also states that further studies should validate the astrocyte finding by increasing subject numbers, especially for BIN1 exon 7 staining in neurons in AD brains.
- Evident from the text: some key validation samples were small (e.g., microglia proteomics used n = 1 AD and n = 1 non-AD; neuron imaging used n = 3 AD and n = 4 non-AD), and the human data are observational, so causal mechanisms are not established.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
2 of 42 cited sources checked · 0 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Downregulation of BIN1 in a Drosophila model reduced Tau accumulation.
“downregulation of BIN1 in a Drosophila model reduced Tau accumulation [13]”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [13] Chapuis J, Hansmannel F, Gistelinck M, Mounier A, Van Cauwenberghe C, Kolen KV, et al. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry. 2013;18(11):1225–34. source
The Results section reports that knocking down Amph, the Drosophila BIN1 ortholog, suppressed Tau-induced neurotoxicity. It does not report reduced Tau accumulation; the authors also state that altering Amph expression did not affect human Tau transgene expression levels. The cited result concerns toxicity, not accumulation (page unavailable in our copy). (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Findingown data
BIN1 exons 11, 13, and 16 are expressed in both neurons and astrocytes (by immunostaining).
“The same approach was used for the antibodies recognizing exons 11, 13 and 16 which are also expressed in both neurons and astrocytes (Fig. 2b, c, d).”
Quote in the paperSubstantial claim - Findingown data
Isoforms 1 and 9 are the most highly expressed BIN1 isoforms in human DLPFC, followed by isoforms 6, 7 and 10.
“Isoforms 1 and 9 are the ones most highly expressed, followed by isoforms 6, 7 and 10.”
Quote in the paperNot a substantial claim - Findingown data
Exon 7 of BIN1 co-localizes with NeuN (neuronal marker) and ALDH1L1 (astrocyte marker) in human post-mortem brain tissue.
“Immunostaining using the antibody recognizing exon 7 showed co-localization with NeuN, a neuronal marker, and with ALDH1L1, an astrocyte marker (Fig. 2a).”
Quote in the paperSubstantial claim - Findingown data
Exon 11 of BIN1 is detected in the nucleus of CD45+ cells.
“The BIN1 antibody recognizing exon 11, contained in isoforms 4, 8 and 12 (Fig. 3c), produced a positive staining in the nucleus of CD45+ cells”
Quote in the paperSubstantial claim
- Findingown data
Peptides contained in exon 7 of BIN1's N-BAR domain are significantly associated with tau tangles.
“Peptides contained in exon 7 of BIN1’s N-BAR domain were found to be significantly associated with AD-related traits and, particularly, tau tangles.”
Quote in the paperSubstantial claim- Rests on an assumption: The abundance of selected BIN1 peptides measured by SRM reflects the abundance of the corresponding BIN1 protein isoforms in DLPFC.
- Findingown data
In a joint model, the effect of tangles on cognitive decline is unchanged (from r2 = 20% to r2 = 19.7%).
“whereas the effect of tangles on cognitive decline is unchanged (from r2 = 20% to r2 = 19.7%)”
Quote in the paperSubstantial claim - Findingown data
Tangles explain 20% of the variance in cognitive decline (p = 7.59×10−67).
“tangles explain 20% of the variance in cognitive decline (p = 7.59.10− 67)”
Quote in the paperSubstantial claim - Findingown data
The associations between BIN1 exon 7 peptides and tau tangles are diminished but remain significant when accounting for amyloid.
“On the other hand, the associations with tangles are diminished but remain significant when we account for the effect of amyloid”
Quote in the paperSubstantial claim - Findingown data
BIN1 mRNA is present in purified human microglia.
“Overall, these results support the presence of BIN1 mRNA in purified human microglia”
Quote in the paperSubstantial claim - Findingown data
Isoform 10 is the most highly expressed BIN1 isoform in purified cortical microglia in both batches of samples.
“with isoform 10 being the most highly expressed isoform in both batches of samples (Fig. 3a).”
Quote in the paperNot a substantial claim - Findingown data
In a conditional model containing both LQAHLVAQTNLLR peptide and APOEε4, APOEε4 explains 6% of the variance in cognitive decline.
“whereas APOEε4 explains 6% of the variance in cognitive decline”
Quote in the paperNot a substantial claim - Findingown data
BIN1 isoforms 6, 9, 10, and 12 are expressed in microglia.
“we identified three isoforms expressed in neurons and astrocytes (isoforms 1, 2 and 3) and four isoforms expressed in microglia (isoforms 6, 9, 10 and 12).”
Quote in the paperNot a substantial claim - Findingown data
BIN1 peptide LQAHLVAQTNLLR explains 2.8% of the variance in tangles.
“while the BIN1 peptide LQAHLVAQTNLLR explains 2.8%”
Quote in the paperNot a substantial claim - Findingown data
No co-localization is observed between BIN1 (exon 7) and CD45 in human post-mortem brain tissue.
“Subsequently, we tested a BIN1 antibody against exon 7 (which is present in isoforms 1, 2 and 3) but observed no co-localization between BIN1 and CD45 (Fig. 3d)”
Quote in the paperSubstantial claim - Findingown data
BIN1 is expressed in the nucleus of CD45+ cells with a morphology consistent with microglia in human post-mortem brain tissue.
“The results showed expression of BIN1 in the nucleus of CD45+ cells with a morphology consistent with microglia”
Quote in the paperSubstantial claim - Findingown data
The effects of decreased exon 7 BIN1 on tangles and cognitive decline are independent of the BIN1 AD risk variant.
“These effects are independent of the BIN1 AD risk variant.”
Quote in the paperSubstantial claim- Rests on an assumption: The abundance of selected BIN1 peptides measured by SRM reflects the abundance of the corresponding BIN1 protein isoforms in DLPFC.
- Findingown data
Decreased expression of BIN1 isoforms containing exon 7 is associated with subsequent cognitive decline.
“Decreased expression of BIN1 isoforms containing exon 7 is associated with greater accumulation of tangles and subsequent cognitive decline, with astrocytic rather than neuronal BIN1 being the more likely culprit.”
Quote in the paperSubstantial claim- Rests on an assumption: The abundance of selected BIN1 peptides measured by SRM reflects the abundance of the corresponding BIN1 protein isoforms in DLPFC.
- Findingown data
BIN1 isoforms 6, 9, 10, and 12 are expressed in purified cortical microglia.
“Using estimates of isoform abundance derived from RNA-seq data, we observed expression of isoforms 6, 9, 10 and 12 in these purified cortical microglia, with isoform 10 being the most highly expressed isoform in both batches of samples (Fig. 3a).”
Quote in the paperSubstantial claim - Findingown data
There is no evidence of association between other known AD susceptibility variants and BIN1 peptides after correcting for multiple hypothesis testing.
“we found no evidence of association between AD variants and BIN1 peptides after correcting for the testing of multiple hypotheses”
Quote in the paperNot a substantial claim - Findingown data
SNP rs74490912 is in weak linkage disequilibrium with the BIN1 AD SNP rs6733839 (R2 = 0.156).
“this SNP is only in weak linkage disequilibrium (LD) with the BIN1 AD SNP rs6733839 (R [2] = 0.156)”
Quote in the paperSubstantial claim - Findingown data
BIN1 isoforms 4 and 8 are not detected at the RNA level in purified microglia.
“Isoforms 4 and 8 also contain exon 11, but they can be excluded since we didn’t detect these isoforms at the RNA level in purified microglia (Fig. 3a).”
Quote in the paperSubstantial claim - Findingcitation
BIN1 SNPs previously associated with AD had no effect on gene or isoform mRNA expression in a well-powered sample of cortical tissue (n=508) or in purified microglia (n=21).
“However, these variants had no effect on gene or isoform mRNA expression in a well-powered sample of cortical tissue data [6] (n = 508) or in the small sample of subjects with purified microglia RNA described above (n = 21) (Suppl. Fig. 3b and c).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [6] Mostafavi S, Gaiteri C, Sullivan SE, White CC, Tasaki S, Xu J, et al. A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer's disease. Nat Neurosci. 2018;21(6):811–9. source
- Findingown data
BIN1 isoform 6 is detected in microglia at the RNA level.
“confirming our results of RNA expression analysis of microglia, where isoform 6 was detected.”
Quote in the paperNot a substantial claim - Findingown data
Higher expression of BIN1 peptide LQAHLVAQTNLLR is associated with slower cognitive decline.
“with higher protein expression of this peptide we see slower cognitive decline”
Quote in the paperSubstantial claim - Findingown data
BIN1 isoforms 4 and 8 are not expressed in the CNS.
“Since isoforms 4 and 8 are not expressed in the CNS (Fig. 1c), we excluded them from this annotation relating to neurons and astrocytes.”
Quote in the paperNot a substantial claim - Findingown data
Six BIN1 peptides encoded by different exons were present in proteomic data from purified microglia.
