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VPS35 haploinsufficiency increases Alzheimer’s disease neuropathology
Open accessAbstract
VPS35, a major component of the retromer complex, is important for endosome-to-Golgi retrieval of membrane proteins. Although implicated in Alzheimer’s disease (AD), how VPS35 regulates AD-associated pathology is unknown. In this paper, we show that hemizygous deletion of Vps35 in the Tg2576 mouse model of AD led to earlier-onset AD-like phenotypes, including cognitive memory deficits, defective long-term potentiation, and impaired postsynaptic glutamatergic neurotransmission in young adult age. These deficits correlated well with an increase of β-amyloid peptide (Aβ) level in the mutant hippocampus. We further demonstrate that VPS35 is predominantly expressed in pyramidal neurons of young adult hippocampus and interacts with BACE1, a protease responsible for Aβ production. Loss of VPS35 function in the mouse hippocampus increased BACE1 activity. Suppression of VPS35 expression in culture decreased BACE1 trans-Golgi localization but enriched it in endosomes. These results demonstrate an essential role for VPS35 in suppression of AD neuropathology and in inhibition of BACE1 activation and Aβ production by promoting BACE1 endosome-to-Golgi retrieval.
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Written from the paper’s full text.
TL;DR
VPS35 haploinsufficiency accelerates Alzheimer’s disease–like neuropathology in Tg2576 mice by impairing endosome-to-Golgi retrieval of BACE1, increasing BACE1 activity and Aβ production. The double mutant mice show earlier cognitive, synaptic, and amyloid phenotypes than Tg2576 mice alone.
Key findings
- Vps35+/m;Tg2576+/− mice showed earlier spatial learning/memory deficits at 3 and 6 mo, impaired LTP in CA1 and dentate gyrus, and reduced AMPA/NMDA receptor–mediated mEPSC amplitudes and frequencies, with no change in GABAergic transmission.
- Aβ deposits were more numerous and larger in 6- and 12-mo-old Vps35+/m;Tg2576+/− brains than in Tg2576 brains; human Aβ40 was higher in 2-mo-old double mutant hippocampus and cortex by 30% and 15%, respectively, and mouse Aβ40 was also increased in Vps35+/m and double mutants. Aβ42 increased, but the Aβ40/Aβ42 ratio was unchanged.
- VPS35 interacted with BACE1, with a BACE1-binding site at VPS35 amino acids 390–606; loss of VPS35 increased BACE1 localization to Rab5/Rab7/LAMP1-positive endosomal compartments and reduced Rab11 recycling endosome localization.
- BACE1 activity increased by ∼50% in Vps35+/m hippocampus and ∼20% in cortex versus WT, with further increases in double mutants; C99 and sAPPβ were increased in Tg2576+/−;Vps35+/m hippocampus.
Methods
- Vps35 mutant mice were generated by gene trapping; homozygotes died before E10, while heterozygotes expressed Vps35 at ∼50% of WT and were crossed with Tg2576 APPswe mice to produce WT, Tg2576+/−, Vps35+/m, and Tg2576+/−;Vps35+/m littermates.
- Behavioral testing used the Morris water maze at 1–2, 3, and 6 mo; electrophysiology measured fEPSPs, LTP, mEPSCs, eEPSCs, mIPSCs, and eIPSCs in hippocampal slices; biochemistry included Aβ40/42 ELISAs, BACE1 activity assays, Western blots for APP cleavage products, immunohistochemistry, coimmunoprecipitation, and GST pull-down.
- Data were analyzed with one-way or repeated measures ANOVA, post hoc tests, or t tests, with significance at P < 0.05.
Limitations
- The paper states that it remains to be investigated whether Golgi/endosome-associated BACE1 activity is altered by loss of Vps35, where Aβ is produced in Vps35-deficient neurons, and whether APP and APPswe trafficking are differentially regulated by VPS35; it also notes that an Aβ-independent mechanism for synapse/synaptic activity loss cannot be excluded.
- Evident from the text: the study relies on mouse and cultured-cell models, with no human tissue validation; some supporting results are described as “unpublished data” or “not depicted,” and several biochemical/plaque quantifications use small n values (e.g., n = 4 for ELISA and plaque analyses).
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Claims the paper makes
13 of 46 cited sources checked · 9 supported · 0 flagged · accuracy not yet measured
- Findingown data
Tg2576 and Vps35+/m mice had normal spatial learning and memory response as compared with age-matched wild-type control at 3 and 6 months of age.
“Tg2576 and Vps35+/m mice had normal spatial learning and memory response as compared with the age-matched WT control in viewing their learning the location of the submerged platform with repeated testing (Fig. 1).”
Quote in the paperSubstantial claim - Findingown data
Vps35 homozygous mutant mice are lethal at an early embryonic stage under embryonic day 10.
“Homozygotes, named Vps35m/m, were lethal at an early embryonic stage (under embryonic day 10 [E10]), but heterozygotes, named Vps35+/m, whose expression of Vps35 was ∼50% of that in wild type (WT; Fig. S1 B), survived to adulthood.”
Quote in the paperNot a substantial claim - Findingown data
Vps35 heterozygotes have expression of Vps35 approximately 50% of that in wild type.
“Homozygotes, named Vps35m/m, were lethal at an early embryonic stage (under embryonic day 10 [E10]), but heterozygotes, named Vps35+/m, whose expression of Vps35 was ∼50% of that in wild type (WT; Fig. S1 B), survived to adulthood.”
Quote in the paperSubstantial claim - Findingown data
Vps35 heterozygotes survive to adulthood.
“Homozygotes, named Vps35m/m, were lethal at an early embryonic stage (under embryonic day 10 [E10]), but heterozygotes, named Vps35+/m, whose expression of Vps35 was ∼50% of that in wild type (WT; Fig. S1 B), survived to adulthood.”
Quote in the paperSubstantial claim - Findingown data
BACE1 and VPS35 colocalized largely at perinuclear compartments in NLT cells and in mouse cortical neurons.
“BACE1 and VPS35 were colocalized largely at perinuclear compartments in NLT cells, a cell line derived from GnRH neurons, and in mouse cortical neurons (Fig. 6, A and B).”
Quote in the paperSubstantial claim
- Findingown data
No significant difference was observed in velocity among the four groups.
“Note that no significant difference was observed in velocity among the four groups (Fig. 1, G and H).”
Quote in the paperSubstantial claim - Findingnone given
VPS35 is highly expressed in pyramidal neurons in young adult CA1-3 hippocampus.
“VPS35 is highly expressed in pyramidal neurons in young adult CA1–3 hippocampus”
Quote in the paperNot a substantial claim - Findingown data
C83 levels were not consistently altered by Vps35 mutation.
“C83 levels were not consistently altered by Vps35 mutation (Fig. 8, C and E)”
Quote in the paperNot a substantial claim - Findingown data
The ratio of paired-pulse facilitation was not significantly different among the four groups of mice.
“The ratio of paired-pulse facilitation was not significantly different among the four groups of mice (Fig. 3 H), suggesting that the decreased frequencies of both currents in the double mutant CA1 neurons may be caused by a reduction of the number of postsynaptic glutamatergic neurons/synapses.”
Quote in the paperSubstantial claim - Findingown data
Both amplitudes of evoked AMPA receptor-mediated and NMDA receptor-mediated excitatory postsynaptic currents were lower in CA1 neurons from double mutant slices as compared with the other three groups.
“Consistent with the results in mEPSCs recordings, both amplitudes of evoked AMPA receptor-mediated and NMDA receptor-mediated EPSCs were lower in CA1 neurons from the double mutant slices as compared with the other three groups (Fig. 3 G), confirming the deficits of the glutamatergic synaptic transmission at the SC-CA1 synapses of young adult Tg2576+/−;Vps35+/m mice.”
Quote in the paperSubstantial claim - Findingown data
Approximately 25% increase of BACE1 activity was found in Tg2576+/− hippocampus compared with WT control.
“Approximately 25 and 10% increases of BACE1 activity were found in Tg2576+/− hippocampus and cortex, respectively (compared with the WT control; Fig. 8 G)”
Quote in the paperSubstantial claim - Findingown data
The BACE1-binding site in VPS35 is amino acids 390-606.
“reveal a BACE1-binding site in VPS35 (the amino acids of 390–606; Fig. 6 F).”
Quote in the paperNot a substantial claim - Findingown data
The ratio of Aβ40/Aβ42 was not changed.
“However, the ratio of Aβ40/Aβ42 was not changed (Fig. S3 B), implicating that changes in VPS35 levels may not modulate the specificity of the γ-secretase cleavage of APP.”
Quote in the paperSubstantial claim - Findingown data
No Aβ deposit was observed in brain samples of wild-type or Vps35+/m mice as old as 12 months.
“No Aβ deposit was observed in brain samples of WT or Vps35+/m mice as old as 12 mo (Fig. 4, A and B).”
Quote in the paperSubstantial claim - Findingown data
Long-term potentiation at the dentate gyrus was defective in Tg2576+/;Vps35+/m mice compared with that in wild-type, Tg2576+/−, or Vps35+/m mice.
“In addition, LTP at the DG was defective in Tg2576+/;Vps35+/m mice compared with that in WT, Tg2576+/−, or Vps35+/m mice (Fig. 2, G and H).”
Quote in the paperSubstantial claim - Findingown data
There are more, larger Aβ plaques in both 6- and 12-month-old Tg2576+/−;Vps35+/m brains in comparison with those in Tg2576 brain samples at respective ages.
“Interestingly, there are more, larger Aβ plaques in both 6- and 12-mo-old Tg2576+/−;Vps35+/m brains in comparison with those in Tg2576 brain samples at respective ages (Fig. 4, A and B).”
Quote in the paperSubstantial claim - Findingown data
Aβ deposits or plaques were undetectable in brain sections of Vps35+/m;Tg2576+/− mice or the other three genotypes at the age of 2-4 months old.
“Aβ deposits or plaques were undetectable in brain sections of Vps35+/m;Tg2576+/− mice or the other three genotypes at the age of 2–4 mo old (unpublished data).”
Quote in the paperNot a substantial claim - Findingown data
Double mutant mice at 1-2 months old did not exhibit significant impairment.
“Moreover, double mutant mice at 1–2 mo old did not exhibit significant impairment (unpublished data).”
Quote in the paperNot a substantial claim - Findingown data
VPS351-606 showed stronger association with BACE1 than VPS35Fl in coimmunoprecipitation analysis.
“In coimmunoprecipitation analysis, however, VPS351–606 showed stronger association than that of the VPS35Fl (Fig. 6, E and F).”
Quote in the paperNot a substantial claim - Findingown data
fEPSP slopes in both CA1 and dentate gyrus were reduced in Tg2576+/−;Vps35+/m hippocampal slices compared with those of wild-type, Tg2576, or Vps35+/m mice.
“However, the fEPSP slopes in both CA1 and DG were reduced in Tg2576+/−;Vps35+/m hippocampal slices compared with those of WT, Tg2576, or Vps35+/m mice (Fig. 2, A and B), indicating that synaptic transmission is more vulnerable in Tg2576 mice when VPS35 level was reduced.”
Quote in the paperSubstantial claim - Findingown data
Approximately 10% increase of BACE1 activity was found in Tg2576+/− cortex compared with WT control.
“Approximately 25 and 10% increases of BACE1 activity were found in Tg2576+/− hippocampus and cortex, respectively (compared with the WT control; Fig. 8 G)”
Quote in the paperSubstantial claim - Findingown data
BACE1-Rab7 colocalization was increased in neurons of Vps35+/m mice.
“BACE1-Rab7 colocalization was increased in neurons of Vps35+/m mice (Fig. 7, D and E).”
Quote in the paperSubstantial claim - Findingown data
The increase of BACE1 activity in mutant hippocampus was more dramatic than in cortex.
“Note that the increase of BACE1 activity in the mutant hippocampus was more dramatic as compared with that in the cortex (Fig. 8 G).”
Quote in the paperNot a substantial claim - Findingown data
Long-term potentiation impairment worsened in 4-month-old hippocampal slices in the CA1 area.
“The impairment worsened in 4-mo-old hippocampal slices in the CA1 area (Fig. 2, E and F).”
Quote in the paperSubstantial claim - Findingown data
Vps35+/m cortex exhibited significant increase of BACE1 activity by ∼20% compared with WT controls.
“Vps35+/m hippocampus and cortex exhibited significant increases of BACE1 activity by ∼50 and 20%, respectively, as compared with that of WT controls (Fig. 8 G).”
Quote in the paperSubstantial claim - Findingown data
Human Aβ40 levels were significantly higher in 2-month-old Tg2576+/−;Vps35+/m hippocampus and cerebral cortex as compared with Tg2576 littermate controls, by 30 and 15%, respectively.
“Remarkably, Aβ40 levels were significantly higher in 2-mo-old Tg2576+/−;Vps35+/m hippocampus and cerebral cortex as compared with Tg2576 littermate controls (by 30 and 15%, respectively; Fig. 4 C).”
Quote in the paperSubstantial claim - Findingown data
BACE1 displayed greater binding affinity for full-length VPS35 than for VPS351-390 in in vitro GST pull-down assays.
“BACE1 displayed seemingly greater binding affinity for full-length VPS35 (VPS35Fl) as compared with that of VPS351–390 in in vitro GST pull-down assays (Fig. 6, D and F).”
