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Tau and other proteins found in Alzheimer’s disease spinal fluid are linked to retromer-mediated endosomal traffic in mice and humans
Abstract
Endosomal secreted proteins can be detected in the CSF and inform on how Alzheimer’s defective trafficking pathway can contribute to disease spread.
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VPS35 deficiency leads to a similar increase in APP-related proteins APLP1 and APLP2 at the cell surface, which are thought to be processed by secretases in the same way as APP.
“As has been shown previously, VPS35 deficiency also leads to a similar increase in APP-related proteins APLP1 and APLP2 at the cell surface, which are thought to be processed by secretases in the same way as APP [79,93,141].”
From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [141]
The Results section on CSF proteins in Vps35 knockout mice (page unavailable) reports elevated APLP1, APLP2, and APP fragments and identifies all three as BACE1 substrates. The Discussion (page unavailable) says BACE1 cleaves them at endosomal membranes. The paper does not show that APLP1 or APLP2 increases at the cell surface, so the claimed location is unsupported. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAt 3 months of age, VPS35 nsKO mice have no cell or synaptic loss.
“an age when previous studies have established that there is no cell or synaptic loss in these mice (Simoes et al., 2020).”
From The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease (2022) · cites this paper as Simoes et al., 2020
The Results section (“Validating BACE1 substrates and Tau accumulation in mouse CSF”; page not provided) reports no signs of neuronal loss in the hippocampus of 3-month-old Vps35 cKO mice and unchanged pre- and postsynaptic marker expression. The Methods identify these as neuronal-selective knockout mice, but unchanged marker expression does not directly establish that no synapses were lost, and the neuronal-loss assessment was limited to the hippocampus. (LLM, conf=0.85)
Experimental — accuracy not yet measuredIn a previous CSF proteomic screen, elevation in CSF tau was the most reliable effect in VPS35 nsKO mice.
“in a recent study (Simoes et al., 2020), where we used CSF proteomics to essentially establish the secretome of the VPS35 nsKO mice, an elevation in CSF tau was the most reliable effect.”
From The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease (2022) · cites this paper as Simoes et al., 2020
The Results section, “Validating BACE1 substrates and Tau accumulation in mouse CSF” (page unavailable), reports replicated elevations of CSF tau in Vps35 cKO mice. The Introduction (page unavailable) calls tau one of three reliable findings validated from the CSF proteomic screen, but does not rank it as the most reliable effect. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRecent studies have established a CSF biomarker of retromer-dependent neuronal dysfunction.
“recent studies have established a CSF biomarker of retromer-dependent neuronal dysfunction (Simoes et al., 2020).”
From The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease (2022) · cites this paper as Simoes et al., 2020
The Discussion identifies a joint increase in CSF tau with n-APLP1 or n-CHL1 as a potential biomarker of impaired retromer-dependent trafficking. But it says such a biomarker 'can be developed,' not that one has been established; the Discussion also notes that precise diagnostic cutoffs could not yet be established. (LLM, conf=0.88)
Experimental — accuracy not yet measuredRetromer deficiency or dysregulation has been observed in AD brain and can perturb APOE levels; neuronal Vps35 deletion can elevate APOE in mouse CSF and hippocampus, likely through glial activation.
“Retromer deficiency or dysregulation which has been observed in AD brain (Small, Kent et al. 2005) can also perturb APOE levels, for example neuronal Vps35 deletion can elevate APOE in mouse CSF (Simoes, Neufeld et al. 2020) as well as hippocampus, likely through glial activation observed with neuronal Vps35 deletion (Qureshi, Berman et al. 2022).”
From SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain (2026) · cites this paper as Simoes, Neufeld et al. 2020
The citation to Simoes et al. is attached to the claim that neuronal Vps35 deletion elevates APOE in mouse CSF. The Results describe a CSF proteomic screen in neuronal-selective Vps35 knockout mice, but the reported elevations concern proteins including APLP1, CHL1, and tau; searches for APOE and apolipoprotein E found no passage reporting an APOE increase. The hippocampal and glial-activation claims are attributed to a different citation. (LLM, conf=0.76)
Experimental — accuracy not yet measured
VPS35 is selectively depleted in forebrain and hippocampal neurons in VPS35 nsKO mice.
“we generated VPS35 nsKO mice (Figure 1A), in whom VPS35 is selectively depleted in forebrain and hippocampal neurons (Simoes et al., 2020).”
From The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease (2022) · cites this paper as Simoes et al., 2020
The authors previously developed a mouse model in which VPS35 is genetically depleted selectively in hippocampal and forebrain neurons, allowing survival into adulthood.
“we have recently developed a mouse model in which VPS35 is genetically depleted selectively in hippocampal and forebrain neurons, allowing survival into adulthood (Simoes et al., 2020).”
From The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease (2022) · cites this paper as Simoes et al., 2020
In a previous proteomic screen of CSF from VPS35 nsKO mice, the neuronal retromer can phenocopy the accelerated secretion component of tau pathology.
“In a previous proteomic screen of the CSF of VPS35 nsKO mice (Simoes et al., 2020), we found that the neuronal retromer can phenocopy the accelerated secretion component of tau pathology.”
From The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease (2022) · cites this paper as Simoes et al., 2020
At the age when initial microglia changes are observed in the hippocampus of VPS35 nsKO mice, there is no evidence of neuronal cell death.
“We have previously found that at the age that we observe initial microglia changes in the hippocampus of VPS35 nsKO mice, there is no evidence of neuronal cell death (Simoes et al., 2020)”
From The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease (2022) · cites this paper as Simoes et al., 2020
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Citations
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Metadata
- Authors
- Simoes, S., Neufeld, J. L., Triana-Baltzer, G., Moughadam, S., Chen, E. I., Kothiya, M., Qureshi, Y. H., Patel, V., Honig, L. S., Kolb, H., & Small, S. A.
- Venue
- Science Translational Medicine
- Published
- 2020-11-25
- Volume
- 12
- Issue
- 571
- ISSN
- 1946-6234
- 1946-6242
- PMC
- PMC7901670
- Cited by
- 51
- References
- 12
- Language
- en
- Funders
- National Institutes of Health (R01AG034618, R01AG035015, P50AG008702)
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