“As seen in Supplementary Table 3, 6 BIN1 peptides encoded by different exons were present in these proteomic data”
Quote in the paperNot a substantial claim - Findingown data
BIN1 exon 7 peptides are inversely related to tangles.
“there is an inverse relationship between the two factors”
- Also stated in: § Discussion · plain
“exon 7 peptides of BIN1 are negatively correlated with tangles”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
The abundance of BIN1 peptides is associated with amyloid and tangles after adjusting for the other form of AD-related pathology.
“Association between the abundance of BIN1 peptides and amyloid (left) or tangles (right) after adjusting for the other form of AD-related pathology.”
Quote in the paperSubstantial claim - Findingown data
The association of LQAHLVAQTNLLR peptide with cognitive decline persists after adjustment with APOEε4 (p = 0.00386).
“the association of LQAHLVAQTNLLR peptide with cognitive decline persists after adjustment with APOEε4 (p = 0.00386)”
Quote in the paperSubstantial claim - Findingown data
Exon 13 of BIN1 is detected in the nucleus of CD45+ cells.
“As seen in Fig. 3e, we detected positive staining in the nucleus of CD45+ cells”
Quote in the paperSubstantial claim - Findingown data
In a joint model, the effect of BIN1 peptide LQAHLVAQTNLLR on cognitive decline is reduced from r2 = 1.48% to r2 = 0.49%.
“When modeled jointly, the effect of the peptide LQAHLVAQTNLLR on cognitive decline is reduced significantly (from r2 = 1.48% to r2 = 0.49%)”
Quote in the paperSubstantial claim - Findingown data
For most BIN1 isoforms, there is no significant association with AD-related traits (cognitive decline slope, AD dementia, tau tangle burden) in DLPFC RNA-seq data from 508 ROSMAP participants.
“For most of the isoforms, we did not find significant association between BIN1 isoforms and AD-related traits such as a person’s slope of cognitive decline prior to death, AD dementia or quantitative measures of tau tangle burden, which measures the presence of an AD-associated phosphorylated epitope of MAPT.”
Quote in the paperSubstantial claim - Findingown data
Peptides contained in exon 7 of BIN1's N-BAR domain are significantly associated with AD-related traits.
“Peptides contained in exon 7 of BIN1’s N-BAR domain were found to be significantly associated with AD-related traits and, particularly, tau tangles.”
Quote in the paperSubstantial claim- Rests on an assumption: The abundance of selected BIN1 peptides measured by SRM reflects the abundance of the corresponding BIN1 protein isoforms in DLPFC.
- Findingown data
APOEε4 explains approximately 7.7% of the variance in tangles.
“APOEε4 explains approximately 7.7% of the variance in tangles”
Quote in the paperNot a substantial claim - Findingown data
Genetic variation in the vicinity of BIN1 has minimal effects on peptide expression.
“we found minimal effects of genetic variation in the vicinity of BIN1 on peptide expression”
Quote in the paperNot a substantial claim - Findingown data
In a conditional model containing both LQAHLVAQTNLLR peptide and APOEε4, LQAHLVAQTNLLR peptide explains 0.76% of the variance in cognitive decline.
“In a conditional model containing both the LQAHLVAQTNLLR peptide and APOEε4, the LQAHLVAQTNLLR peptide explains 0.76% of the variance in cognitive decline”
Quote in the paperNot a substantial claim - Findingown data
BIN1 isoform 1 is significantly associated with residual cognition and amyloid burden at the RNA level.
“Only BIN1 isoform 1 was significantly associated with residual cognition (a measure of how well someone is performing cognitively given their burden of aging-related neuropathologies [32]) and amyloid burden at the RNA level.”
Quote in the paperSubstantial claim - Findingown data
Decreased expression of BIN1 isoforms containing exon 7 is associated with greater accumulation of tangles.
“Decreased expression of BIN1 isoforms containing exon 7 is associated with greater accumulation of tangles and subsequent cognitive decline, with astrocytic rather than neuronal BIN1 being the more likely culprit.”
Quote in the paperSubstantial claim- Rests on an assumption: The abundance of selected BIN1 peptides measured by SRM reflects the abundance of the corresponding BIN1 protein isoforms in DLPFC.
- Findingown data
In an independent model, BIN1 peptide LQAHLVAQTNLLR expression explains 1.48% of the variance in cognitive decline (p = 4.63×10−5).
“we found that the peptide LQAHLVAQTNLLR explains 1.48% of the variance in cognitive decline (p = 4.63.10− 5) when modeled independently”
- Also stated in: § Effect of genetic variants and known risk-associated molecular features on peptide measures · plain
“Similarly, LQAHLVAQTNLLR explains 1.48% of the variance in cognitive decline”
Quote in the paperSubstantial claim - Also stated in: § Effect of genetic variants and known risk-associated molecular features on peptide measures · plain
- Findingown data
BIN1 isoforms 2, 3, 5, and 12 are expressed at low levels in human DLPFC.
“Isoforms 2, 3, 5, and 12 are expressed at low levels, and isoform 4 and isoform 8, which has been reported to be specific to muscle [10], are absent.”
Quote in the paperNot a substantial claim - Findingown data
BIN1 isoforms 1, 2, and 3 are expressed in neurons and astrocytes.
“we identified three isoforms expressed in neurons and astrocytes (isoforms 1, 2 and 3) and four isoforms expressed in microglia (isoforms 6, 9, 10 and 12).”
Quote in the paperSubstantial claim - Findingown data
BIN1 isoforms 10 and 12 are significantly increased in MDMi compared to corresponding monocytes.
“We note a significant increase of BIN1 isoforms 10 and 12 in MDMi compared to corresponding monocytes.”
Quote in the paperSubstantial claim - Findingown data
APOEε4 explains 5.7% of the variance in cognitive decline when assessed independently.
“APOEε4 explains 5.7% when they are assessed independently”
Quote in the paperNot a substantial claim - Findingown data
BIN1 protein is detected in purified human microglia by shotgun proteomic data.
“shotgun proteomic data generated from purified microglia derived from other human samples by the same pipeline confirmed the detection of BIN1 at the protein level.”
Quote in the paperSubstantial claim - Findingown data
SNP rs74490912 is associated with expression of BIN1 peptide LQAHLVAQTNLLR (p = 4.9 × 10−6).
“the top SNP rs74490912 is associated with expression of BIN1 peptide LQAHLVAQTNLLR (p = 4.9 × 10− 6)”
Quote in the paperNot a substantial claim - Findingown data
Except for isoform 6, the BIN1 isoforms expressed by microglia lack a CLAP domain.
“Except for isoform 6, these isoforms are characterized by the lack of a CLAP domain”
Quote in the paperSubstantial claim - Findingown data
Expression level of exon 7 peptides (AAPQWCQGK, LQAHLVAQTNLLR, NQAEEELIK) is associated with tangles and cognitive decline.
“we have shown that the expression level of exon 7 peptides (AAPQWCQGK, LQAHLVAQTNLLR, NQAEEELIK) is associated with tangles and cognitive decline”
Quote in the paperSubstantial claim - Findingown data
Four specific BIN1 protein isoforms (isoforms 6, 9, 10 and 12) are expressed by microglia.
“our multidisciplinary approach identified 4 specific BIN1 protein isoforms (isoforms 6, 9, 10 and 12) expressed by these cells”
Quote in the paperSubstantial claim - Findingown data
BIN1 isoforms 10 and 12 are expressed in MDMi and not in peripheral monocytes.
“we show that BIN1 isoforms 10 and 12 are expressed in MDMi and not in peripheral monocytes”
Quote in the paperSubstantial claim - Findingown data
These BIN1 isoforms appear to be expressed at higher level in microglia-like cells than in peripheral myeloid cells.
“they appear to be expressed at higher level in microglia-like cells than in peripheral myeloid cells”
Quote in the paperNot a substantial claim - Findingown data
The number of BIN1 exon 7+ neurons shows no difference between AD and cognitively non-impaired subjects.
“the number of BIN1 exon 7+ neurons shows no difference between the two sets of subjects”
Quote in the paperSubstantial claim - Findingown data
The number of astrocytes expressing BIN1 exon 7 is significantly decreased in AD compared to cognitively non-impaired subjects.
“we find, in the same individuals, a significant decrease in the number of astrocytes expressing BIN1 exon 7 in AD compared to cognitively non-impaired subjects”
- Also stated in: § Discussion · plain
“our in situ validation revealed a loss of BIN1 exon 7 expression in astrocytes in AD subjects”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingreasoning
The study's exon-specific antibodies did not detect BIN1 isoforms expressed by oligodendrocytes.
“which could explain why our exon-specific antibodies did not detect BIN1 isoforms expressed by oligodendrocytes, since exons 7, 11, 13 or 16 are not contained within isoform 9.”
