VPS35 haploinsufficiency increases Alzheimer’s disease neuropathology

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Luo et al., 2001 source
• ?Not checked — no full text of the sourcecites Ohno et al., 2004 source
• Supported

  In “Deletion of BACE1 prevents age-dependent cognitive deficits” (page not provided), the paper reports that Aβ1-40 and Aβ1-42 were abolished in APPswe;PS1ΔE9 mice lacking BACE1. The same section reports that complete BACE1 deletion prevented the mice’s age-dependent cognitive deficits; the discussion also reports prevention of amyloid deposits and neuropathological abnormalities. (LLM, conf=0.94)

  cites Laird et al., 2005 source

In the paper

“Tg2576 mice began to show impaired LTP and synaptic transmission in dentate gyrus (DG) at 4–5 mo or older (Jacobsen et al., 2006).”

What the sources say

• Supported

  The Results report reduced basal synaptic transmission and LTP in 4- to 5-month-old Tg mice compared with age-matched controls, with neither deficit detected at 2 months. The Abstract identifies the LTP measurement as occurring in the dentate gyrus after perforant-path stimulation. The paper does not establish the electrophysiological findings at every older age, but supports the stated onset. (LLM, conf=0.91)

  cites Jacobsen et al., 2006 source

In the paper

“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).”

What the sources say

• Supported

  The Results section states that SorL1 directly interacts with APP and reports that Vps35 is required for SorL1 to modulate APP metabolism. The Introduction also describes SorL1 as a VPS10-domain family member that interacts with Vps35, a core retromer component. (LLM, conf=0.91)

  cites Lane et al., 2010 source

In the paper

“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).”

What the sources say

• Partly supported

  The Discussion (page unavailable) reports impaired reaction to spatial novelty and place orientation in 7-month-old AD-model mice, and relates their early hippocampal dysfunction to the progression described in AD patients. The paper describes early human AD in terms of episodic-memory loss, however; it does not establish defective spatial learning and memory specifically as early symptoms in patients. (LLM, conf=0.84)

  cites Middei et al., 2006 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Bizon et al., 2007 source
• ?Not checked — no full text of the sourcecites Good and Hale, 2007 source

In the paper

“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).”

What the sources say

• Supported

  The Introduction says the amyloid hypothesis assigns Aβ a central role in initiating the AD pathogenic cascade and rests on genetic, molecular, biochemical, and neuropathological findings. The section on Aβ toxicity also discusses evidence from animal models, supporting the citing sentence’s broad characterization of Aβ as a major contributor to AD pathogenesis. (LLM, conf=0.91)

  cites Tanzi and Bertram, 2005 source
• Supported

  The opening passage [1] says neuropathological, biochemical, genetic and human studies support the hypothesis that Aβ accumulation triggers the changes producing Alzheimer’s disease. It also reports animal experiments in which Aβ oligomers impair synaptic plasticity and memory, supporting the citing sentence’s qualified wording that these studies have ‘pointed to’ Aβ as a major culprit. (LLM, conf=0.92)

  cites Selkoe, 2008 source

In the paper

“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)”

What the sources say

• Partly supported

  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)

  cites Nimmrich et al., 2008 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites Selkoe, 2008 sourceExperimental — accuracy not yet measured

In the paper

“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).”

What the sources say

• Partly supported

  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)

  cites Rogaeva et al., 2007 sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites Willnow et al., 2010 sourceExperimental — accuracy not yet measured

In the paper

“The retromer contains two subprotein complexes: the cargo-selective subcomplex and membrane deformation subcomplex (Seaman, 2005; Bonifacino and Hurley, 2008).”

What the sources say

• ?Not checked — no full text of the sourcecites Seaman, 2005 source
• Supported

  The Summary identifies two components of mammalian retromer: a sorting nexin dimer and a cargo-recognition trimer. The Introduction describes the sorting nexin dimer’s role in forming membrane tubules, supporting the paraphrase “membrane deformation subcomplex.” (LLM, conf=0.92)

  cites Bonifacino and Hurley, 2008 source

In the paper

“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).”

What the sources say

• Supported

  The Results report that SORL1 directly binds APP, with co-immunoprecipitation showing an interaction with APP holoprotein. The Abstract associates SORL1 variants with late-onset AD, and the Discussion suggests that changes in SORL1 expression or function contribute to AD pathogenesis. (LLM, conf=0.94)

  cites Rogaeva et al., 2007 source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Willnow et al., 2010 source

In the paper

“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)”

What the sources say

• Supported

  The Abstract describes a Swiss family with late-onset Parkinson disease and identifies a VPS35 mutation as the likely genetic cause. The case-control passage also reports the mutation in additional patients with Parkinson disease. (LLM, conf=0.94)

  cites Vilariño-Güell et al., 2011 source
• Supported

  The supplied Abstract reports a VPS35 missense mutation in affected family members and says that p.Asp620Asn cosegregated with late-onset Parkinson disease in three families. (LLM, conf=0.94)

  cites Zimprich et al., 2011 source

In the paper

“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).”

