Pathways underlying selective neuronal vulnerability in Alzheimer's disease: Contrasting the vulnerable locus coeruleus to the resilient substantia nigra

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2025-03-26 DOI:10.1002/alz.70087

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

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引用次数: 0

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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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

期刊介绍： Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.