Tgf Beta Pathway Deregulation And Abnormal Phospho-Smad2/3 Staining In Hereditary Cerebral Hemorrhage With Amyloidosis-Dutch Type

Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is an early onset hereditary form of cerebral amyloid angiopathy (CAA) pathology, caused by the E22Q mutation in the amyloid beta (A beta) peptide. Transforming growth factor beta 1 (TGF beta 1) is a key player in vascular fibrosis and in the formation of angiopathic vessels in transgenic mice. Therefore, we investigated whether the TGF beta pathway is involved in HCHWA-D pathogenesis in human postmortem brain tissue from frontal and occipital lobes. Components of the TGF pathway were analyzed with quantitative RT-PCR. TGF beta 1 and TGF beta Receptor 2 (TGFBR2) gene expression levels were significantly increased in HCHWA-D in comparison to the controls, in both frontal and occipital lobes. TGF beta-induced pro-fibrotic target genes were also upregulated. We further assessed pathway activation by detecting phospho-SMAD2/3 (pSMAD2/3), a direct TGF beta down-stream signaling mediator, using immunohistochemistry. We found abnormal pSMAD2/3 granular deposits specifically on HCHWA-D angiopathic frontal and occipital vessels. We graded pSMAD2/3 accumulation in angiopathic vessels and found a positive correlation with the CAA load independent of the brain area. We also observed pSMAD2/3 granules in a halo surrounding occipital vessels, which was specific for HCHWA-D. The result of this study indicates an upregulation of TGF beta 1 in HCHWA-D, as was found previously in AD with CAA pathology. We discuss the possible origins and implications of the TGF beta pathway deregulation in the microvasculature in HCHWA-D. These findings identify the TGF beta pathway as a potential biomarker of disease progression and a possible target of therapeutic intervention in HCHWA-D.