Quote in the paperNot a substantial claim - Findingown data
BIN1 isoforms expressed by neurons and astrocytes are strongly associated with tangles in AD.
“Our findings showed a strong association between BIN1 isoforms expressed by neurons/astrocytes and tangles that contributes to cognitive decline in AD”
Quote in the paperSubstantial claim - Findingown data
Isoforms 1, 2, 3, 4, 5, 6, 7, 9, 10 and 12 are expressed in the human DLPFC at the RNA level.
“we detected expression of isoforms 1, 2, 3, 4, 5, 6, 7, 9, 10 and 12 in the human DLPFC”
Quote in the paperSubstantial claim - Findingown data
Isoforms 1, 2 and 3 are expressed in both neurons and astrocytes in post-mortem human brain.
“we deduced that isoforms 1, 2 and 3 are expressed in both neurons and astrocytes”
Quote in the paperSubstantial claim- Rests on an assumption: The antibody used specifically recognizes BIN1 exon 7 and does not cross-react with other BIN1 epitopes.
- Findingown data
Tau-related epigenomic alterations (H3K9ac histone marks) are not associated with LQAHLVAQTNLLR or other BIN1 peptides.
“we found that there is no association between Tau-related epigenomic alterations (defined by the H3K9ac histone marks) and the LQAHLVAQTNLLR or other BIN1 peptides”
Quote in the paperSubstantial claim - Findingown data
Isoforms 1 and 9 are highly expressed compared to other BIN1 isoforms in the human DLPFC.
“we observed that isoforms 1 and 9 are highly expressed compared to the other isoforms”
Quote in the paperNot a substantial claim - Findingown data
There is no significant difference in the total number of astrocytes between AD and cognitively non-impaired subjects.
“there is not a significant difference in the total number of astrocytes between the two classes of subjects”
Quote in the paperSubstantial claim - Findingown data
Isoforms 1, 2 and 3 are absent in microglia in RNA-seq data from purified human microglia.
“these isoforms are absent in microglia in our RNA-seq data from purified human microglia”
Quote in the paperSubstantial claim - Interpretationreasoning
BIN1 isoform 12 is expressed in neurons and astrocytes.
“BIN1 isoform 12, which contains exon 11 (Fig. 1b), is also expressed in neurons and astrocytes.”
Quote in the paperSubstantial claim - Premisecitation
The rs59335482 insertion/deletion variant is associated with an increase of BIN1 mRNA expression in the brain.
“Genetic analysis of BIN1 has shown that the rs59335482 insertion/deletion variant is associated with an increase of BIN1 mRNA expression in the brain [13]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [13] Chapuis J, Hansmannel F, Gistelinck M, Mounier A, Van Cauwenberghe C, Kolen KV, et al. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry. 2013;18(11):1225–34. source
- Premisecitation
The level of isoform 9 seems to be correlated with the abundance of astrocyte (GFAP) and microglia (CD45) markers.
“On the other hand, the level of isoform 9 seems to be correlated with the abundance of astrocyte (GFAP) and microglia (CD45) markers [12].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] De Rossi P, Buggia-Prevot V, Clayton BL, Vasquez JB, van Sanford C, Andrew RJ, et al. Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts. Mol Neurodegener. 2016;11(1):59. source
- Study design and conductown data
The associations between BIN1 exon 7 peptides and AD pathologies remain significant after correction for different cell types in a subset of 508 individuals.
“As seen in Supplementary Table 7, the results of these analyses remain significant for AD pathologies after including a correction for the different cell types.”
Quote in the paperSubstantial claim - Interpretationcitation
A polymorphism associated with an increase of BIN1 expression in the CNS is associated with AD risk.
“These findings highlight that a polymorphism associated with an increase of BIN1 expression in the CNS is associated with AD risk.”
Quote in the paperSubstantial claim - Study design and conductown data
Estimates of BIN1 isoform expression level from RNA-seq data are supported by an alternative approach counting reads mapped to each exon.
“Estimates of isoform expression level from these RNA-seq data are supported by the results of an alternative approach which counts the number of reads mapped to each exon (Suppl. Fig. 3a).”
Quote in the paperNot a substantial claim - Premisecitation
BIN1 mRNA expression is increased in the CNS of AD patients compared to non-AD patients.
“this manuscript also reports an increase of BIN1 mRNA expression in the central nervous system (CNS) of AD patients compared to non-AD patients [13].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Chapuis J, Hansmannel F, Gistelinck M, Mounier A, Van Cauwenberghe C, Kolen KV, et al. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry. 2013;18(11):1225–34. source
- Premisecitation
BIN1 is involved in Tau-mediated neurotoxicity in a Drosophila melanogaster model.
“and is involved in Tau-mediated neurotoxicity in a Drosophila melanogaster model [13].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Chapuis J, Hansmannel F, Gistelinck M, Mounier A, Van Cauwenberghe C, Kolen KV, et al. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry. 2013;18(11):1225–34. source
- Interpretationreasoning
There may be an increase of isoform 9 expression by reactive astrocytes and microglia at the protein level during AD.
“These findings suggest that there may be an increase of isoform 9 expression by reactive astrocytes and microglia at the protein level during AD.”
Quote in the paperSubstantial claim - Interpretationown data
Astrocytic rather than neuronal BIN1 is the more likely culprit for the association between decreased exon 7 BIN1 and tangles/cognitive decline.
“Decreased expression of BIN1 isoforms containing exon 7 is associated with greater accumulation of tangles and subsequent cognitive decline, with astrocytic rather than neuronal BIN1 being the more likely culprit.”
Quote in the paperSubstantial claim- Rests on an assumption: The abundance of selected BIN1 peptides measured by SRM reflects the abundance of the corresponding BIN1 protein isoforms in DLPFC.
- Interpretationown data
Exon 7 of BIN1 is expressed at the protein level in both neurons and astrocytes.
“This observation suggests that exon 7 of BIN1 is expressed at the protein level in both neurons and astrocytes.”
Quote in the paperSubstantial claim - Interpretationown data
BIN1 isoforms 1, 2, and 3 are not expressed by microglia.
“suggesting that BIN1 isoforms 1, 2 and 3 are not expressed by microglia.”
Quote in the paperSubstantial claim - Interpretationcitation
BIN1 is clearly expressed in myeloid cells of the CNS.
“Nonetheless, BIN1 is clearly expressed in myeloid cells of the CNS.”
Quote in the paperNot a substantial claim - Study design and conductown data
The 4 custom antibodies against different epitopes of BIN1 recognized the selected isoform according to the scheme depicted in Fig. 1b.
“As expected, the 4 custom antibodies against different epitopes of BIN1 recognized the selected isoform, according to the scheme depicted in Fig. 1b (Suppl. Fig. 1b).”
Quote in the paperSubstantial claim - Premisecitation
BIN1 mRNA encoding isoform 9 is highly transcribed by glial cells.
“Indeed, BIN1 mRNA encoding isoform 9 is highly transcribed by glial cells [21, 22].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [21] Adams SL, Tilton K, Kozubek JA, Seshadri S, Delalle I. Subcellular changes in bridging integrator 1 protein expression in the cerebral cortex during the progression of Alzheimer disease pathology. J Neuropathol Exp Neurol. 2016;75(8):779–90. source
- cites [22] Gosselin D, Skola D, Coufal NG, Holtman IR, Schlachetzki JCM, Sajti E, et al. An environment-dependent transcriptional network specifies human microglia identity. Science. 2017;356:6344. source
- Interpretationown data
The association of LQAHLVAQTNLLR peptide with cognitive decline is not entirely independent of APOEε4.
“but is not entirely independent”
Quote in the paperNot a substantial claim - Interpretationown data
Higher tangle burden increases the rate of cognitive decline.
“where higher tangles increase the rate of cognitive decline”
Quote in the paperSubstantial claim - Interpretationown data
BIN1 isoform 12 is expressed in microglia (protein level).
“confirming the expression of isoform 12 which was also observed at the mRNA level.”
Quote in the paperSubstantial claim - Interpretationown data
Microglia express BIN1 containing exon 13.
“suggesting that microglia express BIN1 containing exon 13”
Quote in the paperNot a substantial claim - Premisecitation
BIN1 interacts with Tau.
“mechanistic dissection has shown that BIN1 interacts with Tau [15]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [15] Sottejeau Y, Bretteville A, Cantrelle FX, Malmanche N, Demiaute F, Mendes T, et al. Tau phosphorylation regulates the interaction between BIN1's SH3 domain and Tau's proline-rich domain. Acta Neuropathol Commun. 2015;3:58. source
- Interpretationreasoning
APOEε4 plays some role in the decrease of exon 7 inclusion in AD.
“APOEε4 plays some role in the decrease of exon 7 inclusion in AD”
Quote in the paperNot a substantial claim - Interpretationown data
BIN1 isoforms 6, and potentially 9 and 12, are expressed by microglia in the aged human brain.
