BIN1 regulates BACE1 intracellular trafficking and amyloid-β production
Open accessAbstract
BIN1 is a genetic risk factor of late-onset Alzheimer disease (AD), which was identified in multiple genome-wide association studies. BIN1 is a member of the amphiphysin family of proteins, and contains N-terminal Bin-Amphiphysin-Rvs and C-terminal Src homology 3 domains. BIN1 is widely expressed in the mouse and human brains, and has been reported to function in the endocytosis and the endosomal sorting of membrane proteins. BACE1 is a type 1 transmembrane aspartyl protease expressed predominantly in neurons of the brain and responsible for the production of amyloid-β peptide (Aβ). Here we report that the depletion of BIN1 increases cellular BACE1 levels through impaired endosomal trafficking and reduces BACE1 lysosomal degradation, resulting in increased Aβ production. Our findings provide a mechanistic role of BIN1 in the pathogenesis of AD as a novel genetic regulator of BACE1 levels and Aβ production.
AI snapshot
Written from the paper’s full text.
TL;DR
BIN1 depletion increases cellular BACE1 by impairing its trafficking from early endosomes to lysosomes, reducing BACE1 degradation and increasing amyloid-β production. The BIN1 BAR domain binds the BACE1 C-terminal intracellular domain, linking an Alzheimer disease risk gene to BACE1 metabolism.
Key findings
- In primary cortical neurons from Bin1 flox/flox mice, Cre-mediated Bin1 depletion increased BACE1 protein and sAPPβ secretion and increased secreted Aβ40 and Aβ42 (n = 6, P < 0.05), without altering the Aβ42 proportion; BACE1 mRNA was unchanged at 99.8 ± 0.5% of control (n = 6).
- Bin1 RNAi in Neuro2a and HeLa cells increased BACE1 and Aβ; membrane BACE1 activity was significantly increased in Neuro2a cells (n = 9), and Bin1-ablated HeLa cells expressing APP C99 showed no change in Aβ secretion.
- SNAP-BACE1 tracking showed labeled BACE1 largely disappeared from EEA1-positive early endosomes by 120 min in control cells but remained in Bin1-depleted cells; sucrose gradients showed reduced BACE1 in the LAMP1-enriched lysosomal fraction 2.
- GST pulldown showed the BIN1 BAR domain, but not the SH3 domain, bound the BACE1 C-terminal intracellular domain; BIN1ΔBAR expression increased BACE1 and Aβ similarly to Bin1 depletion.
Methods
- Primary cortical neurons from P1 Bin1 flox/flox mice were infected with EGFP-NLS or EGFP-NLS-Cre lentivirus; Neuro2a and HeLa cells were treated with Bin1 siRNA. Readouts included immunoblotting, sandwich ELISAs for Aβ40/Aβ42, qRT-PCR, and an in vitro BACE1 activity assay using JMV2236.
- BACE1 trafficking was assessed by SNAP-BACE1 surface labeling and uptake at 30 and 120 min with EEA1 immunostaining, sucrose density gradient fractionation, GST pulldown, and coimmunoprecipitation. Groups were compared by two-tailed Student’s t-test with SEM; significance set at P < 0.05 and P < 0.005.
Limitations
- Stated: whether BIN1 directly or indirectly associates with the BACE1 cytoplasmic domain remains unclear, and whether BIN1 expression is altered in AD patients with the rs6733839 polymorphism is controversial and requires systematic expression and splicing analyses.
- Evident from the text: the experimental evidence comes from cultured primary neurons and cell lines (Neuro2a, HeLa) using depletion and mutant overexpression, with no in vivo AD model or human AD tissue validation presented in this paper.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
17 of 23 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Ubiquitination at lysine 501 in the C-terminus of BACE1 is required for GGA3-mediated lysosomal targeting and degradation of BACE1.
“Ubiquitination at lysine 501 in the C-terminus of BACE1 is required for GGA3-mediated lysosomal targeting and the degradation of BACE1 (29,30).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [29] source
- cites [30] source
Figure 5 and its accompanying results (page not provided) show that Lys-501 is in BACE1’s C-terminus and that the K501R substitution greatly reduces BACE1 ubiquitination. The paper also links GGA3’s ubiquitin-binding ability to regulation of BACE1 levels and discusses lysosomal degradation, but it does not show that ubiquitination specifically at Lys-501 is required for GGA3-mediated lysosomal targeting or degradation. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Findingown data
The BAR domain, but not the SH3 domain, of BIN1 is required for binding of BIN1 with BACE1.
“We found that the BAR domain, but not the SH3 domain of BIN1, was required for the binding of BIN1 with BACE1 (Fig. 5C).”
- Also stated in: § Discussion · plain
“We found that the BAR domain of BIN1 was a BACE1-interaction domain, although it still remains unclear as to whether BIN1 directly or indirectly associates with the cytoplasmic domain of BACE1.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Neuro2a cells expressing BIN1DBAR showed increased Ab secretion.
“Furthermore, Neuro2a cells expressing BIN1DBAR showed increased level of BACE1 as well as Ab secretion, similarly to that observed in Bin1-depleted cells (Fig. 6).”
Quote in the paperSubstantial claim - Findingown data
In Bin1-depleted cells, at 120 minutes after labeling, the majority of labeled SNAP-tagged BACE1 remained in EEA1-positive early endosomes.
“Intriguingly, in the Bin1-depleted cells, the majority of labeled SNAP-tagged BACE1 still remained in the EEA1-positive early endosomes, suggesting that BIN1 functions in the intracellular trafficking of BACE1 from the early endosomes.”
Quote in the paperSubstantial claim - Findingown data
GST-fused BACE1 C-terminal intracellular domain (B1CT) bound to BIN1 holoprotein expressed in Neuro2a cells.
“We found that the GST-fused BACE1 C-terminal intracellular domain (B1CT) bound to the BIN1 holoprotein expressed in Neuro2a cells.”
Quote in the paperSubstantial claim
- Findingown data
The BIN1DBAR mutant showed dominant-negative effects.
“We also found that the BIN1DBAR mutant showed dominantnegative effects.”
Quote in the paperSubstantial claim - Findingnone given
Ubiquitination at Lys-501 in the C-terminal intracellular domain of BACE1 is not required for its interaction with BIN1.
“Intriguingly, ubiquitination at Lys-501 in the C-terminal intracellular domain of BACE1 was not required for its interaction with BIN1.”
Quote in the paperNot a substantial claim - Findingown data
Bin1 RNAi increased levels of ubiquitinated BACE1.
“Moreover, levels of ubiquitinated BACE1 was increased by Bin1 RNAi (Fig. 4E), indicating that BACE1 was recruited and degraded by ubiquitin-dependent pathway in Bin1-depleted cells.”
Quote in the paperSubstantial claim - Findingown data
Bin1 depletion increased BACE1 levels in HeLa cells expressing the BACE1/K501R mutant.
“However, Bin1 depletion increased the levels of BACE1 and Ab secretion in the HeLa cells expressing the BACE1/K501R mutant (Fig. 4C and D), which cannot be ubiquitinated.”
