Frontiers in Neuroscience (Feb 2023)
Golgi fragmentation – One of the earliest organelle phenotypes in Alzheimer’s disease neurons
- Henriette Haukedal,
- Giulia I. Corsi,
- Giulia I. Corsi,
- Veerendra P. Gadekar,
- Veerendra P. Gadekar,
- Nadezhda T. Doncheva,
- Nadezhda T. Doncheva,
- Nadezhda T. Doncheva,
- Shekhar Kedia,
- Noortje de Haan,
- Abinaya Chandrasekaran,
- Pia Jensen,
- Pernille Schiønning,
- Sarah Vallin,
- Frederik Ravnkilde Marlet,
- Anna Poon,
- Carlota Pires,
- Fawzi Khoder Agha,
- Hans H. Wandall,
- Susanna Cirera,
- Anja Hviid Simonsen,
- Troels Tolstrup Nielsen,
- Jørgen Erik Nielsen,
- Poul Hyttel,
- Ravi Muddashetty,
- Blanca I. Aldana,
- Jan Gorodkin,
- Jan Gorodkin,
- Deepak Nair,
- Morten Meyer,
- Morten Meyer,
- Martin Røssel Larsen,
- Kristine Freude
Affiliations
- Henriette Haukedal
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
- Giulia I. Corsi
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
- Giulia I. Corsi
- Center for Non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg, Denmark
- Veerendra P. Gadekar
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
- Veerendra P. Gadekar
- Center for Non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg, Denmark
- Nadezhda T. Doncheva
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
- Nadezhda T. Doncheva
- Center for Non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg, Denmark
- Nadezhda T. Doncheva
- Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark
- Shekhar Kedia
- Centre for Neuroscience, Indian Institute of Science, Bengaluru, India
- Noortje de Haan
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Abinaya Chandrasekaran
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
- Pia Jensen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
- Pernille Schiønning
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
- Sarah Vallin
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
- Frederik Ravnkilde Marlet
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Anna Poon
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
- Carlota Pires
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
- Fawzi Khoder Agha
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Hans H. Wandall
- Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Susanna Cirera
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
- Anja Hviid Simonsen
- Danish Dementia Research Centre, Department of Neurology, Neuroscience Centre, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Troels Tolstrup Nielsen
- Danish Dementia Research Centre, Department of Neurology, Neuroscience Centre, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Jørgen Erik Nielsen
- Danish Dementia Research Centre, Department of Neurology, Neuroscience Centre, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Poul Hyttel
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
- Ravi Muddashetty
- Institute for Stem Cell Science and Regenerative Medicine, Bengaluru, India
- Blanca I. Aldana
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Jan Gorodkin
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
- Jan Gorodkin
- Center for Non-coding RNA in Technology and Health, University of Copenhagen, Frederiksberg, Denmark
- Deepak Nair
- Centre for Neuroscience, Indian Institute of Science, Bengaluru, India
- Morten Meyer
- 0Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
- Morten Meyer
- 1Department of Neurology, Odense University Hospital, Odense, Denmark
- Martin Røssel Larsen
- Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
- Kristine Freude
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
- DOI
- https://doi.org/10.3389/fnins.2023.1120086
- Journal volume & issue
-
Vol. 17
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia, with no current cure. Consequently, alternative approaches focusing on early pathological events in specific neuronal populations, besides targeting the well-studied amyloid beta (Aβ) accumulations and Tau tangles, are needed. In this study, we have investigated disease phenotypes specific to glutamatergic forebrain neurons and mapped the timeline of their occurrence, by implementing familial and sporadic human induced pluripotent stem cell models as well as the 5xFAD mouse model. We recapitulated characteristic late AD phenotypes, such as increased Aβ secretion and Tau hyperphosphorylation, as well as previously well documented mitochondrial and synaptic deficits. Intriguingly, we identified Golgi fragmentation as one of the earliest AD phenotypes, indicating potential impairments in protein processing and post-translational modifications. Computational analysis of RNA sequencing data revealed differentially expressed genes involved in glycosylation and glycan patterns, whilst total glycan profiling revealed minor glycosylation differences. This indicates general robustness of glycosylation besides the observed fragmented morphology. Importantly, we identified that genetic variants in Sortilin-related receptor 1 (SORL1) associated with AD could aggravate the Golgi fragmentation and subsequent glycosylation changes. In summary, we identified Golgi fragmentation as one of the earliest disease phenotypes in AD neurons in various in vivo and in vitro complementary disease models, which can be exacerbated via additional risk variants in SORL1.
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