“In summary, using antibodies against selected BIN1 epitopes, we find that BIN1 isoforms 6, and potentially 9 and 12 are expressed by microglia in the aged human brain.”
Quote in the paperSubstantial claim - Interpretationown data
BIN1 isoforms 5 and 6 (containing exon 13) and isoform 7 (containing exon 16) appear to be expressed in both neurons and astrocytes.
“Similarly, isoforms 5 and 6 that contain exon 13, and isoform 7 which contains exon 16 (Fig. 1b) appear to be expressed in both cell types.”
Quote in the paperSubstantial claim - Interpretationcitation
There is a convergence of a genetic factor and an environmental or experiential factor mediated by epigenomic changes on risk of AD in the BIN1 locus.
“Thus, there appears to be a convergence of a genetic factor and an environmental or experiential factor mediated by epigenomic changes on risk of AD in the BIN1 locus.”
Quote in the paperNot a substantial claim - Interpretationreasoning
BIN1 isoforms 1, 2, and 3 might be expressed in neurons and astrocytes.
“Considering that exon 7 is only present in BIN1 isoforms 1, 2, and 3 (Fig. 1b), the results indicate that these three isoforms might be expressed in neurons and astrocytes.”
Quote in the paperSubstantial claim - Interpretationown data
The genetic effect of rs74490912 on BIN1 peptide expression is not related to known AD genetic susceptibility.
“Thus, this genetic effect is not related to known AD genetic susceptibility.”
Quote in the paperSubstantial claim - Interpretationown data
BIN1's expression in microglia may be unrelated to the convergence of other AD risk factors in microglia.
“Given our results, BIN1’s expression in microglia may be unrelated to the convergence of other AD risk factors in microglia, although we need larger microglia-specific datasets to fully explore the function of microglial BIN1 in AD.”
Quote in the paperNot a substantial claim- Rests on an assumption: BIN1 expression measured in MDMi (monocyte-derived microglia-like) cells reflects BIN1 expression by microglia in the brain.
- Premisecitation
An increase in the incidence of inflammation has been reported in BIN1 knock out mice.
“an increase of incidence of inflammation has been reported in BIN1 knock out mice [18]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Chang MY, Boulden J, Katz JB, Wang L, Meyer TJ, Soler AP, et al. Bin1 ablation increases susceptibility to cancer during aging, particularly lung cancer. Cancer Res. 2007;67(16):7605–12. source
- Interpretationown data
The in situ studies refined the association of BIN1 isoforms with tangles to prioritize astrocytes as the target cell type.
“our in situ studies refined these association to prioritize astrocytes as the target cell type”
Quote in the paperSubstantial claim - Interpretationown data
Loss of a class of BIN1 exon 7+ astrocytes contributes to the accumulation of tangle burden.
“perhaps that a loss of a class of BIN1 exon 7+ astrocytes contributes to the accumulation of tangle burden”
- Also stated in: § Discussion · hedged
“suggesting that the lack of expression of these specific BIN1 isoforms in astrocytes might be involved in AD pathology”
Quote in the paperSubstantial claim - Also stated in: § Discussion · hedged
- Interpretationcitation
BIN1 may have an anti-inflammatory function.
“suggesting a possible anti-inflammatory function of BIN1”
Quote in the paperNot a substantial claim - Interpretationreasoning
The absence of exon 7 and the CLAP domain in the BIN1 isoforms expressed by microglia suggests that BIN1 may have a function during aging and AD that is unrelated to clathrin-mediated endocytosis.
“The absence of exon 7 and the CLAP domain in BIN1 isoforms expressed by microglia suggest that BIN1 may have a function during aging and AD that is unrelated to clathrin-mediated endocytosis.”
Quote in the paperSubstantial claim - Interpretationown data
The role of BIN1 exon 7 in AD is related to its role in astrocytes.
“This suggests that the role of BIN1 exon 7 in AD is related to its role in astrocytes”
Quote in the paperSubstantial claim - Interpretationown data
The relation of BIN1 protein expression to the accumulation of tangles appears to be independent of miRNA, co-expressed gene modules, and Tau-related epigenomic alterations.
“Thus, the relation of BIN1 protein expression to the accumulation of tangles appears to be independent of these factors.”
Quote in the paperSubstantial claim - Interpretationnone given
The rs6733839 AD risk variant does not appear to function through alterations in the splicing of the N-BAR domain.
“However, the BIN1 AD variant itself does not appear to function through these alterations in the splicing of the N-BAR domain: the rs6733839 variant’s mechanism remains unclear and independent of the role of the N-BAR domain in AD.”
Quote in the paperNot a substantial claim - Interpretationreasoning
BIN1 is implicated in the altered endocytosis suggested by several known AD susceptibility loci.
“Overall, our model implicates BIN1 in the narrative of altered endocytosis that is suggested by several of the known AD susceptibility loci.”
Quote in the paperSubstantial claim - Interpretationown data
There is context-specific expression of BIN1 protein isoforms by microglia.
“highlighting the existence of context-specific expression of BIN1 protein isoforms by microglia”
Quote in the paperSubstantial claim - Interpretationreasoning
The absence of exons 7, 11, 13 and 16 from BIN1 isoform 9 explains why the exon-specific antibodies did not detect BIN1 isoforms expressed by oligodendrocytes.
“which could explain why our exon-specific antibodies did not detect BIN1 isoforms expressed by oligodendrocytes, since exons 7, 11, 13 or 16 are not contained within isoform 9.”
Quote in the paperNot a substantial claim
- Probably not a substantial claim. 36
- It may state two separate claims as one. 34
- The quote only partly states this claim. 1
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationBIN1 has 10 isoforms expressed in the central nervous system.
“BIN1 has 10 isoforms that are expressed in the Central Nervous System (CNS).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [10] Butler MH, David C, Ochoa GC, Freyberg Z, Daniell L, Grabs D, et al. Amphiphysin II (SH3P9; BIN1), a member of the amphiphysin/Rvs family, is concentrated in the cortical cytomatrix of axon initial segments and nodes of ranvier in brain and around T tubules in skeletal muscle. J Cell Biol. 1997;137(6):1355–67. source
The Results sections on cloning and tissue expression describe alternatively spliced amphiphysin II (BIN1) variants and their expression in brain. They do not establish that 10 isoforms are expressed in the CNS; searches for that number and for brain isoform counts found no supporting passage. Page numbers were not available in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [11] Zhou Y, Hayashi I, Wong J, Tugusheva K, Renger JJ, Zerbinatti C. Intracellular clusterin interacts with brain isoforms of the bridging integrator 1 and with the microtubule-associated protein tau in Alzheimer's disease. PLoS One. 2014;9(7):e103187. source
It may state two separate claims as one.
Findingown dataIn astrocytes and neurons, BIN1 exons 13 and 16 are detected in the nucleus, and exons 7 and 11 in the cytoplasm.
“In addition, we observed that antibodies recognizing different exons are detected in different subcellular compartments in astrocytes and neurons (nuclear for exons 13 & 16 and cytoplasmic for exons 7 & 11), confirming the observation reported by other studies that BIN1 is found both in the nucleus and cytosol [29–31].”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataOther AD SNPs in the BIN1 locus have a modest effect on expression of isoform 10 in cortical tissue but not in purified microglia.
“Other AD SNPs in the BIN1 locus were seen to have a modest effect on expression in cortical tissue data for isoform 10, which is expressed in microglia (Suppl.Table.4a and 4b), but this was not seen in the small dataset derived from purified microglia.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataAfter adjusting for tau tangle burden, most associations between BIN1 exon 7 peptides and amyloid are no longer significant, except for the peptide bridging exons 7 and 8, which is diminished by 49.2%.
“When we adjust for the burden of tau tangles, most of the associations with amyloid are no longer significant, aside for the peptide that bridges exons 7 and 8, which is diminished by 49.2% (Fig. 5a).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThere is no association of BIN1 exon 7 peptides with neurovascular measures, cerebral amyloid angiopathy, hippocampal sclerosis, Lewy Bodies, or TDP43 pathology burden.
“In secondary analyses, we also evaluated other neuropathologic traits that are available in these subjects and find no association with neurovascular measures, cerebral amyloid angiopathy, hippocampal sclerosis, Lewy Bodies, or the burden of TDP43 pathology (Suppl.Table.6).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataOnly the three BIN1 peptides containing exon 7 sequences display associations with AD-related traits (AD dementia, cognitive decline trajectory, residual cognition, amyloid and tau pathology) in DLPFC proteomic data from 1377 ROSMAP participants.
