Abstract
INTRODUCTION
Alzheimer’s disease (AD) selectively affects certain brain regions, yet the mechanisms of selective vulnerability remain poorly understood. The neuromodulatory subcortical system, which includes nuclei exhibiting a range of vulnerability and resilience to AD-type degeneration, presents a framework for uncovering these mechanisms.
METHODS
We leveraged transcriptomics and immunohistochemistry in paired samples from human post mortem tissue representing a vulnerable and resilient region—the locus coeruleus (LC) and substantia nigra (SN). These regions have comparable anatomical features but distinct vulnerability to AD.
RESULTS
We identified significant differences in cholesterol homeostasis, antioxidant pathways, KRAS signaling, and estrogen signaling at a bulk transcriptomic level. Notably, evidence of sigma-2 receptor upregulation was detected in the LC.
DISCUSSION
Our findings highlight pathways differentiating the LC and SN, potentially explaining the LC’s selective vulnerability in AD. Such pathways offer potential targets of disease-modifying therapies for AD.
Highlights
Intraindividual comparative RNAseq was used to study selective vulnerability.
Metallothionein genes are significantly enriched in the substantia nigra.
Cholesterol homeostatic genes are significantly enriched in the locus coeruleus.
The locus coeruleus is likely more susceptible to toxic amyloid beta oligomers.
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This post is Copyright: Alexander J. Ehrenberg,
Cathrine Sant,
Felipe L. Pereira,
Song Hua Li,
Jessica Buxton,
Sonali Langlois,
Marena Trinidad,
Ian Oh,
Renata Elaine Paraizo Leite,
Roberta Diehl Rodriguez,
Vitor Ribeiro Paes,
Carlos Agusto Pasqualucci,
William W. Seeley,
Salvatore Spina,
Claudia K. Suemoto,
Sally Temple,
Daniela Kaufer,
Lea T. Grinberg | March 26, 2025