Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genomics
• Cell Biology

Background:

• Alzheimer's disease (AD) is increasingly linked to mitochondrial dysfunction and reactive oxygen species (ROS) impacting neuronal health.
• Mitochondrial-nuclear crosstalk and its role in cell-type-specific functions in AD are not well understood.

Purpose of the Study:

• To investigate cell-type-specific mitochondrial alterations and their impact on the nuclear transcriptome in Alzheimer's disease.
• To identify mitochondrial-nuclear gene signatures predictive of AD risk and explore sex-biased patterns.

Main Methods:

• Utilized the largest single-nucleus RNA sequencing dataset of AD (424 patients, healthy controls) from ROSMAP.
• Applied supervised latent factor modeling to analyze 5,427 nuclear and 13 mitochondrial genes across 6 major brain cell types.
• Screened over 1 million gene expression profiles from drug perturbations to identify predictive AD signatures.

Main Results:

• Nuclear-mitochondrial crosstalk varies by cell identity, with specific complexes (ATP synthase, NADH dehydrogenase) playing key roles in different cell types.
• Mitochondrial-nuclear signatures resembling those activated by parthenolide and niclosamide were most predictive of AD, particularly in microglia and OPCs, with higher accuracy in males.
• Clinical phenotyping revealed males with higher glial mitochondrial-nuclear scores had greater AD pathology, including amyloid load and Parkinson's-like symptoms.

Conclusions:

• Distinct transcriptional signatures of mitochondria-nuclear crosstalk are associated with AD risk in glial and neural cells.
• These associations exhibit significant sex-biased patterns, highlighting differential impacts in males and females.
• The findings provide insights into AD pathogenesis and potential therapeutic targets based on cell-type-specific mitochondrial responses.