Quote in the paperNot a substantial claim - Findingown data
sAPPβ levels were increased in Tg2576+/−;Vps35+/m hippocampus compared with Tg2576 alone.
“levels of sAPPβ and C99 were increased in Tg2576+/−;Vps35+/m hippocampus compared with Tg2576 alone (Fig. 8, B–F).”
Quote in the paperSubstantial claim - Findingown data
A similar increase in Aβ40 was also detected in 4-6-month-old mice.
“A similar increase was also detected in 4–6-mo-old mice (unpublished data).”
Quote in the paperNot a substantial claim - Findingown data
Vps35 expression in CA1 and cortical neurons is reduced with age.
“Fig. S4 demonstrates an age-dependent reduction of Vps35 expression in CA1 and cortical neurons.”
Quote in the paperNot a substantial claim - Findingown data
Reductions of frequencies of both AMPA and NMDA receptor-mediated miniature excitatory postsynaptic currents were observed in double mutant CA1 neurons.
“Interestingly, we also observed reductions of the frequencies of both AMPA and NMDA receptor-mediated mEPSCs in the double mutant CA1 neurons (Fig. 3, A, B, E, and F).”
Quote in the paperSubstantial claim - Findingown data
VPS35 was detected in BACE1-immunoprecipitated complexes from mouse brain lysates.
“VPS35 was detected in BACE1-immunoprecipitated complexes (Fig. 6 C).”
Quote in the paperSubstantial claim - Findingown data
Both amplitudes of AMPA and NMDA receptor-mediated miniature excitatory postsynaptic currents were significantly reduced in CA1 pyramidal neurons from Tg2576+/−;Vps35+/m mutant mice as compared with the other three groups.
“Both amplitudes of AMPA and NMDA receptor-mediated mEPSCs were significantly reduced in the CA1 pyramidal neurons from Tg2576+/−;Vps35+/m mutant mice as compared with the other three groups (Fig. 3, A–D).”
Quote in the paperSubstantial claim - Findingown data
β-gal activity was detectable in many layers or regions of the cortex and the hippocampus in neonatal mice but became restricted to layers IV-V in the cortex and CA2-3 regions of the hippocampus in adult mice.
“The β-gal activity was detectable in many layers or regions of the cortex and the hippocampus in neonatal mice but became restricted to layers IV–V in the cortex and CA2–3 regions of the hippocampus in adult mice (Fig. 5, A and B; and Fig. S4).”
Quote in the paperNot a substantial claim - Findingown data
Levels of VPS35 were low in interneurons labeled by parvalbumin in wild-type mice or GFP in GAD67-GFP mice.
“In contrast, the levels of VPS35 were low in interneurons, i.e., neurons labeled by parvalbumin in WT mice or GFP in GAD67-GFP mice (Fig. 5, C and D).”
Quote in the paperNot a substantial claim - Findingown data
Mouse Aβ40 was higher in the 2-month-old Tg2576+/−;Vps35+/m hippocampus and cerebral cortex than in Tg2576 samples.
“Moreover, mouse Aβ40 was also higher in the 2-mo-old Tg2576+/−;Vps35+/m hippocampus and cerebral cortex than that of Tg2576 samples (Fig. 4 D).”
Quote in the paperSubstantial claim - Findingown data
Vps35+/m hippocampus exhibited significant increase of BACE1 activity by ∼50% compared with WT controls.
“Vps35+/m hippocampus and cortex exhibited significant increases of BACE1 activity by ∼50 and 20%, respectively, as compared with that of WT controls (Fig. 8 G).”
Quote in the paperSubstantial claim - Findingown data
Mouse Aβ40 levels were increased in the hippocampus and cerebral cortex of 2-month-old Vps35+/m compared with wild type.
“Indeed, ELISA analyses of mouse Aβ40 revealed an increase in the hippocampus and cerebral cortex of 2-mo-old Vps35+/m compared with WT (Fig. 4 D).”
Quote in the paperSubstantial claim - Findingown data
Levels of human and mouse Aβ42 were also increased by Vps35+/m mutation.
“In addition to Aβ40, levels of human and mouse Aβ42 were also increased by Vps35+/m mutation (Fig. S3 A and not depicted).”
Quote in the paperSubstantial claim - Findingown data
In young adult Tg2576+/−;Vps35+/m mice, Aβ42 is increased in the hippocampus.
“Fig. S3 shows an increase of Aβ42 in young adult Tg2576+/−;Vps35+/m hippocampus without a change of the ratio of Aβ40 versus Aβ42 in the mutant mice.”
Quote in the paperSubstantial claim - Findingcitation
Posttetanic potentiation and long-term potentiation in the CA1 area were apparently normal in Tg2576 hippocampal slices at both ages.
“Note that posttetanic potentiation and LTP in the CA1 area were apparently normal in Tg2576 hippocampal slices at both ages, which is in agreement with previous reports that LTP was not impaired until at the age of >12 mo old (Chapman et al., 1999; Fitzjohn et al., 2001).”
Quote in the paperSubstantial claim0 of 2 sources checked - Findingown data
In VPS35-suppressed NLT cells, BACE1 became colocalized with LAMP1, a marker of late endosomes/lysosomes.
“Instead, BACE1 became colocalized with LAMP1, a marker of late endosomes/lysosomes (Fig. 7, A and C)”
Quote in the paperSubstantial claim - Findingown data
The double mutant showed a further increase of BACE1 activity in both hippocampus and cortex compared with single mutant mice.
“The double mutant showed a further increase of BACE1 activity in both hippocampus and cortex as compared with the single mutant mice (Fig. 8 G).”
Quote in the paperSubstantial claim - Findingown data
Long-term potentiation was reduced in the double mutant in CA1 at 2 months of age.
“However, LTP was reduced in the double mutant (Fig. 2, C and D), suggesting impaired synaptic plasticity in CA1 in the 2-mo-old Vps35+/m;Tg2576+/− hippocampus.”
Quote in the paperSubstantial claim - Findingown data
Posttetanic potentiation of synaptic transmission within 3 minutes of tetanic stimulation initiation was similar in CA1 2-month-old hippocampal slices of all four groups.
“The posttetanic potentiation of synaptic transmission (within 3 min of tetanic stimulation initiation) was similar in CA1 2-mo-old hippocampal slices of all four groups (WT, Vps35+/m, Tg2576, or Vps35+/m;Tg2576+/−) of mice.”
Quote in the paperNot a substantial claim - Findingown data
VPS35 was codistributed with CaMKII in the soma and processes of neurons in the cortex and hippocampus.
“Indeed, VPS35 was codistributed with CaMKII in the soma and processes of neurons in the cortex and hippocampus (Fig. 5 C).”
Quote in the paperNot a substantial claim - Findingown data
In control NLT cells, HA-tagged BACE1 was present in perinuclear vesicles close to Golgi apparatus.
“HA-tagged BACE1 was present in perinuclear vesicles, close to Golgi apparatus, in control NLT cells (Fig. 7 A).”
Quote in the paperSubstantial claim - Findingown data
In young adult Tg2576+/−;Vps35+/m mice, the ratio of Aβ40 to Aβ42 in the hippocampus is unchanged.
“Fig. S3 shows an increase of Aβ42 in young adult Tg2576+/−;Vps35+/m hippocampus without a change of the ratio of Aβ40 versus Aβ42 in the mutant mice.”
Quote in the paperNot a substantial claim - Interpretationnone given
VPS35 prevents activation of BACE1.
“The retromer complex component VPS35 prevents activation of the BACE1 and Aβ production and thus plays an essential role in limiting Alzheimer’s disease neuropathology.”
Quote in the paperSubstantial claim - Interpretationreasoning
VPS35 plays an essential role in limiting Alzheimer's disease neuropathology.
“The retromer complex component VPS35 prevents activation of the BACE1 and Aβ production and thus plays an essential role in limiting Alzheimer’s disease neuropathology.”
Quote in the paperSubstantial claim - Premisecitation
The retromer may be involved in Alzheimer's disease pathogenesis.
“These observations suggest that the retromer may be involved in the AD pathogenesis.”
Quote in the paperSubstantial claim - Premisecitation
The cargo-selective retromer proteins VPS35 and VPS26 are decreased in the postmortem hippocampus of Alzheimer's disease patients.
“In addition, the cargo-selective retromer proteins VPS35 and VPS26 are decreased in the postmortem hippocampus of AD patients (Small et al., 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Small et al., 2005 source
- Interpretationown data
VPS35 plays an important role in control of early onset of AD neuropathology.
“These observations demonstrate that VPS35 plays an important role in the control of the early onset of AD neuropathology”
Quote in the paperSubstantial claim - Interpretationown data
Knocking down VPS35 expression in cultured cells increased BACE1 localization to endosomal compartments where BACE1 cleavage of APP is favored.
“We also demonstrated that knocking down VPS35 expression in cultured cells increased BACE1 localization to the endosomal compartments where the BACE1 cleavage of APP is favored, providing a mechanism underlying VPS35/retromer regulation of BACE1 activation (Fig. 7 F).”
Quote in the paperSubstantial claim- Rests on an assumption: BACE1 cleavage of APP is favored in endosomal compartments.
- Interpretationreasoning
Increased Aβ levels may be a key detrimental factor for the cognitive and long-term potentiation deficits associated with the Alzheimer's disease mice.
“Together, these data suggest that VPS35 negatively regulates Aβ production and support the view that increased Aβ levels may be a key detrimental factor for the cognitive and LTP deficits associated with the AD mice.”
Quote in the paperSubstantial claim - Premisecitation
Tg2576 mice express the Swedish mutant form of human APP (APPswe) under the control of prion promoter.
“we crossed Tg2576 mice, a well-established AD mouse model that expresses the Swedish mutant form of human APP (APPswe) under the control of prion promoter (Chapman et al., 1999; Rockenstein et al., 2007)”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
Tg2576 mice normally develop AD-like phenotypes, including cognitive deficits and Aβ deposits, at age at least 10 mo or older.
“Tg2576 mice normally develop AD-like phenotypes, including cognitive deficits and Aβ deposits, at the age of at least 10 mo or older (Chapman et al., 1999; Middei et al., 2006; Bizon et al., 2007).”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationown data
VPS35 negatively regulates Aβ40 production.
“These results indicated that Aβ40 production is enhanced when VPS35 levels were reduced, suggesting that VPS35 negatively regulates Aβ40 production.”
Quote in the paperSubstantial claim - Interpretationown data
VPS35 is required for the endosome-to-Golgi retrieval of BACE1.
“We have investigated underlying mechanisms, and our results suggest that VPS35 is required for the endosome-to-Golgi retrieval of BACE1.”
Quote in the paperSubstantial claim - Interpretationown data
VPS35 is required for retrieval of BACE1 from endosomes to the Golgi apparatus in both NLT and hippocampal neurons.
“Collectively, these results demonstrate that VPS35 is required for the retrieval of BACE1 from endosomes to the Golgi apparatus in both NLT and hippocampal neurons (Fig. 7 F).”
Quote in the paperSubstantial claim - Interpretationown data
VPS35 negatively regulates Aβ production.
“Together, these data suggest that VPS35 negatively regulates Aβ production and support the view that increased Aβ levels may be a key detrimental factor for the cognitive and LTP deficits associated with the AD mice.”
Quote in the paperSubstantial claim - Interpretationcitation
Altered APP metabolism also contributes to elevated Aβ levels in Vps35-deficient neurons.
“It is likely that, in addition to BACE1 activation, altered APP metabolism also contributes to the elevated Aβ levels in Vps35-deficient neurons.”
Quote in the paperNot a substantial claim - Interpretationown data
Loss of Vps35 function accelerates the development of synaptic plasticity deficits in both CA1 and dentate gyrus hippocampus of Tg2576 mice.
“These results demonstrated that loss of Vps35 function accelerates the development of synaptic plasticity deficits in both CA1 and DG hippocampus of Tg2576 mice.”
Quote in the paperSubstantial claim - Interpretationown data
Impaired spatial learning and memory in double mutant mice at 3 and 6 months old suggests an earlier onset of Tg2576-associated cognitive deficit by loss of VPS35 function.
“Thus, these results demonstrate an impaired spatial learning and memory in the double mutant mice at the age of 3 and 6 mo old, suggesting an earlier onset of Tg2576-associated cognitive deficit by loss of VPS35 function.”
Quote in the paperSubstantial claim - Interpretationown data
BACE1 activation in Vps35+/m hippocampus may be essential for retromer regulation of Aβ production.
“Our data suggest that BACE1 activation in the Vps35+/m hippocampus may be essential for this event.”
Quote in the paperSubstantial claim - Interpretationcitation
Mechanisms underlying VPS35 regulation of APPswe and WT APP may be different.
“However, mechanisms underlying VPS35 regulation of APPswe and WT APP may be different”
Quote in the paperNot a substantial claim - Interpretationreasoning
Impairment of Vps35 retromer is a general risk factor for a growing number of chronic degenerative disorders, including AD and PD.
“Thus, these observations together with our results support the view for the impairment of Vps35 retromer as a general risky factor for a growing number of chronic degenerative disorders, including AD and PD.”
Quote in the paperNot a substantial claim - Premisecitation
VPS35 is decreased in postmortem hippocampus of AD patients.
“VPS35 is decreased in the postmortem hippocampus of AD patients (Small et al., 2005).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Small et al., 2005 source
- Interpretationreasoning
Dysfunction of VPS35-containing retromer is a risk factor for AD.
