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Molecular profiling of frontal and occipital subcortical white matter hyperintensities in Alzheimer's disease
Sulochan Malla1,2, Annie G Bryant1,3, Rojashree Jayakumar1
1Department of Neurology, Massachusetts General Hospital, Charlestown, MA, USA.
Abstract:
White matter hyperintensities (WMHs) are commonly detected on T2-weighted magnetic resonance imaging (MRI) scans, occurring in both typical aging and Alzheimer's disease. Despite their frequent appearance and their association with cognitive decline, the molecular factors contributing to WMHs remain unclear. In this study, we investigated the transcriptomic profiles of two commonly affected brain regions with coincident AD pathology-frontal subcortical white matter (frontal-WM) and occipital subcortical white matter (occipital-WM)-and compared with age-matched healthy controls. Through RNA-sequencing in frontal- and occipital-WM bulk tissues, we identified an upregulation of genes associated with brain vasculature function in AD white matter. To further elucidate vasculature-specific transcriptomic features, we performed RNA-seq analysis on blood vessels isolated from these white matter regions, which revealed an upregulation of genes related to protein folding pathways. Finally, comparing gene expression profiles between AD individuals with high- versus low-WMH burden showed an increased expression of pathways associated with immune function. Taken together, our study characterizes the diverse molecular profiles of white matter changes in AD compared to normal aging and provides new mechanistic insights processes underlying AD-related WMHs.
Insights
Investigating white matter hyperintensities (WMH) in Alzheimer's disease (AD) reveals distinct molecular signatures. Our study uncovers key gene expression changes in AD white matter, offering new insights into disease mechanisms.
Area of Science:
- Neuroscience
- Genomics
- Biochemistry
Background:
- White matter hyperintensities (WMH) are common in aging and Alzheimer's disease (AD), linked to cognitive decline.
- The molecular drivers of WMH in AD remain largely unknown.
- Understanding these molecular changes is crucial for developing targeted therapies.
Purpose of the Study:
- To characterize the transcriptomic profiles of white matter in AD.
- To compare gene expression in frontal and occipital white matter between AD patients and healthy controls.
- To identify molecular pathways associated with WMH burden in AD.
Main Methods:
- RNA-sequencing of bulk white matter tissue from frontal and occipital regions.
- Isolation and RNA-sequencing of blood vessels from white matter.
- Differential gene expression analysis comparing AD and control groups, and high vs. low WMH burden groups.
Main Results:
- Upregulation of vasculature-associated genes in AD white matter.
- Upregulation of protein folding pathway genes in isolated white matter blood vessels.
- Increased expression of immune function pathways in AD individuals with higher WMH burden.
Conclusions:
- AD white matter exhibits unique transcriptomic alterations compared to normal aging.
- Specific pathways, including vascular, protein folding, and immune functions, are implicated in AD-related WMH.
- These findings provide novel mechanistic insights into AD pathogenesis and WMH development.
