Distinct brain regional proteome changes in the rTg-DI rat model of cerebral amyloid angiopathy
Joseph M Schrader1, Feng Xu1, William E Van Nostrand1
1Department of Biomedical and Pharmaceutical Sciences, George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, USA.
Insights
Cerebral amyloid angiopathy (CAA) proteomic changes vary by brain region in rats. The thalamus shows unique thrombotic events, suggesting distinct pathogenic mechanisms in this neurodegenerative disease model.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Cerebral amyloid angiopathy (CAA) is a common small vessel disease in the elderly, linked to Alzheimer's disease.
- CAA involves amyloid accumulation in cerebral vessels, leading to stroke, microbleeds, and cognitive impairment.
- Understanding regional proteome changes in CAA is crucial for identifying disease mechanisms.
Purpose of the Study:
- To investigate region-specific proteome alterations in a preclinical model of CAA (rTg-DI rats).
- To correlate proteomic changes with distinct pathological features across different brain regions.
- To identify molecular pathways involved in regional CAA pathologies.
Main Methods:
- Proteomic analysis using SWATHLC-MS/MS on isolated brain regions of rTg-DI rats.
- Pathway analysis to identify significantly altered molecular pathways.
- Comparison of proteomic profiles across brain regions with varying CAA severity and pathology.
Main Results:
- Microvascular amyloid and neuroinflammation were widespread, but microbleeds and vessel occlusion were concentrated in the thalamus.
- Common pathway activations across regions included TNFα, abnormal nervous system morphology, and neutrophil degranulation.
- The hippocampus and thalamus showed TGF-β1 activation, while the thalamus uniquely displayed thrombin activation and blood cell aggregation.
Conclusions:
- Distinct brain regions in the rTg-DI rat model exhibit unique proteomic signatures associated with differential CAA pathologies.
- These findings provide new insights into the regional pathogenic mechanisms of CAA.
- Identifying region-specific pathways may reveal novel therapeutic targets for CAA-related cognitive decline.
Abstract:
Cerebral amyloid angiopathy (CAA), a prevalent cerebral small vessel disease in the elderly and a common comorbidity of Alzheimer's disease, is characterized by cerebral vascular amyloid accumulation, cerebral infarction, microbleeds, and intracerebral hemorrhages and is a prominent contributor to vascular cognitive impairment and dementia. Here, we investigate proteome changes associated with specific pathological features in several brain regions of rTg-DI rats, a preclinical model of CAA. Whereas varying degrees of microvascular amyloid and associated neuroinflammation are found in several brain regions, the presence of microbleeds and occluded small vessels is largely restricted to the thalamic region of rTg-DI rats, indicating different levels of CAA and associated pathologies occur in distinct brain regions in this model. Here, using SWATHLC-MS/MS, we report specific proteomic analysis of isolated brain regions and employ pathway analysis to correlate regionally specific proteomic changes with uniquely implicated molecular pathways. Pathway analysis suggested common activation of tumor necrosis factor α (TNFα), abnormal nervous system morphology, and neutrophil degranulation in all three regions. Activation of transforming growth factor-β1 (TGF-β1) was common to the hippocampus and thalamus, which share high CAA loads, while the thalamus, which uniquely exhibits thrombotic events, additionally displayed activation of thrombin and aggregation of blood cells. Thus, we present significant and new insight into the cerebral proteome changes found in distinct brain regions with differential CAA-related pathologies of rTg-DI rats and provide new information on potential pathogenic mechanisms associated with these regional disease processes.