“Our results, in line with these observations, support the view for the dysfunction of VPS35-containing retromer as a risk factor for AD.”
Quote in the paperSubstantial claim - Interpretationown data
Reduced VPS35 levels may exacerbate Aβ toxicity.
“These earlier-onset AD-like phenotypes in the double mutant mice suggest that reduced VPS35 levels may exacerbate Aβ toxicity.”
Quote in the paperSubstantial claim
- Probably not a substantial claim. 26
- It may state two separate claims as one. 40
- The quote only partly states this claim. 2
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationGenetic ablation of BACE1 in Alzheimer's disease animals abolishes Aβ production and rescues Alzheimer's disease-like phenotypes.
“Genetic ablation of BACE1 in AD animals abolishes Aβ production and rescues AD-like phenotypes (Luo et al., 2001; Ohno et al., 2004; Laird et al., 2005).”
Quote in the paperNot a substantial claim1 of 3 sources checkedProbably not a substantial claim.
PremisecitationTg2576 mice begin to show impaired long-term potentiation and synaptic transmission in dentate gyrus at 4-5 months or older.
“Tg2576 mice began to show impaired LTP and synaptic transmission in dentate gyrus (DG) at 4–5 mo or older (Jacobsen et al., 2006).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Jacobsen et al., 2006 source
It may state two separate claims as one.
PremisecitationSorL1 interacts with APP and VPS35, and interaction of SorL1 with VPS35 is necessary for SorL1 to control APP metabolism.
“SorL1 is a Vps10 family member in the retromer complex that interacts with APP and VPS35, and the interaction of SorL1 with VPS35 is necessary for SorL1 to control APP metabolism (Lane et al., 2010).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Lane et al., 2010 source
Probably not a substantial claim.
PremisecitationAβ peptide is a major culprit in AD pathogenesis.
“Genetic, biochemical, animal, and human studies have all pointed to Aβ peptide to be a major culprit in AD pathogenesis (Tanzi and Bertram, 2005; Selkoe, 2008).”
Quote in the paperSubstantial claim2 of 2 sources checkedIt may state two separate claims as one.
PremisecitationDecreased NMDA and AMPA currents may be induced by increase of soluble Aβ oligomers, but not Aβ deposits, in the double mutant brain.
“Our data corroborate with the view that the decreased NMDA and AMPA currents may be induced by the increase of soluble Aβ oligomers, but not Aβ deposits, in the double mutant brain (Nimmrich et al., 2008; Selkoe, 2008)”
Quote in the paperSubstantial claim2 of 2 sources checked- cites Nimmrich et al., 2008 source
The Introduction says soluble Aβ forms, rather than plaques, are associated with impairment, and the Results report that an Aβ oligomer reduces excitatory synaptic activity in cultured hippocampal neurons. But the Discussion says the study found no indication that its oligomer directly affects NMDA receptors. It does not establish decreased NMDA and AMPA currents caused by soluble oligomers rather than deposits in a double-mutant brain. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites Selkoe, 2008 source
The Introduction (page not provided) reports reduced NMDA-receptor-mediated calcium influx and a slight reduction in AMPA-receptor-mediated miniature current amplitude after exposure to soluble Aβ oligomers. The Conclusions propose impaired NMDA signaling, but the paper does not establish that these changes occur in a double-mutant brain or compare oligomers with Aβ deposits as their cause. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationApoE4 and SorL1 affect APP metabolism and increase Aβ production.
“Many risky factors associated with the late-onset AD also affect APP metabolism and increase Aβ production, which include ApoE4 and SorL1 (Rogaeva et al., 2007; Willnow et al., 2010).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites Rogaeva et al., 2007 source
The Results show that suppressing SORL1 changes APP sorting and increases Aβ production; the Discussion likewise describes SORL1’s role in APP processing. The Introduction associates APOE variants with Aβ accumulation, but our copy does not establish that ApoE4 alters APP metabolism or increases Aβ production. The increase shown for SORL1 is specifically with reduced expression, not SORL1 activity generally. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites Willnow et al., 2010 source
The section on SORLA deficiency (p. 8) reports that loss of SORLA increases APP turnover and Aβ production in mouse models. The paper describes normal SORLA activity as reducing amyloidogenic processing (p. 7), and the passages found do not establish that ApoE4 increases Aβ production. Thus the claim is supported for reduced SORL1 activity, not for both factors as stated. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe retromer contains two subprotein complexes: the cargo-selective subcomplex and membrane deformation subcomplex.
“The retromer contains two subprotein complexes: the cargo-selective subcomplex and membrane deformation subcomplex (Seaman, 2005; Bonifacino and Hurley, 2008).”
Quote in the paperNot a substantial claim1 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationSorL1 is an APP-binding protein and is involved in the pathogenesis of late-onset Alzheimer's disease.
“Recent studies have suggested that SorL1, also called SorLA and LR11, is an APP-binding protein and is involved in the pathogenesis of late-onset AD (Rogaeva et al., 2007; Willnow et al., 2010).”
Quote in the paperNot a substantial claim1 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationMutation in Vps35 gene has been identified in patients of late-onset Parkinson's disease.
“mutation in Vps35 gene has recently been identified in patients of late-onset Parkinson’s disease (PD; Vilariño-Güell et al., 2011; Zimprich et al., 2011)”
Quote in the paperNot a substantial claim2 of 2 sources checkedIt may state two separate claims as one.
Findingown dataDouble mutant Tg2576+/−;Vps35+/m mice performed worse than all other groups in probe trials, with less frequency to probe the hidden platform.
“In addition, Tg2576+/−;Vps35+/m mutant mice performed worse than all other groups in probe trials, with less frequency to probe the hidden platform (Fig. 1, E and F).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataVps35 heterozygotes can survive into adulthood with relatively normal behavior, synaptic plasticity, and life span.
“Vps35 homozygous mutant mice died during early embryonic development, but heterozygotes can survive into adulthood with relatively normal behavior, synaptic plasticity, and life span.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataNo significant difference in fEPSP slopes was detected at the tested stimulus intensities in both CA1 and dentate gyrus areas of Tg2576, Vps35+/m, and wild-type littermate controls, suggesting similar strength of basal synaptic transmission.
“No significant difference in fEPSP slopes was detected at the tested stimulus intensities in both CA1 and DG areas of Tg2576, Vps35+/m, and their WT littermate controls (Fig. 2, A and B), suggesting similar strength of basal synaptic transmission.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataVPS35 is codistributed with BACE1 in hippocampus and in cultured cells.
“VPS35 is codistributed with BACE1 in hippocampus (not depicted) and in cultured cells (Fig. 6).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataTg2576 mice with reduced VPS35 expression exhibit an earlier onset of AD-like phenotypes, including cognitive memory deficits, reduced LTP, and decreased glutamatergic neurotransmission in 2-mo-old mice.