“After testing 7 peptides (Suppl. Fig. 5), only the three peptides which contain sequences from exon 7 display associations with AD related-traits: a diagnosis of AD dementia, the participants’ trajectory of cognitive decline, residual cognition and quantitative measures of both amyloid and tau pathology (Fig. 4a-f and Suppl.Table.5).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataBIN1 isoform 4 and isoform 8 are absent in human DLPFC.
“Isoforms 2, 3, 5, and 12 are expressed at low levels, and isoform 4 and isoform 8, which has been reported to be specific to muscle [10], are absent.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataThe association of BIN1 peptide LQAHLVAQTNLLR with tangles is independent of miRNA (miR132, miR129) and co-expressed gene modules.
“we found that the association of the BIN1 peptide LQAHLVAQTNLLR with tangles is independent of all of these factors”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataReduced inclusion of BIN1 exon 7 (decreased expression of neuronal/astrocyte isoforms 1, 2, and 3) contributes to increases in tangle burden, which then causes more rapid cognitive decline.
“we propose that reduced inclusion of exon 7 into BIN1 proteins contributes to increases in tangle burden (Fig. 5b), which then causes more rapid cognitive decline”
- Also stated in: § Discussion · hedged
“suggesting that decreased expression of neuronal/astrocyte isoforms 1, 2, and 3 contributes to greater accumulation of tangles and cognitive decline”
Quote in the paperSubstantial claim- Also stated in: § Discussion · hedged
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationIsoform 1 and 3 are expressed in neurons and isoform 2 in astrocytes.
“are consistent with previously published reports of isoform 1 and 3 expression in neurons and isoform 2 in astrocytes [11].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Zhou Y, Hayashi I, Wong J, Tugusheva K, Renger JJ, Zerbinatti C. Intracellular clusterin interacts with brain isoforms of the bridging integrator 1 and with the microtubule-associated protein tau in Alzheimer's disease. PLoS One. 2014;9(7):e103187. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAltered methylation in the BIN1 locus at cg22883290 is related to neuritic amyloid plaques and a pathologic diagnosis of AD, independent of the rs744373 susceptibility variant.
“A different study found altered methylation in the BIN1 locus at cg22883290 in relation to neuritic amyloid plaques and a pathologic diagnosis of AD, and this altered methylation pattern was independent of the effect of the rs744373 susceptibility variant [14].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, et al. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci. 2014;17(9):1156–63. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
InterpretationcitationIBA1+ cells in published images may be more representative of perivascular macrophages than microglia based on morphology.
“These cells may be microglia, but, upon review of the published images, these IBA1+ cells may be more representative of perivascular macrophages than microglia based on morphology [13].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Chapuis J, Hansmannel F, Gistelinck M, Mounier A, Van Cauwenberghe C, Kolen KV, et al. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry. 2013;18(11):1225–34. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
Interpretationown dataBIN1 isoforms 1-9 are present in microglia.
“suggesting the presence of BIN1 isoforms 1–9 in microglia.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataThe association of alternatively spliced exon 7 of BIN1 with AD is primarily driven by tangles, with a possible minor component involving amyloid independent of tangles.
“suggesting that the association of the alternatively spliced exon 7 of BIN1 with AD is primarily driven by tangles, with a possible minor component involving amyloid independent of tangles (Fig. 5a).”
Quote in the paperSubstantial claimProbably not a substantial claim. It may state two separate claims as one.
Premisenone givenThe distribution of BIN1 isoforms in different cell types and their role in AD pathology remains unclear.
“The distribution of these isoforms in different cell types, as well as their role in AD pathology still remains unclear.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductown dataStaining of oligodendrocytes could not be appreciated relative to background, so BIN1 protein expression was not further characterized in this cell type.
“We note that staining of oligodendrocytes could not be appreciated relative to background staining, and we therefore elected not to characterize BIN1 protein expression further in this cell type.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationDecrease of isoform 1 protein expression is correlated with decreased expression of a neuronal marker, illustrating loss of neurons observed in AD.
“De Rossi and colleagues reported that the decrease of isoform 1 (the largest isoform) protein expression is correlated with a decreased expression of a neuronal marker, illustrating the loss of neurons observed in AD.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataThe majority of the role of BIN1 in cognitive decline is not independent of tangles; BIN1 exon 7 peptide LQAHLVAQTNLLR does not have an independent effect on cognitive decline.
“suggesting that the majority of the role of BIN1 in cognitive decline is not independent of tangles”
- Also stated in: § BIN1 isoforms 1, 2 and 3 are associated with tau tangles · plain
“BIN1 exon 7 peptides (i.e LQAHLVAQTNLLR) play a role in the accumulation of tangles and do not have an independent effect on cognitive decline”
Quote in the paperSubstantial claim- Also stated in: § BIN1 isoforms 1, 2 and 3 are associated with tau tangles · plain
It may state two separate claims as one.
Interpretationown dataAs pathology burden increases, BIN1 exon 7 peptide expression is reduced; as cognitive function worsens, expression of these peptides is diminished.
“Overall, as pathology burden increases, exon 7 peptide expression is reduced. Similarly, the expression of these peptides is diminished as cognitive functions worsens.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationBIN1 isoforms 9 and 10 are ubiquitously expressed and are also detected in the brain.
“Isoforms 9 and 10 are ubiquitously expressed and are also detected in the brain [11].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Zhou Y, Hayashi I, Wong J, Tugusheva K, Renger JJ, Zerbinatti C. Intracellular clusterin interacts with brain isoforms of the bridging integrator 1 and with the microtubule-associated protein tau in Alzheimer's disease. PLoS One. 2014;9(7):e103187. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationHigh expression of BIN1 has been reported in mature oligodendrocytes, especially in the white matter of human brain.
“In addition, high expression of BIN1 has also been reported in mature oligodendrocytes, especially in the white matter of human brain [12].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [12] De Rossi P, Buggia-Prevot V, Clayton BL, Vasquez JB, van Sanford C, Andrew RJ, et al. Predominant expression of Alzheimer's disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts. Mol Neurodegener. 2016;11(1):59. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationBIN1 is found both in the nucleus and cytosol.
“confirming the observation reported by other studies that BIN1 is found both in the nucleus and cytosol [29–31]”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [29] Muller AJ, Baker JF, DuHadaway JB, Ge K, Farmer G, Donover PS, et al. Targeted disruption of the murine Bin1/Amphiphysin II gene does not disable endocytosis but results in embryonic cardiomyopathy with aberrant myofibril formation. Mol Cell Biol. 2003;23(12):4295–306. source
- cites [30] Kadlec L, Pendergast AM. The amphiphysin-like protein 1 (ALP1) interacts functionally with the cABL tyrosine kinase and may play a role in cytoskeletal regulation. Proc Natl Acad Sci U S A. 1997;94(23):12390–5. source
- cites [31] Elliott K, Ge K, Du W, Prendergast GC. The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program. Oncogene. 2000;19(41):4669–84. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe effect size of the BIN1 variant tagged by rs6733839 is among the largest for common AD variants; only APOEε4 and TREM2 have larger effects.
“The effect size of the BIN1 variant (tagged by rs6733839) is among the largest for common AD variants [3]; only APOEε4 and TREM2 [2] have larger effects.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [3] Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013;45(12):1452–8. source
- cites [2] Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010;303(18):1832–40. source
It may state two separate claims as one.
Study design and conductown dataThe 4 custom antibodies against different epitopes of BIN1 recognized the selected isoform expressed in HEK 293 T cells by immunohistochemistry, with specific reactivity and no non-specific reactivity.
“Furthermore, the 4 custom antibodies against different epitopes of BIN1 recognized the selected isoform expressed in HEK 293 T cells by immunohistochemistry (Suppl. Fig. 2). Specific reactivity was demonstrated against the appropriate transfected cell pellet controls, while no non-specific reactivity was observed (Suppl. Fig. 2).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationBIN1 isoform 8 is specifically expressed in muscle.
“Isoform 8 is specifically expressed in muscle [10].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Butler MH, David C, Ochoa GC, Freyberg Z, Daniell L, Grabs D, et al. Amphiphysin II (SH3P9; BIN1), a member of the amphiphysin/Rvs family, is concentrated in the cortical cytomatrix of axon initial segments and nodes of ranvier in brain and around T tubules in skeletal muscle. J Cell Biol. 1997;137(6):1355–67. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataFour out of 25 microglia samples were excluded due to a low percentage of exonic and UTR reads (<30%) or a low total number of reads mapping to the transcriptome (<10^6 reads).
“Four out of 25 samples were excluded due to a low percentage of exonic and UTR reads (< 30%) or a low total number of reads mapping to the transcriptome (< 106 reads).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationSeveral susceptibility loci that contribute to genetic risk for AD, including one containing BIN1, have been identified by GWAS.
“In the last few years, several susceptibility loci that contribute to genetic risk for AD, including one that contains the BIN1 (Bridging integrator 1) gene, have been identified by genome wide association studies (GWAS) [2].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, et al. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA. 2010;303(18):1832–40. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataNo basal expression of BIN1 was detected in the HEK 293 T cell clone used to express the different isoforms.
