Frontal cortex pyramidal neuron expression profiles differentiate the prodromal stage from progressive degeneration across the Alzheimer's disease spectrum Journal Article
| Authors: | Labuza, A.; Alldred, M. J.; Pidikiti, H.; Malek-Ahmadi, M. H.; Lee, S. H.; Heguy, A.; Coleman, P. D.; Chakrabarty, S.; Chiosis, G.; Mufson, E. J.; Ginsberg, S. D. |
| Article Title: | Frontal cortex pyramidal neuron expression profiles differentiate the prodromal stage from progressive degeneration across the Alzheimer's disease spectrum |
| Abstract: | INTRODUCTION: Underlying causes of Alzheimer's disease (AD) remain unknown, making it imperative to identify molecular mechanisms driving the pathobiology of AD onset and progression. METHODS: Laser capture microdissection was used to isolate layer III pyramidal neurons from post mortem human prefrontal cortex (Brodmann area 9). Single population RNA sequencing was conducted using tissue from subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. Differentially expressed genes (DEGs) were compared across groups. RESULTS: DEGs increased from prodromal (MCI vs. NCI) to progression (AD vs. MCI) to frank AD (AD vs. NCI). The majority of DEGs and pathways shared between prodromal and progression exhibited a change in the direction of dysregulation unlike pathways between progression and frank AD. DISCUSSION: Candidate genes and pathways were identified that demarcate early-stage AD onset from AD progression, providing a roadmap to study cortical cellular vulnerability and key targets for intervention at early stages of AD. Highlights: Pyramidal neuron differentially expressed genes (DEGs) are directionally divergent between prodromal, progression, and frank Alzheimer's disease (AD). Pyramidal neuron DEGs are directionally convergent between progression and frank AD. Dysfunctional bioenergetic pathways increased dysregulation as the AD spectrum progressed. Immune response pathways were more dysregulated in frank AD than prodromal stages. DEGs, = biological pathways, and interactomes demarcate specific stages across the AD spectrum. © 2025 Elsevier B.V., All rights reserved. |
| Keywords: | clinical article; controlled study; human tissue; aged; aged, 80 and over; genetics; comparative study; t lymphocyte; metabolism; gene expression; cell differentiation; pathology; endothelium cell; disease progression; down regulation; cognitive defect; upregulation; frontal lobe; bioinformatics; nerve cell; disease exacerbation; alzheimer disease; neuropathology; amyloid precursor protein; frontal cortex; mild cognitive impairment; n methyl dextro aspartic acid receptor; prefrontal cortex; microglia; laser capture microdissection; brain tissue; gene ontology; pyramidal nerve cell; cognitive dysfunction; phospholipase c; pyramidal cells; pyramidal neurons; very elderly; humans; human; male; female; article; rna sequencing; oligodendrocyte precursor cell; differential gene expression; multidimensional scaling; selective vulnerability; kegg; postmortem interval; pathway enrichment analysis; alzheimer's disease spectrum; brodmann area 9; prodromal symptom; prodromal symptoms |
| Journal Title: | Alzheimer's and Dementia |
| Volume: | 21 |
| Issue: | 7 |
| ISSN: | 1552-5260 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2025-07-01 |
| Start Page: | e70395 |
| Language: | English |
| DOI: | 10.1002/alz.70395 |
| PUBMED: | 40709510 |
| PROVIDER: | scopus |
| PMCID: | PMC12290489 |
| DOI/URL: | |
| Notes: | Source: Scopus |