“Tg2576 mice with reduced VPS35 expression exhibit an earlier onset of AD-like phenotypes, including cognitive memory deficits, reduced LTP, and decreased glutamatergic neurotransmission in 2-mo-old mice (Figs. 1–3).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn VPS35-suppressed NLT cells, BACE1 punctae were enlarged and no longer confined to Golgi apparatus.
“In cells whose VPS35 expression was suppressed, BACE1 punctae were enlarged in size and no longer confined to the Golgi apparatus (Fig. 7 A).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTransfection of shRNA-Vps35 or miRNA-Vps35, but not control, inhibited expression of cotransfected Flag-Vps35 in HEK293 cells and endogenous VPS35 in NLT cells.
“Transfection of shRNA-Vps35 or miRNA-Vps35, but not control (a scrambled miRNA), inhibited expression of cotransfected Flag-Vps35 in HEK293 cells (Fig. S5 A) and endogenous VPS35 in NLT cells (Fig. S5 B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe double mutant mice display impairments in NMDA and AMPA receptor-mediated synaptic transmission and synaptic plasticity (LTP) but not GABAergic transmission.
“The double mutant mice (Vps35+/m;Tg2576+/−) display impairments in NMDA and AMPA receptor-mediated synaptic transmission and synaptic plasticity (LTP) but not GABAergic transmission.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe hippocampus of Vps35+/m in WT background exhibits an increase of Aβ levels, a decrease of synaptic activity (both NMDA and AMPA currents), and a loss of synapses (decrease of frequency of mEPSCs) but without obvious defects on cognitive learning and memory or LTP.
“Note that the hippocampus of Vps35+/m in the WT background also exhibits an increase of Aβ levels, a decrease of synaptic activity (both NMDA and AMPA currents), and a loss of synapses (decrease of frequency of mEPSCs) but without obvious defects on cognitive learning and memory or LTP (Figs. 1–4).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAβ deposits were rare in 6-month-old Tg2576+/− brain but increased in number and size in 12-month-old samples.
“Aβ deposits were rare in 6-mo-old Tg2576+/− brain but increased in number and size in 12-mo-old samples (Fig. 4, A and B), which is in agreement with a previous study (Hsiao et al., 1996).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hsiao et al., 1996 source
It may state two separate claims as one.
Findingown dataBoth posttetanic potentiation and long-term potentiation were reduced in 4-month-old Vps35+/m;Tg2576+/− CA1 hippocampus.
“Both the posttetanic potentiation and LTP were reduced in 4-mo-old Vps35+/m;Tg2576+/− CA1 hippocampus (Fig. 2, E and F).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataIn hippocampal CA1 pyramidal neurons of Tg2576+/−;Vps35+/m mice, inhibitory synaptic transmission is normal.
“Fig. S2 depicts the normal inhibitory synaptic transmission in hippocampal CA1 pyramidal neurons of Tg2576+/−;Vps35+/m mice.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataElevated mouse Aβ40 level was also detected in the hippocampus and cortex of 4-6-month-old Vps35+/m mice compared with wild-type controls and Tg2576+/−;Vps35+/m mutant mice compared with Tg2576+/− mice.
“Elevated mouse Aβ40 level was also detected in the hippocampus and cortex of 4–6-mo-old Vps35+/m mice (compared with the WT controls) and Tg2576+/−;Vps35+/m mutant mice (compared with the Tg2576+/− mice; unpublished data).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataVps35 heterozygotes;Tg2576 mice demonstrated an earlier onset of Alzheimer's disease-like neuropathology, including cognitive deficits, impaired glutamatergic transmission, and synaptic plasticity, and more Aβ-positive plaques detected in the brain.
“Remarkably, Vps35 heterozygotes;Tg2576 mice demonstrated an earlier onset of AD-like neuropathology, including cognitive deficits, impaired glutamatergic transmission, and synaptic plasticity, and more Aβ-positive plaques detected in the brain.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataNeither the frequency nor the amplitude of miniature or evoked inhibitory postsynaptic currents was altered in the double mutant hippocampus.
“Neither the frequency nor the amplitude of mIPSCs or eIPSCs was altered in the double mutant hippocampus (Fig. S2).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Findingown dataVPS35 appeared to be enriched in dendrites that were labeled by MAP2 in both the cortex and the CA1-3 regions of the hippocampus.
“Subcellularly, VPS35 appeared to be enriched in dendrites that were labeled by MAP2, a dendritic marker in both the cortex and the CA1–3 regions of the hippocampus (Fig. 5 D).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataTg2576+/− and Vps35+/m mutants also showed reductions of the amplitudes and frequencies of both AMPA and NMDA receptor-mediated miniature excitatory postsynaptic currents and the amplitudes of both evoked AMPA and NMDA receptor-mediated excitatory postsynaptic currents as compared with the wild-type control, but these reductions were not statistically significant.
“Note that Tg2576+/− and Vps35+/m mutants also showed reductions of the amplitudes and frequencies of both AMPA and NMDA receptor-mediated mEPSCs and the amplitudes of both evoked AMPA and NMDA receptor-mediated EPSCs as compared with the WT control (Fig. 3, A–G), but these reductions were not statistically significant.”
Quote in the paperNot a substantial claimIt may state two separate claims as one. The quote only partly states this claim.
Findingown dataVPS35 is expressed in hippocampal and layer IV-V cortical pyramidal neurons.
“The β-gal activity was detectable in many layers or regions of the cortex and the hippocampus in neonatal mice but became restricted to layers IV–V in the cortex and CA2–3 regions of the hippocampus in adult mice (Fig. 5, A and B; and Fig. S4).”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataC99 levels were increased in Tg2576+/−;Vps35+/m hippocampus and cortex compared with Tg2576 alone.
“C99 levels were increased in Tg2576+/−;Vps35+/m (Fig. 8, B–D)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe double mutant mice (Vps35+/m;Tg2576+/−) develop AD-like phenotypes at 2/3 mo old, featured with cognitive memory deficit, synaptic plasticity (LTP) impairments, decrease of glutamatergic transmissions, and increase of Aβ levels.
“Remarkably, the double mutant mice (Vps35+/m;Tg2576+/−) develop AD-like phenotypes at the age of 2/3 mo old, featured with cognitive memory deficit, synaptic plasticity (LTP) impairments, decrease of glutamatergic transmissions, and increase of Aβ levels (Figs. 1–4).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSuppression of VPS35 expression increased BACE1 localization in Rab5- and Rab7-positive endosomal compartments but reduced BACE1 in Rab11-labeled recycling endosomes.
“suppression of VPS35 expression increased BACE1 localization in both Rab5- and Rab7-positive endosomal compartments but reduced BACE1 in Rab11-labeled recycling endosomes.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationBACE1 is essential for Aβ production.