Quote in the paperSubstantial claim- Rests on an assumption: The BACE1/K501R mutant cannot be ubiquitinated.
- Findingown data
In Bin1-depleted Neuro2a cells, BACE1 in fraction 2 (late endosomes/lysosomes) was significantly reduced compared with control cells.
“In the Bin1-depleted cells, BACE1 in the fraction 2, which corresponds to late endosomes/ lysosomes, was significantly reduced compared with the control cells (Fig. 4B).”
Quote in the paperSubstantial claim - Findingown data
Bin1 depletion increased Ab secretion in HeLa cells expressing the BACE1/K501R mutant.
“However, Bin1 depletion increased the levels of BACE1 and Ab secretion in the HeLa cells expressing the BACE1/K501R mutant (Fig. 4C and D), which cannot be ubiquitinated.”
Quote in the paperSubstantial claim- Rests on an assumption: The BACE1/K501R mutant cannot be ubiquitinated.
- Findingown data
At 120 minutes after labeling, a large fraction of labeled SNAP-BACE1 disappeared from EEA1-positive early endosomes in control cells.
“However, 120 min after labeling, a large fraction of the labeled SNAP-BACE1 had disappeared from the EEA1-positive early endosomes in the control cells (Fig. 3C).”
Quote in the paperSubstantial claim - Findingown data
At 30 minutes after labeling, SNAP-BACE1 internalized and accumulated in EEA1-positive early endosomes similarly in Bin1-depleted and control cells.
“Thirty minutes after labeling, labeled SNAP-BACE1 was internalized and accumulated in the EEA1-positive early endosomes without an apparent difference between in the Bin1-depleted cells and the control cells (Fig. 3C).”
Quote in the paperNot a substantial claim - Findingown data
Neuro2a cells expressing BIN1DBAR showed increased BACE1 levels.
“Furthermore, Neuro2a cells expressing BIN1DBAR showed increased level of BACE1 as well as Ab secretion, similarly to that observed in Bin1-depleted cells (Fig. 6).”
Quote in the paperSubstantial claim - Findingnone given
The BAR domain of BIN1 is essential for the protein-protein interaction between BIN1 and BACE1.
“The BAR domain of BIN1 is essential for the protein-protein interaction of BIN1 with BACE1.”
Quote in the paperSubstantial claim - Findingown data
Depletion of BIN1 increased BACE1 levels in primary cortical neurons.
“Depletion of BIN1 increased Ab secretion and BACE1 levels in primary neurons.”
Quote in the paperSubstantial claim - Findingown data
The BAR domain of BIN1 binds the BACE1 C-terminal intracellular domain.
“Binding of the BAR domain of BIN1 to the BACE1 C-terminal intracellular domain.”
Quote in the paperSubstantial claim - Findingown data
BIN1 depletion decreased lysosomal localization of BACE1 in Neuro2a cells.
“Depletion of BIN1 reduced the lysosomal targeting of BACE1.”
- Also stated in: § Statistical analysis · plain
“Note that lysosomal localization (fraction 2) of BACE1 was decreased in Bin1 depleted Neuro2a cells.”
Quote in the paperSubstantial claim - Also stated in: § Statistical analysis · plain
- Findingown data
Depletion of BIN1 expression enhanced BACE1 activity.
“Depletion of BIN1 expression caused Ab overproduction with enhanced BACE1 activity.”
Quote in the paperSubstantial claim - Findingown data
Depletion of BIN1 increased Aβ secretion from primary cortical neurons.
“Depletion of BIN1 increased Ab secretion and BACE1 levels in primary neurons.”
Quote in the paperSubstantial claim - Findingown data
BIN1 depletion increased levels of ubiquitinated BACE1 in HeLa cells.
“Levels of immunoprecipitated Ub-BACE1 was increased in the BIN1 depleted HeLa cells.”
Quote in the paperSubstantial claim - Interpretationown data
BIN1 functions in the intracellular trafficking of BACE1 from early endosomes.
“suggesting that BIN1 functions in the intracellular trafficking of BACE1 from the early endosomes.”
Quote in the paperSubstantial claim - Interpretationreasoning
Regulation of BACE1 trafficking and its degradation by BIN1 is an ubiquitin-independent, novel pathway of BACE1 metabolism.
“These results indicated that the regulation of BACE1 trafficking and its degradation by BIN1 was an ubiquitin-independent, novel pathway of BACE1 metabolism.”
Quote in the paperSubstantial claim- Rests on an assumption: The BACE1/K501R mutant cannot be ubiquitinated.
- Premisecitation
BACE1 degradation involves the lysosomal pathway.
“We next analyzed the BACE1 degradation, in which the lysosomal pathway is involved (26)(27)(28).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites (26)(27)(28)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
BIN1 recognizes the BACE1 intracellular domain without any post-translational modification including ubiquitination.
“As we used B1CT purified from bacterial lysates, these data support the notion that BIN1 recognizes the BACE1 intracellular domain without any post-translational modification including ubiquitination.”
Quote in the paperSubstantial claim - Interpretationown data
The general function of BIN1 is regulation of intracellular trafficking of cargos from the early endosome to the degradation pathway.
“These data support our notion that the general function of BIN1 is regulation of the intracellular trafficking of cargos from the early endosome to the degradation pathway.”
Quote in the paperSubstantial claim - Interpretationown data
A limited amount of partner proteins interacting with these domains is critical to BACE1 trafficking.
“This suggests that a limited amount of partner proteins interacting with these domains is critical to BACE1 trafficking.”
Quote in the paperSubstantial claim - Interpretationown data
Depletion of BIN1 increased Ab secretion by increasing cellular BACE1 levels.
“Here we showed that the depletion of BIN1 increased the Ab secretion by increasing cellular BACE1 levels.”
Quote in the paperSubstantial claim - Premisecitation
Bin1 RNAi failed to affect Ab production in HeLa cells expressing Swedish mutant APP.
“This is also consistent with a previous report that Bin1 RNAi failed to affect Ab production in HeLa cells expressing Swedish mutant APP (39), which is cleaved by BACE1 in early secretory compartments such as the trans-Golgi network (40).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] source
- Interpretationreasoning
The BAR domain of BIN1 recognizes the cytoplasmic domain of BACE1 to regulate lysosomal targeting of BACE1 together with SH3 binding molecules, thereby affecting production of Ab.
“These results indicated that the BAR domain of BIN1 recognizes the cytoplasmic domain of BACE1 to regulate the lysosomal targeting of BACE1 together with SH3 binding molecules, thereby affecting the production of Ab.”
Quote in the paperSubstantial claim - Interpretationreasoning
The neuron-specific CLAP domain involved in clathrin-mediated endocytosis is not necessary for regulation of BACE1 by BIN1.
“These results were observed both in neuronal and non-neuronal cells, indicating that the neuron-specific CLAP domain involved in clathrinmediated endocytosis was not necessary for the regulation of BACE1 by BIN1.”
Quote in the paperSubstantial claim - Interpretationown data
In Bin1-depleted cells, BACE1 is recruited and degraded by a ubiquitin-dependent pathway.
