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Dysfunction of the retromer complex system contributes to amyloid and tau pathology in a stem cell model of Down syndrome
Abstract
Introduction: Retromer complex proteins are decreased in Down syndrome (DS) brains and correlate inversely with brain amyloidosis. However, whether retromer dysfunction contributes to the amyloid beta (Aβ) and tau neuropathology of DS remains unknown. Methods: Human trisomic induced Pluripotent Stem Cells (iPSCs) and isogenic controls were differentiated into forebrain neurons, and changes in retromer proteins, tau phosphorylated epitopes, and Aβ levels were assessed in euploid and trisomic neurons using western blot and enzyme‐linked immunosorbent assay (ELISA). Genetic overexpression and pharmacological retromer stabilization were used to determine the functional role of the retromer complex system in modulating amyloid and tau pathology. Results: Trisomic neurons developed age‐dependent retromer core protein deficiency associated with accumulation of Aβ peptides and phosphorylated tau isoforms. Enhancing retromer function through overexpression or pharmacological retromer stabilization reduced amyloid and tau pathology in trisomic neurons. However, the effect was greater using a pharmacological approach, suggesting that targeting the complex stability may be more effective in addressing this neuropathology in DS. Discussion: Our results demonstrate that the retromer complex is directly involved in the development of the neuropathologic phenotype in DS, and that pharmacological stabilization of the complex should be considered as a novel therapeutic tool in people with DS.
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In vitro enhancement of retromer complex function significantly reduces classical Alzheimer's disease-like pathology measures in Down syndrome iPSC-derived neurons.
“Furthermore, we demonstrated that in vitro enhancement of retromer complex function significantly reduces classical AD-like pathology measures in DS iPSC-derived neurons [9].”
From Retromer Stabilization Improves Cognitive Function and Synaptic Plasticity in a Mouse Model of Down Syndrome (2023) · cites this paper as [9]
Retromer complex proteins are reduced in induced pluripotent stem cell (iPSC)-derived neurons from subjects with Down syndrome.
“We previously showed that the retromer complex proteins are also reduced in postmortem brain tissues and induced pluripotent stem cell (iPSC) derived neurons from subjects with DS [9, 10].”
From Retromer Stabilization Improves Cognitive Function and Synaptic Plasticity in a Mouse Model of Down Syndrome (2023) · cites this paper as [9]
TPT-172 stabilizes the retromer complex by increasing stability of the VPS35-VPS29 binding domain and protecting the VPS35-VPS26-VPS29 recognition core from denaturation.
“TPT-172, which is known to stabilize the retromer complex protein [9]. Thus, this molecule enhances retromer complex function by increasing stability of the VPS35-VPS29 binding domain, the weakest link of the VPS35-VPS26-VPS29 heterotrimer, and consequently protecting the recognition core from denaturation [9,16].”
From Retromer Stabilization Improves Cognitive Function and Synaptic Plasticity in a Mouse Model of Down Syndrome (2023) · cites this paper as [9]
Retromer complex protein levels inversely correlate with Alzheimer's disease-like neuropathology in Down syndrome subjects.
“Retromer complex proteins are decreased in postmortem brain tissues from Down syndrome subjects and inversely correlate with the Alzheimer’s disease-like neuropathology.”
From Retromer Stabilization Improves Cognitive Function and Synaptic Plasticity in a Mouse Model of Down Syndrome (2023) · cites this paper as [9]
Retromer complex proteins are decreased in postmortem brain tissues from Down syndrome subjects.
“Retromer complex proteins are decreased in postmortem brain tissues from Down syndrome subjects and inversely correlate with the Alzheimer’s disease-like neuropathology.”
From Retromer Stabilization Improves Cognitive Function and Synaptic Plasticity in a Mouse Model of Down Syndrome (2023) · cites this paper as [9]
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Retromer: A Master Conductor of Endosome Sorting
Burd, C., & Cullen, P. J. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a016774 · Cited by 435
VPS35 haploinsufficiency increases Alzheimer’s disease neuropathology
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., et al. (2011) · Journal of Cell Biology · doi:10.1083/jcb.201105109 · Cited by 270
Trisomy of human chromosome 21 enhances amyloid-β deposition independently of an extra copy of APP
Wiseman, F. K., Pulford, L. J., Barkus, C., Liao, F., Portelius, E., Webb, R., Chávez-Gutiérrez, L., Cleverley, K., Noy, S., Sheppard, O., et al. (2018) · Brain · doi:10.1093/brain/awy159 · Cited by 133
Retromer stabilization results in neuroprotection in a model of Amyotrophic Lateral Sclerosis
Muzio, L., Sirtori, R., Gornati, D., Eleuteri, S., Fossaghi, A., Brancaccio, D., Manzoni, L., Ottoboni, L., Feo, L. D., Quattrini, A., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17524-7 · Cited by 65
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Curtis, M. E., Smith, T., Nenov, M., Blass, B. E., & Praticò, D. (2023) · Journal of Alzheimer's Disease · doi:10.3233/jad-230205 · Cited by 3
Self-citation
Metadata
- Authors
- Curtis, M. E., Smith, T., Blass, B. E., & Praticò, D.
- Affiliations
- Alzheimer's Center at Temple Lewis Katz School of Medicine Temple University Philadelphia Pennsylvania USA
- School of Pharmacy Temple University Philadelphia Pennsylvania USA
- Venue
- Alzheimer's & Dementia: Translational Research & Clinical Interventions
- Publisher
- Wiley
- Published
- 2022-01
- Volume
- 8
- Issue
- 1
- ISSN
- 2352-8737
- PMC
- PMC9322819
- Cited by
- 4
- References
- 4
- Language
- en
- Funders
- National Institutes of Health (AG055707, AG056689)
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