“β-secretase, also called BACE1, is essential for this event (Hussain et al., 1999; Sinha et al., 1999; Vassar et al., 1999, 2009; Yan et al., 1999; Tanzi and Bertram, 2005; Bertram and Tanzi, 2008).”
Quote in the paperNot a substantial claim0 of 3 sources checkedIt may state two separate claims as one.
PremisecitationVPS26 heterozygote mice show increased levels of endogenous Aβ and impaired long-term potentiation.
“Moreover, VPS26 heterozygote mice show increased levels of endogenous Aβ and impaired LTP (Muhammad et al., 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Muhammad et al., 2008 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationCollectively, evidence from pathological, genetic, biochemical, and physiological studies indicates a crucial role of Aβ in the etiology of Alzheimer's disease.
“Collectively, these lines of evidence from pathological, genetic, biochemical, and physiological studies have indicated a crucial role of Aβ in the etiology of AD.”
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.
PremisecitationBACE1 activity is increased in postmortem brains of Alzheimer's disease patients and in brains of Alzheimer's disease mouse models.
“BACE1 activity is increased in postmortem brains of AD patients and in brains of AD mouse models (Fukumoto et al., 2002; Yang et al., 2003).”
Quote in the paperNot a substantial claim0 of 2 sources checkedIt may state two separate claims as one.
Interpretationown dataVPS35 prevents or negatively regulates Aβ production.
“The retromer complex component VPS35 prevents activation of the BACE1 and Aβ production and thus plays an essential role in limiting Alzheimer’s disease neuropathology.”
- Also stated in: § Increase of Aβ deposits and Aβ40/42 in mouse hippocampus and cerebral cortex by loss of Vps35 function · hedged
“Together, these data suggest that VPS35 negatively regulates Aβ production and support the view that increased Aβ levels may be a key detrimental factor for the cognitive and LTP deficits associated with the AD mice.”
Quote in the paperSubstantial claim- Also stated in: § Increase of Aβ deposits and Aβ40/42 in mouse hippocampus and cerebral cortex by loss of Vps35 function · hedged
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenOnly neurons with a resting potential of at least −60 mV and resistance fluctuating within 15% of initial values (<20 MΩ) were analyzed.
“Neurons with a resting potential of at least −60 mV and resistance fluctuated within 15% of initial values (<20 MΩ) were analyzed.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataLoss of VPS35 function leads to an increase of BACE1 activity and thus Aβ production.
“Thus, these results support the notion that loss of VPS35 function leads to an increase of BACE1 activity and thus Aβ production.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIn the Schaffer collateral pathway (SC-CA1), the deficiency was not detectable until 12-18 months old.
“In the Schaffer collateral (SC) pathway (SC-CA1), the deficiency was not detectable until 12–18 mo old (Chapman et al., 1999; Fitzjohn et al., 2001).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenControl littermates and double mutant were processed in parallel for each experiment.
“Control littermates (WT, Vps35+/m, and Tg2576+/−) and Tg2576+/−;Vps35+/m were processed in parallel for each experiment.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationMutations in APP and presenilins in early-onset AD provide strong genetic support for the amyloid hypothesis.
“Identification of mutations in APP and presenilins in the early-onset AD provides a strong genetic support for the amyloid hypothesis (Hardy and Selkoe, 2002).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hardy and Selkoe, 2002 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationDefective spatial learning and memory are known to be early symptoms of Alzheimer's disease.
“Defective spatial learning and memory are known to be early symptoms of AD (Middei et al., 2006; Bizon et al., 2007; Good and Hale, 2007; Reed et al., 2010).”
Quote in the paperNot a substantial claim0 of 3 sources checkedIt may state two separate claims as one.
Interpretationown dataVPS35 regulates both WT APP and APPswe metabolism.
“The increased Aβ levels in both Vps35+/m and Vps35+/m;Tg2576 mutant mice (Fig. 4, C and D) suggest a role for VPS35 not only in regulating WT APP, but also APPswe, metabolism.”
Quote in the paperSubstantial claimProbably not a substantial claim. It may state two separate claims as one.
Study design and conductown dataTg2576 and Vps35 mutations were confirmed by genotyping using PCR.
“Tg2576 and Vps35 mutations were confirmed by genotyping using PCR (Fig. S1 B).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationDefective spatial learning and memory are also observed in 8-month or older Tg2576 mice that express APPswe.
“They are also observed in 8-mo or older Tg2576 mice that express APPswe (Hsiao et al., 1996; Chapman et al., 1999; Rockenstein et al., 2007).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationAPPswe exhibits much higher affinity to BACE1 compared with WT APP, and APPswe may be cleaved by BACE1 at TGN whereas WT APP may be cleaved at endosome compartments.
“it is reported that APPswe exhibits a much higher affinity to BACE1 as compared with the WT APP, and APPswe may be cleaved by BACE1 at the TGN, whereas WT APP may be cleaved at the endosome compartments (Haass et al., 1995; Selkoe et al., 1996; Thinakaran and Koo, 2008).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim.
Premisenone givenThe retromer selectively mediates retrograde transport of multiple transmembrane proteins from the endosomes to the trans-Golgi network.
“The retromer selectively mediates retrograde transport of multiple transmembrane proteins from the endosomes to the TGN.”
Quote in the paperSubstantial claimProbably not a substantial claim. It may state two separate claims as one.
Premisenone givenThe cargo-selective complex is a trimer of VPS35, VPS29, and VPS26 that sorts cargos into tubules for retrieval to the Golgi apparatus.
“The cargo-selective complex is a trimer of vacuolar protein sorting (Vps) proteins VPS35, VPS29, and VPS26 that sorts cargos into tubules for retrieval to the Golgi apparatus.”
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.
PremisecitationLoss of function of SorCS1 leads to an increase of Aβ and a decrease of VPS35 levels.
“loss of function of SorCS1, a SorL1 family protein and a risk factor for type 2 diabetes, also leads to an increase of Aβ and a decrease of VPS35 levels (Lane et al., 2010)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lane et al., 2010 source
Checked before — its earlier verdict is held back until a new check runs.
It may state two separate claims as one.
Interpretationown dataVPS35 is a crucial component in BACE1 trafficking, APP metabolism, and hippocampal neuronal synaptic function.
“our work provides strong evidence for VPS35 to be a crucial component in BACE1 trafficking, APP metabolism, and hippocampal neuronal synaptic function”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataVPS35 interacts with BACE1 in vitro and in vivo.
“These results support an interaction between VPS35 and BACE1 in vitro and in vivo”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataBehavioral analysis was performed by investigators unaware of genotype.
“Behavioral analysis was performed with 1–2-, 3-, and 6-mo old mice by investigators unaware of their genotype.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataThere is a decrease of glutamatergic, but not GABAnergic, neurotransmission, likely at the postsynaptic sites of the young adult double mutant hippocampus.
