Emergent White Matter Degeneration in the rTg-DI Rat Model of Cerebral Amyloid Angiopathy Exhibits Unique Proteomic Changes

Schrader, Joseph M.; Xu, Feng; Lee, Hedok; Barlock, Benjamin J.; Benveniste, Helene; Nostrand, William E. Van

doi:10.1016/j.ajpath.2021.11.010

Cited by 6 publications

(12 citation statements)

References 73 publications

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“…5 b). This is not entirely surprising, as many of the proteins we reported with reduced expression in the 12 M cortex and hippocampus are linked to neurodegeneration and WM damage 20 , 21 , pathologies not yet observed in the emergent-stage 4 M animals 18 , 21 . However, the proteins longitudinally reduced in the thalamus may provide mechanistic insight to the distinctive pathologies emerging there, and are listed in Fig.…”

Section: Resultssupporting

confidence: 53%

“…We previously demonstrated early onset and age-dependent accumulation of microvascular amyloid in several brain regions of the rTg-DI rat model, beginning at ≈3 M 16 , 17 , 20 , 21 . At each stage of disease, the presence of microvascular CAA occurs in the thalamus > hippocampus > cortex, although at 12 M all regions display moderate/severe microvascular Aβ accumulation 16 , 17 , 20 .…”

Section: Resultsmentioning

confidence: 93%

“…Earlier, we conducted brain regional proteomic analysis of rTg-DI rats with late stage disease (12 M) and identified numerous differentially expressed proteins (DEPs) in the cortex, hippocampus, thalamus, and corpus callosum regions 20 , 21 . More recently, we performed comparative proteomic analysis of the rTg-DI rat brain with the spontaneously hypertensive stroke-prone (SHR-SP) rats 22 , a well characterized non-amyloidal CSVD model of chronic hypertension 23 – 25 , and identified DEPs distinguishing the rTg-DI CAA model from the SHR-SP hypertensive model.…”

Section: Introductionmentioning

confidence: 99%

“…More recently, we performed comparative proteomic analysis of the rTg-DI rat brain with the spontaneously hypertensive stroke-prone (SHR-SP) rats 22 , a well characterized non-amyloidal CSVD model of chronic hypertension 23 – 25 , and identified DEPs distinguishing the rTg-DI CAA model from the SHR-SP hypertensive model. At 12 M the rTg-DI rats exhibits extensive capillary amyloid deposition, strong CAA-ri, and numerous vessel occlusions and microbleeds, and therefore represent late stages of CAA when neuroimaging characteristics are apparent 16 , 18 , 20 , 21 . Since useful diagnosis requires biomarkers detectable in early disease stages, the potential of previously identified rTg-DI DEPs as biomarkers requires further investigation in earlier disease stages.…”

Section: Introductionmentioning

confidence: 99%

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Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats

Schrader,

Xu,

Agostinucci

et al. 2024

Sci Rep

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Cerebral amyloid angiopathy (CAA) is a prevalent vascular dementia and common comorbidity of Alzheimer’s disease (AD). While it is known that vascular fibrillar amyloid β (Aβ) deposits leads to vascular deterioration and can drive parenchymal CAA related inflammation (CAA-ri), underlying mechanisms of CAA pathology remain poorly understood. Here, we conducted brain regional proteomic analysis of early and late disease stages in the rTg-DI CAA rat model to gain molecular insight to mechanisms of CAA/CAA-ri progression and identify potential brain protein markers of CAA/CAA-ri. Longitudinal brain regional proteomic analysis revealed increased differentially expressed proteins (DEP) including ANXA3, HTRA1, APOE, CST3, and CLU, shared between the cortex, hippocampus, and thalamus, at both stages of disease in rTg-DI rats. Subsequent pathway analysis indicated pathway enrichment and predicted activation of TGF-β1, which was confirmed by immunolabeling and ELISA. Further, we identified numerous CAA related DEPs associate with astrocytes (HSPB1 and MLC1) and microglia (ANXA3, SPARC, TGF-β1) not previously associated with astrocytes or microglia in other AD models, possibly indicating that they are specific to CAA-ri. Thus, the data presented here identify several potential brain protein biomarkers of CAA/CAA-ri while providing novel molecular and mechanistic insight to mechanisms of CAA and CAA-ri pathological progression and glial cell mediated responses.

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Section: Resultssupporting

confidence: 53%

Section: Resultsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats

Schrader,

Xu,

Agostinucci

et al. 2024

Sci Rep

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“…Among these candidates, increased levels of CSF cathepsin B (CTSB), cathepsin S (CTSS), and hexosaminidase B (HEXB) were observed. These proteases were also previously identified as upregulated in cerebrovascular tissue of rTg-DI rats (6–8).…”

Section: Introductionmentioning

confidence: 68%

Translational validation of shotgun proteomics findings in cerebrospinal fluid of sporadic cerebral amyloid angiopathy patients

Vervuurt,

de Kort,

Kersten

et al. 2024

Preprint

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Background: Prior research conducted in model rats of CAA Type 1 (rTg-DI) identified a range of cerebrospinal fluid biomarker candidates associated with sCAA pathology. This list of potential biomarkers includes the lysosomal proteases cathepsins B and S (CTSB/CTSS) and hexosaminidase B (HEXB). It is yet unknown if these findings obtained in rTg-DI rats translate to differential protein levels and/or enzyme activities in cerebrospinal fluid (CSF) of sCAA patients. In this study, we attempted to validate CTSB, CTSS and HEXB in CSF as potential biomarkers for sCAA in a human population. Materials and methods: We have included sCAA patients (n = 34) and control participants (n = 27) from our BIONIC/CAFE cohort. We analysed the CSF of these participants with ELISA for protein levels of CTSB and CTSS. Additionally, we used in-house enzyme assays to determine activity levels of total hexosaminidase and hexosaminidase A (HEXA) in CSF. The proportion of HEXA activity to total HEX activity was used as a proxy for HEXB activity. Results: CSF CTSB and CTSS protein levels were not significantly different between sCAA and controls (p = 0.21 and p = 0.34). Total HEX activity was unaltered as well (p = 0.11), whereas a significant decrease was observed in HEXA activity levels (p = 0.05). HEXA / total HEX activity levels (as a proxy for HEXB activity) were unaltered between sCAA patients and controls (p = 0.19). Additionally, CTSB and CTSS protein levels positively associated with total HEX activity (rsp = 0.37, p = 0.005; rsp = 0.40, p = 0.003). Conclusion: The contrasting results between biomarker discovery in rats and validation in human participants highlight the challenges and complexities of biomarker research. These findings offer valuable insights into the nuances of disease and the difficulties in translating laboratory findings using animal models to clinical practice. Understanding these discrepancies is essential for improving the precision of biomarker translation, ensuring clinical relevance, and developing comprehensive biomarker panels for CAA and related conditions.

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Divergent brain solute clearance in rat models of cerebral amyloid angiopathy and Alzheimer’s disease

Koundal,

Chen,

Gursky

et al. 2024

iScience

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Emergent White Matter Degeneration in the rTg-DI Rat Model of Cerebral Amyloid Angiopathy Exhibits Unique Proteomic Changes

Cited by 6 publications

References 73 publications

Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats

Longitudinal markers of cerebral amyloid angiopathy and related inflammation in rTg-DI rats

Translational validation of shotgun proteomics findings in cerebrospinal fluid of sporadic cerebral amyloid angiopathy patients

Divergent brain solute clearance in rat models of cerebral amyloid angiopathy and Alzheimer’s disease

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