“No basal expression of BIN1 was detected in the HEK 293 T cell clone that we used to express the different isoforms.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataBIN1 isoforms present in myeloid cells are expressed in a context-dependent manner and are probably more prominent in microglia than in peripheral myeloid cells.
“These findings showed that isoforms present in myeloid cells are expressed in a context-dependent manner and are probably more prominent in microglia than in peripheral myeloid cells.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataAll participants undergo a uniform structured evaluation for AD including CERAD, Braak Stage, NIA-Reagan, and a global measure of AD pathologic burden.
“All participants undergo a uniform structured evaluation for AD including CERAD, Braak Stage, NIA-Reagan, and a global measure of AD pathologic burden with modified Bielschowsky; amyloid load and PHF Tau tangles by immunocytochemistry and image analysis and stereology; Lewy bodies and TDP-43 by immunocytochemistry; and the age, location, and size of all macro- and microscopic infarcts.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
PremisecitationBIN1 isoforms are translated into proteins differently in neurons and astrocytes: cultured neurons mostly express isoforms 1, 3, 5 and 7 while cultured astrocytes express isoforms 2, 5, 9 and 10.
“It was reported that BIN1 isoforms are translated into proteins differently in neurons and astrocytes: cultured neurons mostly express isoforms 1, 3, 5 and 7 while cultured astrocytes express isoforms 2, 5, 9 and 10 [11].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Zhou Y, Hayashi I, Wong J, Tugusheva K, Renger JJ, Zerbinatti C. Intracellular clusterin interacts with brain isoforms of the bridging integrator 1 and with the microtubule-associated protein tau in Alzheimer's disease. PLoS One. 2014;9(7):e103187. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenThe follow-up rate exceeds 95% and the autopsy rate exceeds 90% in ROS/MAP.
“The follow-up rate exceeds 95% and the autopsy rate exceeds 90%.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationBIN1 expression has been reported in IBA1+ cells in AD brain.
“BIN1 expression has been reported in IBA1+ cells in AD brain [13].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [13] Chapuis J, Hansmannel F, Gistelinck M, Mounier A, Van Cauwenberghe C, Kolen KV, et al. Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology. Mol Psychiatry. 2013;18(11):1225–34. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAll SRM data were manually inspected to ensure correct peak assignment and peak boundaries.
“All the data were manually inspected to ensure correct peak assignment and peak boundaries.”
Quote in the paperNot a substantial claimProbably not a substantial claim.
Premisenone givenThe extent of characterization of BIN1 isoform expression in different cell types has been limited by the small number of commercially available antibodies against exon-selective epitopes of BIN1.
“Finally, the extent of the characterization of the expression of these different BIN1 isoforms in different cell types has been limited by the small number of commercially available antibodies against exon-selective epitopes of BIN1.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataPeptides were identified using MaxQuant with a false discovery rate threshold of 1%.
“The peptides were identified using the MaxQuant software with a false discovery Rate (FDR) threshold of 1%.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationBIN1 isoforms 1 through 7 are brain specific, with isoform 1 being exclusively expressed in neurons.
“Isoforms 1 through 7 are brain specific with isoform 1 being exclusively expressed in neurons [10].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Butler MH, David C, Ochoa GC, Freyberg Z, Daniell L, Grabs D, et al. Amphiphysin II (SH3P9; BIN1), a member of the amphiphysin/Rvs family, is concentrated in the cortical cytomatrix of axon initial segments and nodes of ranvier in brain and around T tubules in skeletal muscle. J Cell Biol. 1997;137(6):1355–67. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenROS and MAP cohorts implement the same annual evaluations including 19 cognitive functional tests and use accepted and validated procedures to diagnose AD and other dementias and MCI.
“Both cohorts implement the same annual evaluations including 19 cognitive functional tests and use accepted and validated procedures to diagnose AD and other dementias and mild cognitive impairment (MCI).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationAn association between expression of some BIN1 RNA isoforms and AD was reported: a decrease of isoform 1 and an increase of isoform 9 expression in small collections of human AD post-mortem brain samples.
“In addition, an association between expression of some BIN1 RNA isoforms and AD was reported: a decrease of isoform 1 and an increase of isoform 9 expression was noted in small collections of human AD post-mortem brain samples [19, 20].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [19] Glennon EB, Whitehouse IJ, Miners JS, Kehoe PG, Love S, Kellett KA, et al. BIN1 is decreased in sporadic but not familial Alzheimer's disease or in aging. PLoS One. 2013;8(10):e78806. source
- cites [20] Holler CJ, Davis PR, Beckett TL, Platt TL, Webb RL, Head E, et al. Bridging integrator 1 (BIN1) protein expression increases in the Alzheimer's disease brain and correlates with neurofibrillary tangle pathology. J Alzheimers Dis. 2014;42(4):1221–7. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisenone givenBIN1 is expressed in 14 RNA transcripts, 11 of which are translated into proteins: isoforms 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 12.
“BIN1 is expressed in 14 RNA transcripts, generated by alternative splicing, and 11 of them are translated into respective proteins: isoforms 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 12 (Fig. 1b).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataBIN1 exon 7 is specifically associated with AD-related pathologies, and amyloid and tau tangles measures are more strongly associated than measures of clinical function.
“These findings suggest a specific association between exon 7 of BIN1 and AD-related pathologies, and our measures of amyloid and tau tangles appear to be more strongly associated than the measures related to clinical function.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationBIN1 has been implicated in inflammation: there is a report of an increase of inflammation in BIN1 knock-out mice.
“BIN1 has been implicated in inflammation: there is a report of an increase of inflammation in BIN1 knock-out mice [18].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18] Chang MY, Boulden J, Katz JB, Wang L, Meyer TJ, Soler AP, et al. Bin1 ablation increases susceptibility to cancer during aging, particularly lung cancer. Cancer Res. 2007;67(16):7605–12. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationA decrease of DNM2 mRNA in AD temporal cortex has been reported.
“a decrease of DNM2 mRNA in AD temporal cortex has been reported [39]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Kamagata E, Kudo T, Kimura R, Tanimukai H, Morihara T, Sadik MG, et al. Decrease of dynamin 2 levels in late-onset Alzheimer's disease alters Abeta metabolism. Biochem Biophys Res Commun. 2009;379(3):691–5. source
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationCurrently, only 2 of the 11 translated isoforms have been described as differentially expressed in AD brain: a decrease of isoform 1 and an increase of isoform 9 expression correlate with AD.
“Currently, only 2 of the 11 translated isoforms have been described as being differentially expressed in the AD brain: a decrease of isoform 1 and an increase of isoform 9 expression correlate with AD [19]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Glennon EB, Whitehouse IJ, Miners JS, Kehoe PG, Love S, Kellett KA, et al. BIN1 is decreased in sporadic but not familial Alzheimer's disease or in aging. PLoS One. 2013;8(10):e78806. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationTau tangles are associated with certain miRNA (miR132 and miR129) and certain modules of co-expressed genes derived from cortical RNA sequence data.
“we have found tau tangles to be associated with certain miRNA previously reported to be associated with AD (miR132 and mir129) [33], as well as certain modules of co-expressed genes derived from cortical RNA sequence data [6]”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [33] Patrick E, Rajagopal S, Wong HA, McCabe C, Xu J, Tang A, et al. Dissecting the role of non-coding RNAs in the accumulation of amyloid and tau neuropathologies in Alzheimer's disease. Mol Neurodegener. 2017;12(1):51. source
- cites [6] Mostafavi S, Gaiteri C, Sullivan SE, White CC, Tasaki S, Xu J, et al. A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer's disease. Nat Neurosci. 2018;21(6):811–9. source
It may state two separate claims as one.
Interpretationown dataDecreased expression of BIN1 isoforms 1, 2 and 3 leads to an increase in the endocytosis process and promotes the phosphorylation of AD-related Tau epitopes in neurons, in a cell-autonomous or non-cell-autonomous fashion.
“In summary, based on our data and evidence from the literature, we propose that decreased expression of isoforms 1, 2, and 3 leads to an increase in the endocytosis process and promotes the phosphorylation of AD-related Tau epitopes in neurons, either in a cell autonomous or non-cell autonomous fashion.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationExon 7 encodes a portion of the N-BAR domain of BIN1 and is specific to isoforms 1, 2 and 3.
“Exon 7 encodes a portion of the N-BAR domain of BIN1 and is specific to isoforms 1, 2 and 3 [7, 37]”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [7] Peter BJ, Kent HM, Mills IG, Vallis Y, Butler PJ, Evans PR, et al. BAR domains as sensors of membrane curvature: the amphiphysin BAR structure. Science. 2004;303(5657):495–9. source
- cites [37] Frost A, Unger VM, De Camilli P. The BAR domain superfamily: membrane-molding macromolecules. Cell. 2009;137(2):191–6. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationExon 7 enables the interaction between BIN1 and dynamin 2 (DNM2), and this interaction facilitates endocytic uptake.