“Thus, these results demonstrate a decrease of glutamatergic, but not GABAnergic, neurotransmission, likely at the postsynaptic sites of the young adult double mutant hippocampus.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataAβ deposits occurred in higher frequency and in younger Vps35+/m;Tg2576+/− mice than in Tg2576 mice.
“These results demonstrate that Aβ deposits occurred in higher frequency and in younger Vps35+/m;Tg2576+/− mice than that in Tg2576 mice.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Interpretationown dataVPS35 functions in suppression of BACE1 activation and Aβ production, thus preventing AD-associated memory cognitive deficits and impairment of glutamatergic synaptic activity.
“Collectively, the data presented in this manuscript suggest an important function of VPS35 in suppression of BACE1 activation and Aβ production, thus preventing AD-associated memory cognitive deficits and impairment of glutamatergic synaptic activity.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAuthenticity of all constructs was verified by DNA sequencing.
“The authenticity of all constructs was verified by DNA sequencing.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataDepletion of Vps35 expression in culture increases BACE1 localization to endosomal compartments, an acidic environment favoring BACE1 activation.
“Depletion of Vps35 expression in culture increases BACE1 localization to the endosomal compartments (Fig. 7), an acidic environment favoring BACE1 activation.”
Quote in the paperSubstantial claim- Rests on an assumption: BACE1 cleavage of APP is favored in endosomal compartments.
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 conductown dataBoth shRNA and miRNA-Vps35 suppress Vps35 expression.
“Fig. S5 shows the suppression of Vps35 expression by both shRNA and miRNA-Vps35.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataLoss of Vps35 promotes BACE1-mediated cleavage of APP or APPswe, thereby increasing Aβ production.
“Together, these results indicate that loss of Vps35 promotes BACE1-mediated cleavage of APP or APPswe, thereby increasing Aβ production.”
Quote in the paperSubstantial claim
The authors state this as an assumption.
The mechanisms by which the retromer is involved in Alzheimer’s disease pathogenesis remain elusive.
“However, the underlying mechanisms remain elusive.”
The paper relies on this without support.
Aβ40/42 production requires BACE1.
“Aβ40/42 production requires BACE1.”
The paper relies on this without support.
Retromer is implicated in the pathogenesis of late-onset AD.
“Although retromer is implicated in the pathogenesis of late-onset AD, the function of VPS35 in AD pathology and the underlying molecular mechanisms remain largely unclear.”
The paper relies on this without support.
The function of VPS35 in AD pathology and the underlying molecular mechanisms remain largely unclear.
“Although retromer is implicated in the pathogenesis of late-onset AD, the function of VPS35 in AD pathology and the underlying molecular mechanisms remain largely unclear.”
The paper relies on this without support.
BACE1 cleavage of APP is favored in endosomal compartments.
“increased BACE1 localization to the endosomal compartments where the BACE1 cleavage of APP is favored”
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?
Suppressing protein expression rather than using a knockout model is physiologically relevant to neurodegenerative patients where Retromer levels are reduced, in contrast with Retromer KO which is embryonically lethal.
“By suppressing protein expression rather than using a knockout (KO) model our approach is physiologically relevant to neurodegenerative patients where Retromer levels are reduced, in contrast with Retromer KO which is embryonically lethal [78].”
From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [78]
Most in vivo mouse studies of retromer in AD have been performed in transgenic mice overexpressing human mutations in APP and PSEN1/2 or FTD-associated mutations in the tau gene MAPT.
“most in vivo mouse studies have been performed in transgenic mice engineered to overexpress human mutations in APP and PSEN1/2 (Wen et al., 2011; Li et al., 2019a) or FTD-associated mutations in the tau gene MAPT (Vagnozzi et al., 2019; Carosi et al., 2020).”
From The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease (2022) · cites this paper as Wen et al., 2011
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.
Adult hippocampal LacZ expression is described in different CA regions
MinorThe Results say adult LacZ activity became restricted to CA2-3, whereas the Figure 5 caption describes activity in CA1-3 for 2-month-old mice.
“The β-gal activity was detectable in many layers or regions of the cortex and the hippocampus in neonatal mice but became restricted to layers IV–V in the cortex and CA2–3 regions of the hippocampus in adult mice (Fig. 5, A and B; and Fig. S4).”
“LacZ activity was only detected in Vps35+/m but not WT and was largely expressed in layer IV–V cortical neurons and CA1–3 hippocampus.”
Western blot sample load differs between figure caption and methods
MinorThe Figure 8 caption says 50 μg of homogenate protein was loaded, while the Western blot method specifies 40 μg.
“Equal amounts of homogenates (50 µg of protein) were loaded and revealed by immunoblot (IB) using anti–β-actin antibody.”
“Specifically, samples (40 µg) were separated by 16% Tris-Tricine SDS-PAGE and electrophoretically transferred onto nitrocellulose membrane at 380 mA for 60 min.”
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Metadata
- Authors
- Wen, L., Tang, F.-L., Hong, Y., Luo, S.-W., Wang, C.-L., He, W., Shen, C., Jung, J.-U., Xiong, F., Lee, D.-H., Zhang, Q.-G., Brann, D., Kim, T.-W., Yan, R., Mei, L., & Xiong, W.-C.
- Affiliations
- Institute of Molecular Medicine and Genetics 1 and 2
- Cleveland Clinic (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Wen, Lei
- He, Wanxia
- Xiong, Fei
- Xiong, Wen-Cheng
- ORCID
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2011-11-21
- Volume
- 195
- Issue
- 5
- Pages
- 765-779
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC3257571
- OpenAlex
- W2150669288
- Semantic Scholar
- 7397ae7e6abe3f924f61057ea04be04dce07adb4
- Cited by
- 270
- References
- 73
- Citations by year
- 2026: 9 · 2025: 3 · 2024: 17 · 2023: 19 · 2022: 17 · 2021: 25 · 2020: 32 · 2019: 17 · 2018: 15 · 2017: 20 · 2016: 23 · 2015: 25 · 2014: 21 · 2013: 12 · 2012: 11
- FWCI
- 5.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (RF1AG045781)
- National Institute of Neurological Disorders and Stroke (R01NS060648)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- VPS35, retromer complex, Alzheimer's disease, haploinsufficiency, BACE1, amyloid-beta production, Tg2576 mice, hippocampus, long-term potentiation, glutamatergic neurotransmission, pyramidal neurons
- MeSH terms
- Alzheimer Disease, Animals, Cerebral Cortex, Hippocampus, Humans, Endosomes, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, trans-Golgi Network, Vesicular Transport Proteins, Mice, Amyloid Precursor Protein Secretases, HEK293 Cells, Haploinsufficiency
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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