Haukedal, H and Corsi, GI and Gadekar, VP and Doncheva, NT and Kedia, S and de Haan, N and Chandrasekaran, A and Jensen, P and Schiønning, P and Vallin, S and Marlet, FR and Poon, A and Pires, C and Agha, FK and Wandall, HH and Cirera, S and Simonsen, AH and Nielsen, TT and Nielsen, JE and Hyttel, P and Muddashetty, R and Aldana, BI and Gorodkin, J and Nair, D and Meyer, M and Larsen, MR and Freude, K (2023) Golgi fragmentation - One of the earliest organelle phenotypes in Alzheimer's disease neurons. In: Frontiers in Neuroscience, 17 .
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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
| Item Type: | Journal Article |
|---|---|
| Publication: | Frontiers in Neuroscience |
| Publisher: | Frontiers Media S.A. |
| Additional Information: | The copyright for this article belongs to the Authors. |
| Keywords: | amyloid beta protein; glycan; sortilin; sortilin related receptor 1; tau protein; unclassified drug, 5xFAD mouse; Alzheimer disease; animal experiment; animal model; animal tissue; Article; cell structure; cellular distribution; computer model; controlled study; differential gene expression; gene; genetic association; genetic risk; genetic variability; Golgi complex; Golgi fragmentation; human; human cell; in vitro study; in vivo study; induced pluripotent stem cell; male; mitochondrion; mouse; nerve cell; nonhuman; pathogenesis; phenotype; protein fingerprinting; protein glycosylation; protein processing; RNA sequencing; SORL1 gene; synapse; synaptic density |
| Department/Centre: | Division of Biological Sciences > Centre for Neuroscience |
| Date Deposited: | 28 Mar 2023 08:53 |
| Last Modified: | 28 Mar 2023 08:53 |
| URI: | https://eprints.iisc.ac.in/id/eprint/81184 |
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