Abstract
Cerebral amyloid angiopathy (CAA), characterized by cerebral vascular amyloid accumulation, neuroinflammation, microbleeds, and white matter (WM) degeneration, is a common comorbidity in Alzheimer disease and a prominent contributor to vascular cognitive impairment and dementia. WM loss was recently reported in the corpus callosum (CC) in the rTg-DI rat model of CAA. The current study shows that the CC exhibits a much lower CAA burden compared with the adjacent cortex. Sequential Window Acquisition of All Theoretical Mass Spectra tandem mass spectrometry was used to show specific proteomic changes in the CC with emerging WM loss and compare them with the proteome of adjacent cortical tissue in rTg-DI rats. In the CC, annexin A3, heat shock protein β1, and cystatin C were elevated at 4 months (M) before WM loss and at 12M with evident WM loss. Although annexin A3 and cystatin C were also enhanced in the cortex at 12M, annexin A5 and the leukodystrophy-associated astrocyte proteins megalencephalic leukoencephalopathy with subcortical cysts 1 and GlialCAM were distinctly elevated in the CC. Pathway analysis indicated neurodegeneration of axons, reflected by reduced expression of myelin and neurofilament proteins, was common to the CC and cortex; activation of Tgf-β1 and F2/thrombin was restricted to the CC. This study provides new insights into the proteomic changes that accompany WM loss in the CC of rTg-DI rats.
Highlights
From the George & Anne Ryan Institute for Neuroscience* and Department of Biomedical and Pharmaceutical Sciences,y University of Rhode Island, Kingston, Rhode Island; and the Department of Anesthesiology,z Yale University, New Haven, Connecticut
Window Acquisition of All Theoretical Mass Spectra liquid chromatography coupled with tandem mass spectrometry, we report specific proteomic changes in the corpus callosum (CC) with emerging white matter (WM) loss and compare them with the proteome of adjacent cortical tissue in rTg-DI rats
WM degeneration compared with WT controls as they age from 6M to approximately 12 months (12M) with advancing microvas[363] cular Cerebral amyloid angiopathy (CAA) burden
Summary
From the George & Anne Ryan Institute for Neuroscience* and Department of Biomedical and Pharmaceutical Sciences,y University of Rhode Island, Kingston, Rhode Island; and the Department of Anesthesiology,z Yale University, New Haven, Connecticut. Van Nostrand, Department of Biomedical and Pharmaceutical Sciences, George and Anne Ryan Institute for Neuroscience, University of Rhode Island, 130. We reported WM loss in the corpus callosum (CC) in the rTg-DI rat model of CAA. We show that the CC exhibits a much lower CAA burden compared with the adjacent cortex. Window Acquisition of All Theoretical Mass Spectra liquid chromatography coupled with tandem mass spectrometry, we report specific proteomic changes in the CC with emerging WM loss and compare them with the proteome of adjacent cortical tissue in rTg-DI rats. In the CC, annexin A3, heat shock protein b1, and cystatin C were elevated at 4 months (M) before WM loss and at 12M with evident WM loss
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