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Distinct Brain Proteomic Signatures in Cerebral Small Vessel Disease Rat Models of Hypertension and Cerebral Amyloid

Joseph M Schrader1,2, Aleksandra Stanisavljevic1,2, Feng Xu1,2

  • 1From the George and Anne Ryan Institute for Neuroscience.

Journal of Neuropathology and Experimental Neurology
|July 20, 2022
PubMed

Insights

Cerebral small vessel diseases (CSVDs) have different molecular causes. Researchers found distinct protein changes in rat models of cerebral amyloid angiopathy (CAA) and hypertension (HTN), offering new insights into these conditions.

Area of Science:

  • Neuroscience
  • Vascular Biology
  • Proteomics

Background:

  • Cerebral small vessel diseases (CSVDs) contribute significantly to cognitive impairment and dementia.
  • Cerebral amyloid angiopathy (CAA) and hypertension (HTN) are common causes of CSVDs in the elderly, leading to various brain pathologies.
  • The specific molecular mechanisms underlying CAA and HTN-related CSVDs remain unclear.

Purpose of the Study:

  • To investigate and compare the distinct molecular events and protein signatures associated with different forms of CSVDs.
  • To elucidate the underlying mechanisms of cerebral microhemorrhages, macrohemorrhages, and white matter damage in CAA and HTN models.
  • To identify unique protein biomarkers for differentiating between CAA and HTN pathologies.

Main Methods:

  • Utilized transgenic rat models: rTg-DI for CAA type 1 and spontaneously hypertensive stroke-prone (SHR-SP) rats for HTN.
  • Performed comparative proteomics analysis to identify differentially expressed proteins between the two models.
  • Employed immunolabeling to validate protein expression and localization.
  • Conducted pathway analysis to predict affected signaling cascades.

Main Results:

  • rTg-DI rats showed perivascular inflammation, while SHR-SP rats exhibited arteriolar perivascular space dilation.
  • Proteomics revealed distinct protein profiles: ANXA3, H2A, and HTRA1 were unique to rTg-DI rats; Nt5e, Flot-1, and Flot-2 were unique to SHR-SP rats.
  • Upregulation of ANXA3, HTRA1, and neutrophil extracellular trap proteins was specific to rTg-DI rats.
  • Pathway analysis indicated TGF-β1 and TNFα activation in rTg-DI rats and reduced insulin signaling in SHR-SP rats.

Conclusions:

  • Reported divergent protein signatures in SHR-SP and rTg-DI rat models, highlighting distinct molecular underpinnings of their respective cerebral vessel pathologies.
  • Provided novel mechanistic insights into the different forms of CSVDs.
  • Identified potential protein biomarkers for distinguishing between CAA and HTN-induced brain damage.

Keywords:
Cerebral amyloid angiopathyExperimental rat modelsHypertensionProteomics

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