In the paper

“Vps35 homozygous mutant mice died during early embryonic development, but heterozygotes can survive into adulthood with relatively normal behavior, synaptic plasticity, and life span.”

In the paper

“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.”

In the paper

“VPS35 is codistributed with BACE1 in hippocampus (not depicted) and in cultured cells (Fig. 6).”

In the paper

“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).”

In the paper

“In cells whose VPS35 expression was suppressed, BACE1 punctae were enlarged in size and no longer confined to the Golgi apparatus (Fig. 7 A).”

In the paper

“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).”

In the paper

“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.”

In the paper

“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).”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Hsiao et al., 1996 source

In the paper

“Both the posttetanic potentiation and LTP were reduced in 4-mo-old Vps35+/m;Tg2576+/− CA1 hippocampus (Fig. 2, E and F).”

In the paper

“Fig. S2 depicts the normal inhibitory synaptic transmission in hippocampal CA1 pyramidal neurons of Tg2576+/−;Vps35+/m mice.”

In the paper

“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).”

In the paper

“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.”

In the paper

“Neither the frequency nor the amplitude of mIPSCs or eIPSCs was altered in the double mutant hippocampus (Fig. S2).”

In the paper

“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).”

In the paper

“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.”

In the paper

“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).”

In the paper

“C99 levels were increased in Tg2576+/−;Vps35+/m (Fig. 8, B–D)”

In the paper

“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).”

In the paper

“suppression of VPS35 expression increased BACE1 localization in both Rab5- and Rab7-positive endosomal compartments but reduced BACE1 in Rab11-labeled recycling endosomes.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Hussain et al., 1999 source
• ?Not checked — no full text of the sourcecites Sinha et al., 1999 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites Vassar et al., 1999, 2009

In the paper

“Moreover, VPS26 heterozygote mice show increased levels of endogenous Aβ and impaired LTP (Muhammad et al., 2008).”

What the sources say

• ?Not checked — no full text of the sourcecites Muhammad et al., 2008 source

In the paper

“Collectively, these lines of evidence from pathological, genetic, biochemical, and physiological studies have indicated a crucial role of Aβ in the etiology of AD.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Fukumoto et al., 2002 source
• ?Not checked — no full text of the sourcecites Yang et al., 2003 source

In the paper

“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.”

In the paper

“Neurons with a resting potential of at least −60 mV and resistance fluctuated within 15% of initial values (<20 MΩ) were analyzed.”

In the paper

“Thus, these results support the notion that loss of VPS35 function leads to an increase of BACE1 activity and thus Aβ production.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Chapman et al., 1999 source
• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Fitzjohn et al., 2001 source

In the paper

“Control littermates (WT, Vps35+/m, and Tg2576+/−) and Tg2576+/−;Vps35+/m were processed in parallel for each experiment.”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Hardy and Selkoe, 2002 source

In the paper

“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.”

In the paper

“Tg2576 and Vps35 mutations were confirmed by genotyping using PCR (Fig. S1 B).”

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Hsiao et al., 1996 source
• ?Not checked — no full text of the sourcecites Chapman et al., 1999 source
• ?Not checked — no full text of the sourcecites Rockenstein et al., 2007 source

In the paper

“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).”

What the sources say

• ?Not checked — no full text of the sourcecites Haass et al., 1995 source
• ?Not checked — no full text of the sourcecites Selkoe et al., 1996 source
• ?Not checked — no full text of the sourcecites Thinakaran and Koo, 2008 source

In the paper

“The retromer selectively mediates retrograde transport of multiple transmembrane proteins from the endosomes to the TGN.”

In the paper

“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.”

In the paper

“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)”

What the sources say

• Not checked yet

  Checked before — its earlier verdict is held back until a new check runs.

  cites Lane et al., 2010 source

In the paper

“our work provides strong evidence for VPS35 to be a crucial component in BACE1 trafficking, APP metabolism, and hippocampal neuronal synaptic function”

In the paper

“These results support an interaction between VPS35 and BACE1 in vitro and in vivo”

In the paper

“Behavioral analysis was performed with 1–2-, 3-, and 6-mo old mice by investigators unaware of their genotype.”

In the paper

“Thus, these results demonstrate a decrease of glutamatergic, but not GABAnergic, neurotransmission, likely at the postsynaptic sites of the young adult double mutant hippocampus.”

In the paper

“These results demonstrate that Aβ deposits occurred in higher frequency and in younger Vps35+/m;Tg2576+/− mice than that in Tg2576 mice.”

In the paper

“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.”

In the paper

“The authenticity of all constructs was verified by DNA sequencing.”

In the paper

“Depletion of Vps35 expression in culture increases BACE1 localization to the endosomal compartments (Fig. 7), an acidic environment favoring BACE1 activation.”

In the paper

“Fig. S5 shows the suppression of Vps35 expression by both shRNA and miRNA-Vps35.”

In the paper

“Together, these results indicate that loss of Vps35 promotes BACE1-mediated cleavage of APP or APPswe, thereby increasing Aβ production.”