“indicating that BACE1 was recruited and degraded by ubiquitin-dependent pathway in Bin1-depleted cells.”
Quote in the paperSubstantial claim - Interpretationown data
Depletion of BIN1 expression caused Aβ overproduction.
“Depletion of BIN1 expression caused Ab overproduction with enhanced BACE1 activity.”
Quote in the paperSubstantial claim - Interpretationown data
Loss of BIN1 expression and/or function leads to increased Alzheimer's disease (AD) risk.
“Our data suggested that a loss of BIN1 expression and/or function leads to the increased Ab production and AD risk.”
Quote in the paperSubstantial claim- Rests on an assumption: Increased amyloid-β (Aβ) production increases Alzheimer's disease (AD) risk.
- Interpretationown data
BIN1 is a genetic regulator of amyloid-β (Aβ) production.
“In conclusion, we identified BIN1 as a novel genetic regulator of BACE1 intracellular trafficking and Ab production.”
Quote in the paperSubstantial claim - Study design and conductown data
The specificity of the BACE1 activity assay was confirmed using an authentic BACE1 inhibitor.
“Specificity of this activity was confirmed by using 10 lM authentic BACE1 inhibitor (Supplementary Material Figure S3C).”
Quote in the paperNot a substantial claim - Interpretationown data
BIN1 is a genetic regulator of BACE1 intracellular trafficking.
“In conclusion, we identified BIN1 as a novel genetic regulator of BACE1 intracellular trafficking and Ab production.”
Quote in the paperSubstantial claim - Study design and conductown data
The specificity of the anti-BACE1c antibody was confirmed using Bace1-knockdown Neuro2a cells generated by CRISPR/Cas9.
“Specificity of anti-BACE1c antibody was confirmed by Bace1 knockdown Neuro2a cells generated by CRISPR/Cas9 system (Supplemental Material Figure S2).”
Quote in the paperNot a substantial claim - Interpretationown data
Deletion of the BAR domain of BIN1 caused increased Aβ production.
“Deletion of the BAR domain of BIN1 caused increased Ab production and accumulation of BACE1.”
Quote in the paperSubstantial claim - Interpretationown data
Loss of BIN1 expression and/or function leads to increased amyloid-β (Aβ) production.
“Our data suggested that a loss of BIN1 expression and/or function leads to the increased Ab production and AD risk.”
Quote in the paperSubstantial claim - Interpretationown data
Deletion of the BAR domain of BIN1 caused accumulation of BACE1.
“Deletion of the BAR domain of BIN1 caused increased Ab production and accumulation of BACE1.”
Quote in the paperSubstantial claim - Interpretationown data
Depletion of BIN1 impaired the trafficking of intracellular BACE1 from early endosomes.
“Depletion of BIN1 impaired the trafficking of intracellular BACE1 from early endosomes.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 9
- May combine two claims. 11
Classified as probably not a substantial claim.
PremisecitationThe BAR domain is known as a binding platform for several protein-protein interactions.
“However, the BAR domain is also known as a binding platform for several protein-protein interactions (37,38), suggesting that BACE1 is a novel cargo protein of BIN1 that is sorted from early endosomes to late endosomes/lysosomes.”
Quote in the paperSubstantial claim2 of 2 sources checkedMay combine two claims.
PremisecitationCellular transferrin levels were increased in Bin1 KO MEFs without an effect on transferrin internalization.
“Consistent with this, cellular transferrin levels were increased in Bin1 KO MEFs without an effect on transferrin internalization (18).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [18] source
May combine two claims.
PremisecitationDepletion of Bin1 in HeLa cells impaired recycling of transferrin, but not endocytosis, and cellular transferrin accumulated in the juxtanuclear compartment.
“In addition, the depletion of Bin1 in HeLa cells impaired the recycling of transferrin, but not endocytosis, and cellular transferrin was accumulated in the juxtanuclear compartment (16).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [16] source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe SH3 domain regulates the conformation of the BAR domain and its interaction with other molecules.
“In addition, the SH3 domain regulates the conformation of the BAR domain and its interaction with other molecules (34,35).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [34] source
- cites [35] source
The Results and Discussion (page unavailable) show that SH3 domains inhibit membrane binding by endophilin and amphiphysin, and that binding dynamin’s proline-rich domain to SH3 reverses this inhibition. The paper suggests an SH3–BAR interaction but does not establish that SH3 regulates the BAR domain’s conformation. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationDepletion of GGA3 resulted in reduced degradation of BACE1 in lysosomes and increased Ab production, similar to Bin1-depleted cells.
“The depletion of GGA3, which recognizes ubiquitinated BACE1, resulted in the reduced degradation of BACE1 in the lysosomes and increased Ab production in a similar manner to that observed in Bin1-depleted cells (30,41).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [30] source
- cites [41] source
The Introduction states that GGA3 depletion impairs BACE1 sorting to lysosomes, where BACE1 is normally degraded. The Results report increased Aβ in Gga3-null primary neuronal cultures, but no increase in young adult Gga3-null mouse brains. Our copy does not establish that GGA3 recognizes ubiquitinated BACE1 or assess the comparison with Bin1-depleted cells. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe BAR domain was initially implicated in lipid binding of BIN1 and in sensing membrane curvature.
“The BAR domain was initially implicated in the lipid binding of BIN1 and in sensing membrane curvature (11,36).”
Quote in the paperNot a substantial claim1 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationEHD proteins regulate BIN1 activity and are required for endocytic vesicle recycling together with Rab8a, Rab11-FIP2 and MICAL-L1.
“EHD proteins regulate BIN1 activity and are required for endocytic vesicle recycling together with Rab8a, Rab11-FIP2 and MICAL-L1 (16,43,44).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [16] source
The Results section (‘Mammalian Bin1/Amphiphysin2 functions in recycling’; page not provided) reports that BIN1 is present on EHD1-positive recycling tubules and that BIN1 depletion delays recycling. The paper describes BIN1 as functioning in EHD1-regulated recycling, but does not establish that EHD proteins regulate BIN1 activity. It also does not show recycling involving Rab8a, Rab11-FIP2 and MICAL-L1 together; Rab11-FIP2 appears in a reference title, not in that finding. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [43] source
The EHD1 section reports that EHD1 regulates receptor recycling and interacts with Rab11-FIP2; the membrane-binders section identifies MICAL-L1 as an EHD1 partner. The latter section describes Rab8a as a marker of EHD1-decorated tubules, not as a demonstrated partner required for recycling. It also describes EHD1 and BIN1 as potentially cooperating in membrane tubulation, not EHD proteins regulating BIN1 activity. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [44] source
The Results section, “EHD1 regulates BIN1 tubule formation” (page not supplied), shows that EHD1 affects BIN1-induced tubules. The Results on defective endosomal trafficking show impaired recycling in EHD1-null myoblasts, and the Introduction names MICAL-L1 as an EHD-interacting protein. Our copy does not establish that EHD proteins recycle vesicles together with Rab8a or Rab11-FIP2; it discusses Rab11, but not Rab11-FIP2. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAmong known BIN1-binding proteins, EHD family proteins play a role in trafficking of internalized BACE1 in neurons.
