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Hippocampal transcriptome-wide association study and pathway analysis of mitochondrial solute carriers in Alzheimer's disease.
Tian, Jing; Jia, Kun; Wang, Tienju; Guo, Lan; Xuan, Zhenyu; Michaelis, Elias K; Swerdlow, Russell H; Du, Heng.
Afiliación
  • Tian J; Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA.
  • Jia K; Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA.
  • Wang T; Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA.
  • Guo L; Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA.
  • Xuan Z; Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA.
  • Michaelis EK; Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, USA.
  • Swerdlow RH; Alzheimer's Disease Research Center, University of Kansas Medical Center, Kansas City, KS, USA.
  • Du H; Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS, USA. heng.du@ku.edu.
Transl Psychiatry ; 14(1): 250, 2024 Jun 10.
Article en En | MEDLINE | ID: mdl-38858380
ABSTRACT
The etiopathogenesis of late-onset Alzheimer's disease (AD) is increasingly recognized as the result of the combination of the aging process, toxic proteins, brain dysmetabolism, and genetic risks. Although the role of mitochondrial dysfunction in the pathogenesis of AD has been well-appreciated, the interaction between mitochondrial function and genetic variability in promoting dementia is still poorly understood. In this study, by tissue-specific transcriptome-wide association study (TWAS) and further meta-analysis, we examined the genetic association between mitochondrial solute carrier family (SLC25) genes and AD in three independent cohorts and identified three AD-susceptibility genes, including SLC25A10, SLC25A17, and SLC25A22. Integrative analysis using neuroimaging data and hippocampal TWAS-predicted gene expression of the three susceptibility genes showed an inverse correlation of SLC25A22 with hippocampal atrophy rate in AD patients, which outweighed the impacts of sex, age, and apolipoprotein E4 (ApoE4). Furthermore, SLC25A22 downregulation demonstrated an association with AD onset, as compared with the other two transcriptome-wide significant genes. Pathway and network analysis related hippocampal SLC25A22 downregulation to defects in neuronal function and development, echoing the enrichment of SLC25A22 expression in human glutamatergic neurons. The most parsimonious interpretation of the results is that we have identified AD-susceptibility genes in the SLC25 family through the prediction of hippocampal gene expression. Moreover, our findings mechanistically yield insight into the mitochondrial cascade hypothesis of AD and pave the way for the future development of diagnostic tools for the early prevention of AD from a perspective of precision medicine by targeting the mitochondria-related genes.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Alzheimer / Transcriptoma / Hipocampo Límite: Aged / Aged80 / Female / Humans / Male Idioma: En Revista: Transl Psychiatry Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Alzheimer / Transcriptoma / Hipocampo Límite: Aged / Aged80 / Female / Humans / Male Idioma: En Revista: Transl Psychiatry Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos