Journal article
Spatial differences in gene expression across the dorsal raphe nucleus in a model of early Alzheimer's disease
Journal of Alzheimer's disease, Vol.103(1), pp.133-148
01/2025
DOI: 10.1177/13872877241299119
PMCID: PMC12047055
PMID: 39584353
Abstract
Persons with Alzheimer's disease (AD) present with changes in mood, sleep, and arousal that may precede the clinical manifestation of cognitive decline. These early symptoms can be driven by changes in the serotonergic (5-HT) nuclei of the brainstem, particularly the dorsal raphe nucleus (DRN). It is unclear why all 5-HT neurons do not simultaneously develop AD pathology that progresses at the same rate.
We sought to identify any underlying genetic components associated with susceptibility or resistance of 5-HT neurons to AD pathology.
The Visium Spatial Gene Expression platform was used to identify transcriptomic changes across the DRN in a preclinical model of early AD, human tau-overexpressing mice (htau mice). We further used RNAscope and immunohistochemical assessment to validate findings of primary interest.
We find that the DRN of htau mice differentially expresses AD-related genes, including those related to kinase binding, ion channel activity, ligand-receptor interactions, and regulation of serine/threonine kinases. We further find that computational sub-clustering of the DRN is consistent with previous circuitry-driven characterizations, allowing for spatial bounding of distinct subregions within the DRN. Of these, we find the dorsolateral DRN is preferentially impacted by 5-HT neuron loss and development of tau pathology, which coincides with increased expression of the long noncoding RNA
.
may serve regulatory roles relevant for tau phosphorylation and warrants further investigation to characterize its interactions. Overall, this report demonstrates the power of large-scale spatial transcriptomics technologies, while underscoring the need for convergent-data validation to overcome their limitations.
Details
- Title: Subtitle
- Spatial differences in gene expression across the dorsal raphe nucleus in a model of early Alzheimer's disease
- Creators
- Louis J Kolling - University of IowaMichael S Chimenti - University of IowaCatherine A Marcinkiewcz - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Journal of Alzheimer's disease, Vol.103(1), pp.133-148
- DOI
- 10.1177/13872877241299119
- PMID
- 39584353
- PMCID
- PMC12047055
- NLM abbreviation
- J Alzheimers Dis
- ISSN
- 1387-2877
- eISSN
- 1875-8908
- Publisher
- SAGE PUBLICATIONS LTD
- Grant note
- National Institute on Aging
We thank Mr Tien Tran and Mrs. Yu Xu for excellent technical assistance and help with mouse husbandry. We also thank Dr Queena Lin of the Iowa Neurobank Core for her helpful discussions and administrative oversight of the Visium reaction.
- Language
- English
- Electronic publication date
- 11/25/2024
- Date published
- 01/2025
- Academic Unit
- Iowa Neuroscience Institute; Neuroscience and Pharmacology; Iowa Institute of Human Genetics
- Record Identifier
- 9984752554702771
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