Altered Gene Expression Within the Renin-Angiotensin System in Normal Aging and Dementia
Hannah M Tayler1, Robert MacLachlan1, Özge Güzel1
1Dementia Research Group, Clinical Neurosciences, Bristol Medical School, University of Bristol, Bristol, UK.
Summary
Age-related imbalances in the brain renin-angiotensin system (RAS) may trigger Alzheimer's disease (AD) dysregulation. This study found altered RAS gene expression in normal aging and dementia, suggesting a link between RAS and neurodegenerative diseases.
Area of Science:
- Neuroscience
- Genetics
- Aging Research
Background:
- The renin-angiotensin system (RAS) plays a crucial role in cardiovascular and brain functions.
- Dysregulation of the brain RAS is implicated in the pathophysiology of Alzheimer's disease (AD).
- Age-related changes in the brain RAS may contribute to AD pathogenesis.
Purpose of the Study:
- To investigate the hypothesis that age-related imbalances in the brain RAS trigger RAS dysregulation in AD.
- To characterize RAS gene expression patterns in normal aging and various dementia subtypes.
Main Methods:
- Quantitative PCR (qPCR) was used to measure the gene expression of key RAS components (ACE1, AGTR1, AGTR2, ACE2, LNPEP, MAS1).
- Gene expression was analyzed in the frontal cortex of normal aging individuals (n=99) and a dementia cohort (n=209) including AD, mixed dementia, and vascular dementia (VaD).
- Data were adjusted for reference and cell-specific genes and stratified by Braak tangle stage (BS) for AD and mixed dementia cohorts.
Main Results:
- In normal aging, ACE1, AGTR1, and AGTR2 gene expression were elevated, while protective RAS signaling markers (ACE2, MAS1, LNPEP) remained unchanged.
- In AD and mixed dementia, AGTR1 and AGTR2 expression increased with Braak stage, and MAS1 expression decreased at later stages, correlating inversely with amyloid-beta and tau load.
- LNPEP gene expression was specifically elevated in pure vascular dementia (VaD).
Conclusions:
- Age-related alterations in the brain RAS, particularly increases in ACE1 and AGTR1, may precede and contribute to AD development.
- Specific changes in RAS gene expression, such as reduced MAS1 and elevated LNPEP, are associated with different dementia pathologies.
- These findings provide novel insights into the role of RAS signaling in normal aging and the progression of neurodegenerative diseases.
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