“It is noteworthy to mention that among the known BIN1-binding proteins, EHD family proteins play a role in the trafficking of internalized BACE1 in neurons (42).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [42] source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationLoss of EHD1 function compromised recycling and axonal sorting of internalized BACE1, thereby reducing Ab production.
“Loss of EHD1 function compromised the recycling and axonal sorting of the internalized BACE1, thereby reducing Ab production (42).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [42] source
The Results section reports that impaired EHD1 function reduced axonal sorting of internalized BACE1, and the Introduction reports that loss of EHD1 expression reduced Aβ production in hippocampal neurons. But the Results do not establish compromised BACE1 recycling: internalized BACE1 still reached recycling endosomes, and its steady-state dendritic surface localization was not significantly affected. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSynaptic protein snapin, an EHD1-binding protein, was identified as a regulator of endosome-to-lysosome retrograde transport of BACE1.
“Recently, the synaptic protein snapin, which is an EHD1-binding protein, was identified as a regulator of the endosome-to-lysosome retrograde transport of BACE1 (27,45).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [27] source
The Discussion states that Snapin-mediated retrograde transport delivers BACE1 from late endosomes to somatic lysosomes for degradation. The Results also show impaired BACE1 retrograde transport in snapin-deficient neurons. Our copy does not identify Snapin as an EHD1-binding protein (searched: “EHD1-binding protein snapin” and “EHD1”), so that descriptor is not supported by this source. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [45] source
May combine two claims.
Findingown dataIn sucrose density gradient fractionation of Neuro2a cells, LAMP1 was detected predominantly in low-density fraction 2, whereas other organelle markers were detected diffusely in the high-density fraction.
“We found that LAMP1 was detected predominantly in the low density fraction (fraction 2), whereas other organelle markers were detected diffusely in the high-density fraction (Fig. 4A).”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningBACE1 is a novel cargo protein of BIN1 that is sorted from early endosomes to late endosomes/lysosomes.
“suggesting that BACE1 is a novel cargo protein of BIN1 that is sorted from early endosomes to late endosomes/lysosomes.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSwedish mutant APP is cleaved by BACE1 in early secretory compartments such as the trans-Golgi network.
“This is also consistent with a previous report that Bin1 RNAi failed to affect Ab production in HeLa cells expressing Swedish mutant APP (39), which is cleaved by BACE1 in early secretory compartments such as the trans-Golgi network (40).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] source
May combine two claims.
Interpretationown dataIn Bin1-depleted cells, intracellular trafficking of BACE1 from early endosomes to the lysosomal pathway is impaired, resulting in reduced degradation of BACE1.
“These results indicated that the intracellular trafficking of BACE1 from the early endosomes to the lysosomal pathway was impaired in the Bin1 depleted cells, resulting in the reduced degradation of BACE1.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningThe level and activity of BACE1 is modulated by both ubiquitin-dependent and ubiquitin-independent trafficking, regulated by GGA3 and BIN1, respectively.
“Thus, the level and activity of BACE1 is modulated by both ubiquitin-dependent and ubiquitin-independent trafficking, which are regulated by GGA3 and BIN1, respectively.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataDepletion of BIN1 caused accumulation of BACE1 in early endosomes, eventually leading to increased Ab production.
“In fact, we found that the depletion of BIN1 caused the accumulation of BACE1 in the early endosomes where most of the b-cleavage of APP occurs, eventually leading to an increase in the production of Ab.”
Quote in the paperSubstantial claim- Rests on an assumption: Most beta-cleavage of APP occurs in early endosomes.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe SH3 domain of BIN1 is a molecular platform for the biogenesis of membrane tubules.
“Previous studies suggested that the SH3 domain of BIN1 is a molecular platform for the biogenesis of membrane tubules (31)(32)(33).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites (31)(32)(33)
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
The paper relies on this without support.
Most beta-cleavage of APP occurs in early endosomes.
“where most of the b-cleavage of APP occurs”
The paper relies on this without support.
The BACE1/K501R mutant cannot be ubiquitinated.
“which cannot be ubiquitinated”
The paper relies on this without support.
Increased amyloid-β (Aβ) production increases Alzheimer's disease (AD) risk.
“Our data suggested that a loss of BIN1 expression and/or function leads to the increased Ab production and AD risk.”
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?
BIN1, CD2AP and PICALM modulate APP metabolism and the subsequent increase in Aβ production.
“Based on pathway enrichment analyses, three GWAS-defined genes linked with endocytosis (BIN1, CD2AP and PICALM) have been proposed to modulate APP metabolism and the subsequent increase in Aβ production:”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [91]
The Abstract (page not supplied) reports that BIN1 depletion impairs BACE1 trafficking and increases Aβ production, supporting the BIN1 portion of the claim. The cited paper does not establish the same effect for CD2AP or PICALM, and the passages do not attribute the three-gene proposal to a pathway enrichment analysis. (LLM, conf=0.90)
Experimental — accuracy not yet measuredBIN1 depletion is associated with an increase in intracellular Aβ42, potentially through regulation of BACE1 trafficking and accumulation in early endosomes.
“BIN1 depletion was associated with an increase in intracellular Aβ42, potentially through the regulation of the β-secretase (BACE1) trafficking and accumulation in early endosomes [91, 137].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [91]
The Discussion reports that BIN1 depletion causes BACE1 to accumulate in early endosomes and increases Aβ production. However, the reported Aβ42 measurements are of secreted Aβ42 (Figures 1B and 2B/E), not intracellular Aβ42; the intracellular increase reported is in BACE1. (LLM, conf=0.90)
Experimental — accuracy not yet measured
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.
GST pull-down assay uses different cell types in the results and figure caption
MinorThe results say the BIN1 protein used in the GST pull-down was expressed in Neuro2a cells, whereas the caption for that assay says the lysate came from HeLa cells.
“We found that the GST-fused BACE1 C-terminal intracellular domain (B1CT) bound to the BIN1 holoprotein expressed in Neuro2a cells.”
“(A) Immunoblot analysis of the pulldown fraction by GST or the GST-B1CT mixed with HeLa cell lysate expressing GFP or GFP-BIN1.”
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Self-citationAmphiphysin 2 (BIN1) in physiology and diseases
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An aberrant sugar modification of BACE1 blocks its lysosomal targeting in Alzheimer's disease
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Self-citationBACE1 activity is modulated by cell-associated sphingosine-1-phosphate
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Self-citationBACE Is Degraded via the Lysosomal Pathway
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Self-citationUbiquitin Regulates GGA3-mediated Degradation of BACE1
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Role of genes linked to sporadic Alzheimer’s disease risk in the production of β-amyloid peptides
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Chapter 21 Monitoring Autophagy in Lysosomal Storage Disorders
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The myotubularin–amphiphysin 2 complex in membrane tubulation and centronuclear myopathies
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BAR the door: Cancer suppression by amphiphysin-like genes
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Self-citationDepletion of GGA1 and GGA3 Mediates Postinjury Elevation of BACE1
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Bin1 Ablation in Mammary Gland Delays Tissue Remodeling and Drives Cancer Progression
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Self-citationProtein trafficking and maturation regulate intramembrane proteolysis
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Self-citationEHD1 is a synaptic protein that modulates exocytosis through binding to snapin
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Bin1 Interacts with and Restrains the DNA End-Binding Protein Complex Ku
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Self-citationP4-182 BACE1 is degraded via the lysosomal pathway
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Arendt, T., Stieler, J. T., & Holzer, M. (2016) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2016.08.018 · Cited by 609 · see citing works
Amyloid-β-independent regulators of tau pathology in Alzheimer disease
van der Kant, R., Goldstein, L. S. B., & Ossenkoppele, R. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0240-3 · Cited by 580 · see citing works
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Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes
Zuroff, L. R., Daley, D. A., Black, K. L., & Koronyo‐Hamaoui, M. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2463-7 · Cited by 275 · see citing works
Untangling Genetic Risk for Alzheimer’s Disease
Pimenova, A. A., Raj, T., & Goate, A. M. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.05.014 · Cited by 223 · see citing works
“and reduces lysosomal degradation of BACE1 thereby increasing Aβ production (101).”
BackgroundEndo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors
Van Acker, Z. P., Bretou, M., & Annaert, W. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0323-7 · Cited by 222 · see citing works
“BACE1- and APP-trafficking to the lysosomes in an ubiquitin-independent and -dependent mechanism, respectively [39, 40].”
Bin1 and CD2AP polarise the endocytic generation of beta‐amyloid
Ubelmann, F., Burrinha, T., Salavessa, L., Gomes, R., Ferreira, C., Moreno, N., & Guimas Almeida, C. (2017) · The EMBO Reports · doi:10.15252/embr.201642738 · Cited by 165 · see citing works
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“BIN1 depletion was associated with an increase in intracellular Aβ42, potentially through the regulation of the β-secretase (BACE1) trafficking and accumulation in early endosomes [91, 137].”
BackgroundEndosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer’s Disease
Small, S. A., Simoes, S., Mayeux, R. P., & Petsko, G. A. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.08.003 · Cited by 163 · see citing works
De Rossi, P., Buggia-Prévot, V., Clayton, B. L. L., Vasquez, J. B., van Sanford, C., Andrew, R. J., Lesnick, R., Botté, A., Deyts, C., Salem, S., et al. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0124-1 · Cited by 151 · see citing works
“In vitro assays and analysis of mutant flies lacking the expression of the Drosophila BIN1 ortholog Amphiphysin have suggested that BIN1 modifies AD risk through Tau pathology [26] or β-amyloid production [27] and studies have reported altered expression of BIN1 in Alzheimer Disease, albeit with discrepancies [26, 28–…”
Endo‐lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?
Whyte, L. S., Lau, A. A., Hemsley, K. M., Hopwood, J. J., & Sargeant, T. J. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.13935 · Cited by 150 · see citing works
“However, research already shows AD-associated genetic variation could result in abnormal trafficking in the endo-lysosomal and autophagic networks (Cormont et al. 2003; Moreau et al. 2014; Miyagawa et al. 2016).”
BackgroundEndo-lysosomal dysfunction: a converging mechanism in neurodegenerative diseases
Wang, C., Telpoukhovskaia, M. A., Bahr, B. A., Chen, X., & Gan, L. (2017) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2017.09.005 · Cited by 140 · see citing works
Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers
Jansen, I. E., van der Lee, S. J., Gomez-Fonseca, D., de Rojas, I., Dalmasso, M. C., Grenier-Boley, B., Zettergren, A., Mishra, A., Ali, M., Andrade, V., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02454-z · Cited by 132 · see citing works
“The involvement of these genes in amyloid-beta pathology is supported by previous studies [15, 46, 63, 79].”
ResultThe Early Events That Initiate β-Amyloid Aggregation in Alzheimer’s Disease
Zhang, X., Fu, Z., Meng, L., He, M., & Zhang, Z. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00359 · Cited by 122 · see citing works
“However, the precise role of BIN1 in the BACE1 recycling remains speculative.”
BackgroundInfluentialNeuronal BIN1 Regulates Presynaptic Neurotransmitter Release and Memory Consolidation
Rossi, P. D., Nomura, T., Andrew, R. J., Masse, N. Y., Sampathkumar, V., Musial, T. F., Sudwarts, A., Recupero, A. J., Metayer, T. L., Hansen, M. T., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.02.026 · Cited by 117 · see citing works
“AD b-amyloid pathogenesis in cultured neurons, but this does not appear to be the case in vivo (Andrew et al., 2019; Miyagawa et al., 2016).”
BackgroundLee, A., Kondapalli, C., Virga, D. M., Lewis, T. L., Koo, S. Y., Ashok, A., Mairet‐Coello, G., Herzig, S., Foretz, M., Viollet, B., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-32130-5 · Cited by 113 · see citing works
Hoogmartens, J., Cacace, R., & Broeckhoven, C. V. (2021) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12155 · Cited by 101 · see citing works
Moving beyond amyloid and tau to capture the biological heterogeneity of Alzheimer’s disease
Young‐Pearse, T. L., Lee, H., Hsieh, Y., Chou, V., & Selkoe, D. J. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.03.005 · Cited by 99 · see citing works
The role of Alzheimer's disease risk genes in endolysosomal pathways
Szabo, M. P., Mishra, S., Knupp, A., & Young, J. E. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105576 · Cited by 81 · see citing works
Sartori, M., Mendes, T., Desai, S., Lasorsa, A., Herledan, A., Malmanche, N., Mäkinen, P., Marttinen, M., Malki, I., Chapuis, J., et al. (2019) · Acta Neuropathologica · doi:10.1007/s00401-019-02017-9 · Cited by 72 · see citing works
The physical approximation of APP and BACE‐1: A key event in alzheimer's disease pathogenesis
Sun, J., & Roy, S. (2017) · Developmental Neurobiology · doi:10.1002/dneu.22556 · Cited by 75 · see citing works
“BIN1, a genetic risk factor of late-onset AD found in GWAS studies, binds to BACE-1, regulating its lysosomal targeting (Lambert et al., 2013; Miyagawa et al., 2016).”
BackgroundGalvão, F., Grokoski, K. C., da Silva, B. B., Lamers, M. L., & Siqueira, I. R. (2018) · Ageing Research Reviews · doi:10.1016/j.arr.2018.11.007 · Cited by 66 · see citing works
Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer’s Disease
Perdigão, C., Barata, M. A., Araújo, M. N., Mirfakhar, F., Castanheira, J., & Almeida, C. G. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00072 · Cited by 56 · see citing works
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) · Acta Neuropathologica Communications · doi:10.1186/s40478-021-01285-5 · Cited by 64 · see citing works
“APP metabolism and endosome trafficking are tightly interconnected processes [23, 34] and previous work has suggested a role for BIN1 in their regulation [42, 62].”