“Exon 7 enables the interaction between BIN1 and dynamin 2 (DNM2), a ubiquitously expressed GTP binding protein, and this interaction facilitates endocytic uptake [38]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Ellis JD, Barrios-Rodiles M, Colak R, Irimia M, Kim T, Calarco JA, et al. Tissue-specific alternative splicing remodels protein-protein interaction networks. Mol Cell. 2012;46(6):884–92. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationOligodendrocytes, which are enriched in white matter, mainly express BIN1 isoform 9.
“These investigators reported that oligodendrocytes, which are enriched in white matter, mainly express BIN1 isoform 9 [42]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] De Rossi P, Buggia-Prevot V, Andrew RJ, Krause SV, Woo E, Nelson PT, et al. BIN1 localization is distinct from tau tangles in Alzheimer's disease. Matters (Zur). 2017;2017. source
Probably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
Premisenone givenThe CLAP domain is involved in clathrin-mediated endocytosis and in the recruitment of dynamin.
“The CLAP domain has been described to be involved in clathrin-mediated endocytosis and in the recruitment of dynamin.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
PremisecitationAbsence of exon 7 leads to inhibition of uptake, suggesting the BIN1 N-BAR domain plays a key role in endocytosis via its interaction with DNM2.
“Absence of exon 7 leads to the inhibition of uptake, suggesting that the BIN1 N-BAR domain plays a key role in endocytosis via its interaction with DNM2 [38]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38] Ellis JD, Barrios-Rodiles M, Colak R, Irimia M, Kim T, Calarco JA, et al. Tissue-specific alternative splicing remodels protein-protein interaction networks. Mol Cell. 2012;46(6):884–92. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe BIN1 N-BAR domain has been implicated in stabilizing the polymerization of actin, including Tau-induced actin polymerization.
“the BIN1 N-BAR domain has also been implicated in stabilizing the polymerization of actin, including the one induced by Tau [40]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Drager NM, Nachman E, Winterhoff M, Bruhmann S, Shah P, Katsinelos T, et al. Bin1 directly remodels actin dynamics through its BAR domain. EMBO Rep. 2017;18(11):2051–66. source
It may state two separate claims as one.
Interpretationown dataThe BIN1 isoforms expressed by neurons and astrocytes, although possibly unrelated to the effect of the rs6733839 AD risk variant, represent a distinct contribution of BIN1 to AD.
“While these isoforms may be unrelated to the effect of the rs6733839 AD risk variant, they nonetheless represent a distinct contribution of this complex protein to AD, offering new insights into how BIN1 could be targeted or could serve as an outcome measure in AD studies.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationBIN1 has been implicated in phagocytosis in macrophages.
“BIN1 has been implicated in phagocytosis in macrophages [43]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [43] Gold ES, Simmons RM, Petersen TW, Campbell LA, Kuo CC, Aderem A. Amphiphysin IIm is required for survival of chlamydia pneumoniae in macrophages. J Exp Med. 2004;200(5):581–6. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationBIN1 has been reported to regulate endocytosis in neurons, and loss of its function appears to promote the propagation of Tau pathology in an in vitro model.
“BIN1 has been reported to regulate endocytosis in neurons, and the loss of its function appears to promote the propagation of Tau pathology in an in vitro model, supporting our findings [41]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] Calafate S, Flavin W, Verstreken P, Moechars D. Loss of Bin1 promotes the propagation of tau pathology. Cell Rep. 2016;17(4):931–40. source
The paper relies on this without support.
The abundance of selected BIN1 peptides measured by SRM reflects the abundance of the corresponding BIN1 protein isoforms in DLPFC.
“The abundance of selected peptides, which correspond to groups of BIN1 protein isoforms, was measured in dorsolateral prefrontal cortex, and their relation to neuropathological features of AD was assessed.”
The paper relies on this without support.
Cell type proportions estimated using DSA with RNA-seq accurately reflect the proportions of myeloid cells, neurons, astrocytes, oligodendrocytes, and endothelial cells in DLPFC.
“adjusting for age at death, sex, and cohort (ROS or MAP), as well as myeloid proportion, neuron proportion, astrocyte proportion, oligodendrocyte proportion, and endothelial cell proportion as estimated using DSA with RNA-seq.”
The paper relies on this without support.
The antibody used specifically recognizes BIN1 exon 7 and does not cross-react with other BIN1 epitopes.
“Utilizing an antibody specifically targeting exon 7 on post-mortem human brain”
“we stained AD and cognitively non-impaired subjects from the New York Brain Bank (see Suppl. Table.1.b for a description of these subjects) with the antibody recognizing BIN1 exon 7 and ALDH1L1, a marker of cortical astrocytes, or NeuN, a neuronal marker”
The paper relies on this without support.
BIN1 expression measured in MDMi (monocyte-derived microglia-like) cells reflects BIN1 expression by microglia in the brain.
“we show that BIN1 isoforms 10 and 12 are expressed in MDMi and not in peripheral monocytes, highlighting the existence of context-specific expression of BIN1 protein isoforms by microglia.”
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.
Astrocyte comparison is described as using the same seven subjects
MajorThe Results describe the astrocyte comparison as being in the same seven individuals assessed for neurons, whereas the Fig. 6 caption specifies nine AD and nine non-AD subjects for the astrocyte comparison.
“While the number of BIN1 exon 7+ neurons shows no difference between the two sets of subjects (with a total of 9735 neurons assessed in our 7 subjects) (Fig. 6a), we find, in the same individuals, a significant decrease in the number of astrocytes expressing BIN1 exon 7 in AD compared to cognitively non-impaired subjects”
“b Co-immunostaining in human post-mortem brain tissues using an antibody recognizing specifically BIN1 exon 7 in red and an astrocyte marker (ALDH1L1) in green for n = 9 AD and n = 9 non-AD subjects.”
Table 2 assigns exon 11 to isoforms 5 and 6
MajorTable 2 lists exon 11 for isoforms 5 and 6, but the text states that exon 11 is present only in isoforms 4, 8 and 12.
“| Isoform 5 | Yes | exon 11, 13 | exon 11, 13 | No | No | | Isoform 6 | Yes | exon 11, 13 | exon 11, 13 | Yes | exon 11, 13 |”
“The phosphoinositide (PI) binding motif is encoded by exon 11 and is only present in a few BIN1 isoforms (isoform 4, 8 and 12).”
Discussion says isoform 4 was detected in DLPFC
MinorThe Discussion includes isoform 4 among those detected at the RNA level in DLPFC, whereas the Results explicitly say it is absent.
“At the RNA level, we detected expression of isoforms 1, 2, 3, 4, 5, 6, 7, 9, 10 and 12 in the human DLPFC”
“isoform 4 and isoform 8, which has been reported to be specific to muscle [10], are absent.”
CNS isoform count conflicts with the isoforms listed
MinorThe abstract says 10 BIN1 isoforms are expressed in the CNS, but the Results list nine expressed isoforms and say that isoforms 4 and 8 are absent.
“BIN1 has 10 isoforms that are expressed in the Central Nervous System (CNS).”
“Isoforms 1 and 9 are the ones most highly expressed, followed by isoforms 6, 7 and 10. Isoforms 2, 3, 5, and 12 are expressed at low levels, and isoform 4 and isoform 8, which has been reported to be specific to muscle [10], are absent.”
Table 2 marks neuronal and astrocytic isoform 12 data unavailable
MinorThe Results state that exon 11 staining establishes expression of isoform 12 in neurons and astrocytes, but Table 2 marks the antibody data for both cell types as unavailable.
“| Isoform 12 | Yes | data N/A | data N/A | Yes | data N/A |”
“BIN1 isoform 12, which contains exon 11 (Fig. 1b), is also expressed in neurons and astrocytes.”
