Elevated protease-activated receptor 4 (PAR4) gene expression in Alzheimer's disease predicts cognitive decline
Rebecca L Winfree1, Kevin Erreger2, Jared Phillips3
1Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA.
Abstract:
Platelet activation of protease-activated receptor 4 (PAR4) and thrombin are at the top of a chain of events leading to fibrin deposition, microinfarcts, blood-brain barrier disruption, and inflammation. We evaluated mRNA expression of the PAR4 gene F2RL3 in human brain and global cognitive performance in participants with and without cognitive impairment or dementia. Data were acquired from the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). F2RL3 mRNA was elevated in AD cases and was associated with worse retrospective longitudinal cognitive performance. Moreover, F2RL3 expression interacted with clinical AD diagnosis on longitudinal cognition whereas this relationship was attenuated in individuals without cognitive impairment. Additionally, when adjusting for the effects of AD neuropathology, F2RL3 expression remained a significant predictor of cognitive decline. F2RL3 expression correlated positively with transcript levels of proinflammatory markers including TNFα, IL-1β, NFκB, and fibrinogen α/β/γ. Together, these results reveal that F2RL3 mRNA expression is associated with multiple AD-relevant outcomes and its encoded product, PAR4, may play a role in disease pathogenesis.
Insights
Elevated F2RL3 mRNA, linked to protease-activated receptor 4 (PAR4), indicates higher Alzheimer's disease (AD) risk and cognitive decline. This gene expression correlates with inflammation and predicts worsening cognition, even after accounting for AD pathology.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- Platelet activation via protease-activated receptor 4 (PAR4) and thrombin initiates cascades leading to fibrin deposition, microinfarcts, blood-brain barrier disruption, and inflammation.
- Alzheimer's disease (AD) pathogenesis involves complex inflammatory and vascular processes.
Purpose of the Study:
- To investigate the association between the mRNA expression of the PAR4 gene F2RL3 and cognitive performance in individuals with and without cognitive impairment or dementia.
- To explore the relationship between F2RL3 expression, AD neuropathology, and pro-inflammatory markers.
Main Methods:
- Analysis of F2RL3 mRNA expression in human brain tissue from participants in the Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP).
- Evaluation of global cognitive performance and correlation of F2RL3 expression with clinical AD diagnosis, neuropathology, and transcript levels of inflammatory markers (TNFα, IL-1β, NFκB, fibrinogen).
Main Results:
- F2RL3 mRNA expression was elevated in Alzheimer's disease (AD) cases.
- Higher F2RL3 expression was associated with worse longitudinal cognitive performance and predicted cognitive decline, independent of AD neuropathology.
- F2RL3 expression positively correlated with transcript levels of pro-inflammatory markers and fibrinogen.
Conclusions:
- F2RL3 mRNA expression is significantly associated with multiple AD-relevant outcomes, including cognitive decline and inflammation.
- The encoded product of F2RL3, PAR4, may play a crucial role in the pathogenesis of Alzheimer's disease.
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