BackgroundAlzheimer’s disease and the autophagic-lysosomal system
Chung, K. M., Hernández, N., Sproul, A. A., & Yu, W. H. (2019) · Neuroscience Letters · doi:10.1016/j.neulet.2018.05.017 · Cited by 63 · see citing works
The role of CD2AP in the Pathogenesis of Alzheimer's Disease
Tao, Q.-Q., Chen, Y.-C., & Wu, Z.-Y. (2019) · Aging and disease · doi:10.14336/ad.2018.1025 · Cited by 61 · see citing works
“(APOE, PICALM, BIN1, SORL1, and PLD3) have been reported to implicate in Aβ42 production [42-46].”
BackgroundKim, S., Cho, Y.-S., Kim, Y., Park, J., Yoo, S., Gwak, J., Kim, Y., Gwon, Y., Kam, T., & Jung, Y. (2023) · Autophagy · doi:10.1080/15548627.2023.2181614 · Cited by 65 · see citing works
Genetics of Alzheimer’s disease: From pathogenesis to clinical usage
Shao, W., Peng, D., & Wang, X. (2017) · Journal of Clinical Neuroscience · doi:10.1016/j.jocn.2017.06.074 · Cited by 61 · see citing works
“concluded that BIN1 might influence the AD risk via modulation of the intracellular trafficking of b-site APP- cleaving enzyme 1 (BACE1) [81].”
BackgroundInfluentialSaha, O., de Farias, A. R. M., Pelletier, A., Siedlecki‐Wullich, D., Landeira, B. S., Gadaut, J., Carrier, A., Vreulx, A.-C., Guyot, K., Shen, Y., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02502-y · Cited by 60 · see citing works
“Reduced BIN1 expression results in a higher amyloid precursor protein (APP) processing towards the production of amyloid-beta (A β ) peptides in Neuroblastoma Neuro2a cells [10, 11].”
BackgroundAndrew, R. J., De Rossi, P., Nguyen, P., Kowalski, H. R., Recupero, A. J., Guerbette, T., Krause, S. V., Rice, R. C., Laury-Kleintop, L., Wagner, S. L., et al. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.006379 · Cited by 55 · see citing works
“The loss of Bin1 expression was shown in one study to increase BACE1 levels and A production in neurons, with the subsequent analysis in immortalized cells lines implicating loss of endosomal trafficking and lysosomal degradation of BACE1 as the cause (26).”
BackgroundResultMalki, I., Cantrelle, F., Sottejeau, Y., Lippens, G., Lambert, J., & Landrieu, I. (2017) · The FEBS Journal · doi:10.1111/febs.14185 · Cited by 54 · see citing works
Bin1 directly remodels actin dynamics through its BAR domain
Dräger, N. M., Nachman, E., Winterhoff, M., Brühmann, S., Shah, P., Katsinelos, T., Boulant, S., Teleman, A. A., Faix, J., & Jahn, T. R. (2017) · The EMBO Reports · doi:10.15252/embr.201744137 · Cited by 51 · see citing works
“Since hBin1 is part of the endocytosis machinery, its depletion impairs the endocytic recycling of the first protease (b-secretase) and thus may promote Ab production [26,27].”
Impact of late-onset Alzheimer’s genetic risk factors on beta-amyloid endocytic production
Almeida, C. G., Mirfakhar, F. S., Perdigão, C., & Burrinha, T. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2825-9 · Cited by 48 · see citing works
“We and Tomita’s lab found Bin1 depletion to increase Aβ production due to the accumulation of BACE1 in endosomes [128, 129].”
BackgroundInfluentialGenetic risk factors for Alzheimer disease: emerging roles of microglia in disease pathomechanisms
Takatori, S., Wang, W., Iguchi, A., & Tomita, T. (2019) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-030-05542-4_5 · Cited by 44 · see citing works
Self-citationIn vivo induction of membrane damage by β-amyloid peptide oligomers
Julien, C., Tomberlin, C., Roberts, C. M., Akram, A., Stein, G. H., Silverman, M. A., & Link, C. D. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0634-x · Cited by 39 · see citing works
Perdigão, C., Barata, M. A., Burrinha, T., & Almeida, C. G. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101056 · Cited by 33 · see citing works
“showed BACE1 accumulation in late endosomes/lysosomes (49).”
BackgroundInfluentialGSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer’s disease
Xu, P., Chang, J. C., Zhou, X., Wang, W., Bamkole, M. A., Wong, E., Bettayeb, K., Jiang, L.-L., Huang, T. Y., Luo, W., et al. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20202446 · Cited by 35 · see citing works
Aberrant accrual of BIN1 near Alzheimer’s disease amyloid deposits in transgenic models
Rossi, P. D., Andrew, R. J., Musial, T. F., Buggia-Prévot, V., Xu, G. M., Ponnusamy, M., Ly, H., Krause, S. V., Rice, R. C., de l’Estoile, V., et al. (2018) · Brain Pathology · doi:10.1111/bpa.12687 · Cited by 32 · see citing works
Gadhave, K., Gehi, B. R., Kumar, P., Xue, B., Uversky, V. N., & Giri, R. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03414-9 · Cited by 33 · see citing works
“Bridging integrator 1(BIN1), a member of amphiphysin family, is involved in endocytosis and the endosomal sorting of membrane proteins that regulate intracellular BACE1 trafficking and Aβ formation [30].”
BackgroundGenetic insights into immune mechanisms of Alzheimer’s and Parkinson’s disease
Nott, A., & Holtman, I. R. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1168539 · Cited by 31 · see citing works
Guix, F. X. (2019) · Journal of Neuroscience Research · doi:10.1002/jnr.24526 · Cited by 29 · see citing works
Protein palmitoylation: biological functions, disease, and therapeutic targets
Qian, Y., Zhao, Y., & Zhang, F. (2025) · MedComm · doi:10.1002/mco2.70096 · Cited by 30 · see citing works
The Mechanistic Role of Bridging Integrator 1 (BIN1) in Alzheimer’s Disease
Gao, P.-R., Ye, L., Cheng, H.-R., & Li, H. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00926-y · Cited by 28 · see citing works
O’Keefe, L. V., & Denton, D. (2018) · BioMed Research International · doi:10.1155/2018/5195416 · Cited by 24 · see citing works
Endosomal traffic disorders: a driving force behind neurodegenerative diseases
Dong, J., Tong, W., Liu, M., Liu, M., Liu, J., Jin, X., Chen, J., Jia, H., Gao, M., Wei, M., et al. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00460-7 · Cited by 25 · see citing works
“When Bin1 levels are reduced, BACE1 becomes trapped in early endosomes and is unable to undergo axonal circulation, resulting in diminished degradation of BACE1 in lysosomes and augmented Aβ production [159].”
Hu, H., Tan, L., Bi, Y., Xu, W., Tan, L., Shen, X., Hou, X., Ma, Y., Dong, Q., & Yu, J. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01218-9 · Cited by 25 · see citing works
Xu, D. C., Sas‐Nowosielska, H., Donahue, G., Huang, H., Pourshafie, N., Good, C. R., & Berger, S. L. (2024) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01696-6 · Cited by 30 · see citing works
“ABCA7 [50, 51] and BIN1 [52– 54] were identified as APP Dup compensatory and also identified as decreased in EP300/CBP KD; these genes reduce amyloid-β by negatively regulating the activity of β-secretase complex member BACE1 [50–53].”
BackgroundBIN1 localization is distinct from Tau tangles in Alzheimer’s disease
Rossi, P. D., Buggia-Prévot, V., Andrew, R. J., Krause, S. V., Woo, E., Nelson, P. T., Pytel, P., & Thinakaran, G. (2017) · Matters · doi:10.19185/matters.201611000018 · Cited by 25 · see citing works
“Our findings that BIN1 protein is not detected in ramified microglia, reactive microglia, and macrophages are notable because BIN1 mRNA expression in microglia and macrophages acutely isolated from mouse and human brain are reported in RNA-seq transcriptome databases [11] [12].”
Genetic discoveries and advances in late‐onset Alzheimer’s disease
Rezazadeh, M., Hosseinzadeh, H., Moradi, M., Esfahani, B. S., Talebian, S., Parvin, S., & Gharesouran, J. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28372 · Cited by 22 · see citing works
Akram, Z., Ahmed, I., Mack, H., Kaur, R., Silva, R. C., Castilho, B. A., Friant, S., Sattlegger, E., & Munn, A. (2020) · Cells · doi:10.3390/cells9030672 · Cited by 20 · see citing works
GPR120 Signaling Controls Amyloid-β Degrading Activity of Matrix Metalloproteinases
Kikuchi, K., Tatebe, T., Sudo, Y., Yokoyama, M., Kidana, K., Chiu, Y. W., Takatori, S., Arita, M., Hori, Y., & Tomita, T. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.2595-20.2021 · Cited by 22 · see citing works
Self-citationKoinuma, S., Shimozawa, N., Yasutomi, Y., & Kimura, N. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.06.022 · Cited by 22 · see citing works
Differential Methylation Levels in CpGs of the BIN1 Gene in Individuals With Alzheimer Disease
Salcedo-Tacuma, D., Melgarejo, J. D., Mahecha, M. F., Ortega-Rojas, J., Bustos, C., Pardo, R., & Arboleda, H. (2019) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0000000000000329 · Cited by 21 · see citing works
EphA4 regulates Aβ production via BACE1 expression in neurons
Tamura, K., Chiu, Y., Shiohara, A., Hori, Y., & Tomita, T. (2020) · The FASEB Journal · doi:10.1096/fj.202001510r · Cited by 17 · see citing works
Self-citationYu, Y., Niccoli, T., Ren, Z., Woodling, N. S., Aleyakpo, B., Szabadkai, G., & Partridge, L. (2020) · Human Molecular Genetics · doi:10.1093/hmg/ddaa125 · Cited by 16 · see citing works
Jin, Y., Zhao, L., Zhang, Y., Chen, T., Shi, H., Sun, H., Ding, S., Chen, S., Cao, H., Zhang, G., et al. (2024) · Autophagy · doi:10.1080/15548627.2024.2393932 · Cited by 14 · see citing works
“In cultured mouse cortical neurons, BIN1 depletion increases production of amyloid-β (Aβ) [4,5], but this effect was not replicated in a subsequent in vivo study [6].”
Kim, B., Vasanthakumar, A., Li, Q.-Q. S., Nudelman, K., Risacher, S., Davis, J., Idler, K., Lee, J., Seo, S., Waring, J., et al. (2022) · Alzheimer's & Dementia · doi:10.1002/dad2.12354 · Cited by 15 · see citing works
Association of the top 20 Alzheimer's disease risk genes with [18F]flortaucipir PET
Stage, E., Risacher, S. L., Lane, K. A., Gao, S., Nho, K. T., Saykin, A. J., Apostolova, L. G., & Initiative, A. D. N. (2022) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12308 · Cited by 11 · see citing works
The Strategies for Treating “Alzheimer’s Disease”: Insulin Signaling May Be a Feasible Target
You, G., Yao, J., Liu, Q., & Li, N. (2022) · Current Issues in Molecular Biology · doi:10.3390/cimb44120421 · Cited by 12 · see citing works
“Moreover, phospholipase D3 (PLD3), bridging integrator 1 (BIN1), phosphatidylinositol-binding clathrin assembly protein (PICALM) [26], and sortilin-related receptor (SORL1)—the next strongest genetic risk factors of AD after APOE4 and TREM2—were also involved in regulating the endocytosis process [27,28].”
BackgroundKirsebom, B., Richter, G., Nordengen, K., Aarsland, D., Bråthen, G., Tijms, B. M., Visser, P. J., Nilsson, J., Selnes, P., Kramberger, M. G., et al. (2022) · Brain Communications · doi:10.1093/braincomms/fcac244 · Cited by 11 · see citing works
“are genetic risk factors for Alzheimer’s disease that mediate Aβ production via regulation of BACE1 transport and activity.(24,25) These findings motivated the development and testing of BACE1 inhibitors in drug trials, without reaching treatment endpoints and with indications of negative cognitive effects, other adve…”
BackgroundBIN1K358R suppresses glial response to plaques in mouse model of Alzheimer's disease
Garcia‐Agudo, L. F., Shi, Z., Smith, I. F., Kramár, E. A., Tran, K., Kawauchi, S., Wang, S., Collins, S., Walker, A., Shi, K., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13767 · Cited by 10 · see citing works
“6,20,32,43 Notably,severalofthe DEGs in our dataset have been described as marker genes for disease-associated astrocytes (DAAs 44 ) and DAOs 45 (Figure 4F).”
BackgroundFacilitating Antiviral Drug Discovery Using Genetic and Evolutionary Knowledge
Xu, X., Zhang, Q., Chu, X., Quan, Y., Lv, B., & Zhang, H. (2021) · Viruses · doi:10.3390/v13112117 · Cited by 11 · see citing works
A single cell brain atlas in human Alzheimer’s diseasePreprint
Grubman, A., Chew, G., Ouyang, J. F., Sun, G., Choo, X. Y., McLean, C., Simmons, R. K., Buckberry, S., Vargas-Landín, D. B., Pflueger, J., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/628347 · Cited by 10 · see citing works
Biofluid biomarkers for Alzheimer’s disease
Wang, S., Xie, S., Zheng, Q., Zhang, Z., Wang, T., & Zhang, G. (2024) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2024.1380237 · Cited by 8 · see citing works
The Role of Genetics in Alzheimer's Disease and Parkinson's Disease
Porter, T., Gozt, A., Mastaglia, F. L., & Laws, S. M. (2019) · Wiley eBooks · doi:10.1002/9781119356752.ch15 · Cited by 7 · see citing works
Chia, R., Sabir, M. S., Bandrés‐Ciga, S., Sáez-Atiénzar, S., Reynolds, R. H., Gustavsson, E. K., Walton, R. L., Ahmed, S., Viollet, C., Ding, J., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.07.06.185066 · Cited by 7 · see citing works
Jin, Y. H., Topaloudi, A., Shekhar, S., Chen, G., Scott, A. N., Colon, B. D., Petros Drineas, B., Rochet, C., & Paschou, P. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-024-01909-6 · Cited by 5 · see citing works
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 · see citing works
“In line with our in vivo results is the in vitro observation that neuronal BIN1 negatively regulates the endocytic transport of BACE1 to recycling endosomes so that, when it is downregulated, BACE1 aberrantly accumulates into Rab5-positive early endosomes, causing an augmented Aβ production [67,68,145].”