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Bi, W., Lei, T., Cai, S., Zhang, X., Yang, Y., Xiao, Z., Wang, L., & Du, H. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109368 · Cited by 13
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Role of Bin‐Amphiphysin‐Rvs (BAR) domain proteins in mediating neuronal signaling and disease
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Alzheimer’s genetic risk factor Bin1 controls synapse vesicle exo-endocytosis in inhibitory synapses
Barata, M. A., Perdigão, C., Ramalho, J. S., Gomes, E. R., & Almeida, C. G. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116005 · Cited by 9
Diverse signaling mechanisms and heterogeneity of astrocyte reactivity in Alzheimer's disease
Qin, H., Zhou, L., Haque, F. T., Martín-Jiménez, C., Trang, A., Benveniste, E. N., & Wang, Q. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.16002 · Cited by 10
Coupling of Alzheimer’s Disease Genetic Risk Factors with Viral Susceptibility and Inflammation
Cao, C., Fu, G., Xu, R., & Li, N. (2023) · Aging and Disease · doi:10.14336/ad.2023.1017 · Cited by 8
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Latina, V., Atlante, A., Malerba, F., Regina, F. L., Balzamino, B. O., Micera, A., Pignataro, A., Stigliano, E., Cavallaro, S., Calissano, P., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119683 · Cited by 5
Proteomic Characterization of the Alzheimer’s Disease Risk Factor BIN1 Interactome
McMillan, J. D., Wang, S., Wohlfahrt, J., Guergues, J., Stevens, S. M., & Thinakaran, G. (2025) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2025.101055 · Cited by 4
Coordination of autophagosome closure and release by the Alzheimer’s disease-associated protein BIN1
Palmer, J. E., Puri, C., O’Rourke, R., Son, S. M., Sang, C., Huang, Y. A., & Rubinsztein, D. C. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116266 · Cited by 4
Heal, M., McFall, G. P., Vergote, D., Jhamandas, J. H., Westaway, D. A., & Dixon, R. A. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220334 · Cited by 4
Genome-wide transcriptome profiling and development of age prediction models in the human brain
Zarrella, J., & Tsurumi, A. (2024) · Aging · doi:10.18632/aging.205609 · Cited by 4
Hudgins, A. D., Zhou, S., Arey, R. N., Rosenfeld, M. G., Murphy, C. T., & Suh, Y. (2024) · Neuron · doi:10.1016/j.neuron.2024.04.009 · Cited by 3
A comprehensive review on novel opportunities for Alzheimer therapy by targeting BIN1
Saha, T., & Karati, D. (2025) · Egyptian Journal of Medical Human Genetics · doi:10.1186/s43042-025-00759-8 · Cited by 3
Bend it like BIN1: how a membrane-curving adaptor protein shapes cardiac physiology
Spooner, H. C., & Dixon, R. E. (2025) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00198.2025 · Cited by 3
Duckhorn, J. C., Kim, D. K., & Huang, Y. A. (2025) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-25-00243 · Cited by 2
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Endocytic scaffolds at the crossroads of Alzheimer’s disease and neuronal aging
Shergill, J. K., & Tehran, D. A. (2026) · Biological Chemistry · doi:10.1515/hsz-2025-0250 · Cited by 2
Hu, M., Esmaeeli, S., Stolzenburg, L. R., Milkovich, B., Jouni, M., Nyamugenda, E., Hammond, R. K., Reinhardt, P., Bahnassawy, L., Gasparini, L., et al. (2026) · Frontiers in Aging Neuroscience · doi:10.1101/2025.03.31.646439 · Cited by 2
Ranganathan, R., Li, S., Sapozhnikov, G., Wang, S., & Song, Y. (2025) · Journal of Alzheimer s Disease Reports · doi:10.1177/25424823241296018 · Cited by 2
FMNL2 interacts with cerebrovascular risk factors to alter Alzheimer’s disease riskPreprint
Raghavan, N. S., Sariya, S., Lee, A., Gao, Y., Reyes‐Dumeyer, D., Jager, P. L. D., Bennett, D. A., Menon, V., Lantigua, R., Kukull, W. A., et al. (2020) · medRxiv · doi:10.1101/2020.08.30.20184879 · Cited by 2
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High cell-type specificity of eQTLs revealed by single-nucleus analyses of brain and bloodPreprint
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Exploring the Protein–Metabolite Interplay to Discover Novel Drug Targets for Alzheimer's Disease
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Nuclear BIN1 isoforms regulate c-Myc-mediated cell cycle control in oligodendrocytesPreprint
Ma, I. W.-T., Cheng, G. W., Yeung, S. H., Yeung, M. H. Y., Kofler, J., Herrup, K., & Tse, K. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.30.676706
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Sudwarts, A., Ramesha, S., Gao, T., Ponnusamy, M., Wang, S., Hansen, M. T., Kozlova, A., Bitarafan, S., Kumar, P., Beaulieu‐Abdelahad, D., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19728373
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Lambert, E., Saha, O., Landeira, B. S., de Farias, A. R. M., Hermant, X., Carrier, A., Pelletier, A., Gadaut, J., Davoine, L., Dupont, C., et al. (2022) · Figshare · doi:10.6084/m9.figshare.18093105
Lambert, E., Saha, O., Landeira, B. S., de Farias, A. R. M., Hermant, X., Carrier, A., Pelletier, A., Gadaut, J., Davoine, L., Dupont, C., et al. (2022) · Figshare · doi:10.6084/m9.figshare.18093096
Sudwarts, A., Ramesha, S., Gao, T., Ponnusamy, M., Wang, S., Hansen, M. T., Kozlova, A., Bitarafan, S., Kumar, P., Beaulieu‐Abdelahad, D., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19728388
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Sudwarts, A., Ramesha, S., Gao, T., Ponnusamy, M., Wang, S., Hansen, M. T., Kozlova, A., Bitarafan, S., Kumar, P., Beaulieu‐Abdelahad, D., et al. (2022) · Figshare · doi:10.6084/m9.figshare.19728379
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BIN1 (amphiphysin 2) in the pathogenesis of cognitive impairment
Shamakina, I. Y., Kokhan, V. S., Venkova, V. A., Баронец, В. Ю., Popov, S. S., & Anokhin, P. K. (2026) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro202612603145
BIN1 gain-of-function in the presynaptic compartment leads to isoform-specific synaptotoxicity
Lambert, E., Gelle, C., Leclerc, V., Freire‐Regatillo, A., Liefooghe, L., Barois, N., Malfoi, T., Hermant, X., Demiautte, F., Gallienne, I., et al. (2026) · Alzheimer s Research & Therapy · doi:10.1186/s13195-026-02103-7
Quantitation of Spatial Proteoforms in Alzheimer’s DiseasePreprint
McClatchy, D. B., Turner, N. P., & Yates, J. R. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.30.735694
RNA Splicing Dysregulation in Parkinson’s Disease
Bruno, M. G., Menichetti, G., Valentino, A., Javaid, A., Belpinati, F., Ruggiero, A., Valenti, M. T., Paolone, G., Cavaliere, F., Trabetti, E., et al. (2026) · Genes · doi:10.3390/genes17080911
BIN1 (Amphiphysin 2) in the Pathogenesis of Cognitive Impairment
Shamakina, I. Y., Kokhan, V. S., Venkova, V. A., Баронец, В. Ю., Popov, S. S., & Anokhin, P. K. (2026) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-026-02059-z
Μαργαρίτη, Μ., Thanou, I., Papadimitriou, E., Pelletier, A., Xingi, E., Antoniou, C., Kyrargyri, V., Costa, M. R., & Thomaidou, D. (2026) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-026-06434-4
Cross-Species and Cell-Type-Specific H3K27ac Dynamics Link Brain Aging to Alzheimer’s Disease Genes
Choo, C., Ngian, Z., & Ong, C. (2026) · Cells · doi:10.3390/cells15212007
Metadata
- Authors
- Taga, M., Petyuk, V. A., White, C., Marsh, G., Ma, Y., Klein, H.-U., Connor, S. M., Kroshilina, A., Yung, C. J., Khairallah, A., Olah, M., Schneider, J., Karhohs, K., Carpenter, A. E., Ransohoff, R., Bennett, D. A., Crotti, A., Bradshaw, E. M., & De Jager, P. L.
- Affiliations
- Broad Institute (US)
- Pacific Northwest National Laboratory (US)
- Biogen (United States) (US)
- Columbia University Irving Medical Center (US)
- Rush University Medical Center (US)
- Harvard University (US)
- ORCID
- Venue
- Molecular Neurodegeneration
- Published
- 2020-07-29
- Volume
- 15
- Issue
- 1
- Pages
- 44-44
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC7389646
- OpenAlex
- W3045809806
- Semantic Scholar
- b41f3622de1c6585fa4e1f5ccba7e71049c53729
- Cited by
- 81
- References
- 45
- Citations by year
- 2026: 12 · 2025: 14 · 2024: 7 · 2023: 9 · 2022: 28 · 2021: 7 · 2020: 2
- FWCI
- 4.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (U01 AG046152, R01 AG048015, R01 NS089674)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- BIN1, Alzheimer's disease, tau pathology, tau tangles, astrocytes, neurons, microglia, N-BAR domain, exon 7, dorsolateral prefrontal cortex, cognitive decline, postmortem brain, cell type-specific gene expression
- MeSH terms
- Alzheimer Disease, Astrocytes, Brain, Humans, Neurons, Nuclear Proteins, tau Proteins, Microglia, Protein Isoforms, Tumor Suppressor Proteins, Adaptor Proteins, Signal Transducing
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