BackgroundResultДобрынина, Л. А., Геннадьевна, М. А., Шабалина, А. А., Burmak, A. G., Shlapakova, P. S., Витальевна, Ш. К., Tsypushtanova, M. M., Kremneva, E. I., Zabitova, M. R., Filatov, A. S., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25158113 · Cited by 5 · see citing works
“BIN1 has been shown to be associated with tau and amyloid pathology [63] and is involved in inflammatory reactions [64] and apoptosis [65].”
BackgroundProteomic 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 · see citing works
“Two recent in vitro studies suggested that BIN1 plays a role in A β generation, one through BIN1 interaction with BACE1 (105) and the other through BIN1 interaction with RIN3 (35, 106).”
Thomas, S., & Prendergast, G. C. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1183932 · Cited by 7 · see citing works
“Depletion of Bin1 increases cellular BACE1 levels through impaired endosomal trafficking and reduces BACE1 lysosomal degradation, resulting in increased Aβ production (Miyagawa et al., 2016).”
BackgroundSelf-citationZhu, Y., Zang, F., Liu, X., Fan, D., Zhang, Q., Ren, Q., Xie, C., & Initiative, A. D. N. (2020) · Brain Imaging and Behavior · doi:10.1007/s11682-020-00316-4 · Cited by 4 · see citing works
Faborode, O. S., Dallé, E., & Mabandla, M. V. (2021) · Behavioural Brain Research · doi:10.1016/j.bbr.2021.113679 · Cited by 3 · see citing works
Belapurkar, V., Swamy, H. S. M., Singh, N., Kedia, S., Setty, S. R. G., Jose, M., & Nair, D. K. (2023) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-023-04939-w · Cited by 3 · see citing works
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 · see citing works
“…membrane in axons, leading to its accumulation in enlarged early endosomes, impaired transport to lysosomes, and reduced degradation, thereby favoring APP cleavage within early endosomes and enhancing A β generation (Miyagawa et al. 2016; Perdigão et al. 2021; Ubelmann et al. 2017) (Figure 3).”
Добрынина, Л. А., Геннадьевна, М. А., Шабалина, А. А., Burmak, A. G., Shlapakova, P. S., Витальевна, Ш. К., Tsypushtanova, M. M., Trubitsyna, V. V., & Gnedovskaya, E. V. (2023) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro202312309158 · Cited by 1 · see citing works
Genetic Risk Factors for Complex Forms of Alzheimer’s Disease
Bellenguez, C., & Lambert, J. (2018) · Springer eBooks · doi:10.1007/978-3-319-72938-1_4
Saha, O., de Farias, A. R. M., Pelletier, A., Siedlecki‐Wullich, D., Gadaut, J., Landeira, B. S., Carrier, A., Vreulx, A.-C., Guyot, K., Bonnefond, A., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.01.18.476601
“…regulation of neuronal and circuit activity through numerous mechanisms, including increased APP processing and production of amyloid-beta peptides (Miyagawa et al., 2016; Ubelmann et al., 2017), alterations in Tau phosphorylation and propagation (Calafate et al., 2016; Lasorsa et al., 2018;…”
BackgroundXu, D. C., Sas‐Nowosielska, H., Donahue, G., Huang, H., Pourshafie, N., Good, C. R., & Berger, S. L. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.18.558276
Jin, Y. H., Topaloudi, A., Shekhar, S., Scott, A. N., Colon, B. D., Petros Drineas, B., Rochet, C., & Paschou, P. (2023) · medRxiv · doi:10.1101/2023.12.17.23300106
“BIN1 plays a prominent role in regulating endocytosis and synaptic vesicle trafficking, and it is implicated in the generation of amyloid beta and the propagation of Tau 18–20 .”
BackgroundДобрынина, Л. А., Makarova, A. G., Шабалина, А. А., Burmak, A. G., Shlapakova, P. S., Витальевна, Ш. К., Tsypushtanova, M. M., Trubitsyna, V. V., & Gnedovskaya, E. V. (2024) · Neuroscience and Behavioral Physiology · doi:10.1007/s11055-024-01587-w
Mitochondrial Dysfunction in Alzheimer’s Disease: A Comprehensive Review of Synaptopathy Mechanisms
Yoon, S. (2025) · IntechOpen eBooks · doi:10.5772/intechopen.1009341
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
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.18093090
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.18093108
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.18093111
Xu, D. C., Sas‐Nowosielska, H., Donahue, G., Huang, H., Pourshafie, N., Good, C. R., & Berger, S. L. (2024) · Figshare · doi:10.6084/m9.figshare.26658526
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.18093117
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
Xu, D. C., Sas‐Nowosielska, H., Donahue, G., Huang, H., Pourshafie, N., Good, C. R., & Berger, S. L. (2024) · Figshare · doi:10.6084/m9.figshare.26658529
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.18093093
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.18093099
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.18093102
Autophagy-lysosomal pathway in neurodegeneration
McDonough, S. R., Rao, A. K., McAleer, J. M., Babrowicz, B. M., & Sharma, M. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00041-0
- Authors
- Miyagawa, T., Ebinuma, I., Morohashi, Y., Hori, Y., Young Chang, M., Hattori, H., Maehara, T., Yokoshima, S., Fukuyama, T., Tsuji, S., Iwatsubo, T., Prendergast, G. C., & Tomita, T.
- Affiliations
- The University of Tokyo (JP)
- Nagoya University (JP)
- Lankenau Institute for Medical Research (US)
- Corresponding author
- Tomita, Taisuke
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-05-14
- Volume
- 25
- Issue
- 14
- Pages
- ddw146
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2393854800
- Semantic Scholar
- 0af6f9644e857ae027e0c71bad193cbeb472c25a
- Cited by
- 95
- References
- 60
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 9 · 2023: 9 · 2022: 17 · 2021: 11 · 2020: 9 · 2019: 11 · 2018: 9 · 2017: 9 · 2016: 4
- FWCI
- 7.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by-nc-nd)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Japan Society for the Promotion of Science (15H02492, 14J11303)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- BIN1, BACE1, amyloid-beta production, Alzheimer's disease, late-onset Alzheimer's disease, endosomal trafficking, lysosomal degradation, endocytosis, amphiphysin, genetic risk factors
- MeSH terms
- Alzheimer Disease, Animals, Brain, Endocytosis, Humans, Lysosomes, Neurons, Nuclear Proteins, Endosomes, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Mice, Knockout, Protein Transport, Tumor Suppressor Proteins, Adaptor Proteins, Signal Transducing, Mice, Amyloid Precursor Protein Secretases, Proteolysis
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