TGFβ pathway deregulation and abnormal phospho-SMAD2/3 staining in hereditary cerebral hemorrhage with amyloidosis-Dutch type.

Laure Grand Moursel,Leon P Munting,Sjoerd G Van Duinen,Louise Van Der Weerd,Remco Natté,Uwe Ueberham,Willeke M C Van Roon‐Mom,Marie‐Jose T H Goumans,Mark A Van Buchem,Linda M Van Der Graaf

doi:10.1111/bpa.12533

Abstract

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 β (Aβ) peptide. Transforming growth factor β1 (TGFβ1) is a key player in vascular fibrosis and in the formation of angiopathic vessels in transgenic mice. Therefore, we investigated whether the TGFβ pathway is involved in HCHWA‐D pathogenesis in human postmortem brain tissue from frontal and occipital lobes. Components of the TGFβ pathway were analyzed with quantitative RT‐PCR. TGFβ1 and TGFβ Receptor 2 (TGFBR2) gene expression levels were significantly increased in HCHWA‐D in comparison to the controls, in both frontal and occipital lobes. TGFβ‐induced pro‐fibrotic target genes were also upregulated. We further assessed pathway activation by detecting phospho‐SMAD2/3 (pSMAD2/3), a direct TGFβ 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 TGFβ1 in HCHWA‐D, as was found previously in AD with CAA pathology. We discuss the possible origins and implications of the TGFβ pathway deregulation in the microvasculature in HCHWA‐D. These findings identify the TGFβ pathway as a potential biomarker of disease progression and a possible target of therapeutic intervention in HCHWA‐D.

Highlights

Sporadic cerebral amyloid angiopathy is a disease of the elderly due to amyloid b (Ab) deposition in cerebral leptomeningeal and cortical vessels, and is associated with intracerebral hemorrhages
Both frontal and occipital cortex were used in all studies, based on the assumption that the cerebral amyloid angiopathy (CAA) pathology seems more severe in the occipital lobes in Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) [23] which is expected to represent a more advanced disease stage compared with the frontal lobe. Sporadic cerebral amyloid angiopathy (sCAA) individuals were included to investigate whether the Dutch mutation in HCHWA-D results in a different effect on TGFb signaling compared to CAA pathology in general
We found an upregulation in gene expression of several components of the TGFb pathway and its direct downstream signaling targets as well as a strong correlation of pSMAD2/3 deposits with CAA load

Summary

Introduction

Sporadic cerebral amyloid angiopathy (sCAA) is a disease of the elderly due to amyloid b (Ab) deposition in cerebral leptomeningeal and cortical vessels, and is associated with intracerebral hemorrhages. Some earlier studies of HCHWA-D postmortem brain material have focused on Ab clearance and deposition in the vasculature by the induction and modification of extracellular matrix (ECM) proteins [15, 39]. In postmortem AD brain material, TGFb1 mRNA levels correlate positively with the extent of CAA pathology [47]. Mouse models of TGFb1 overexpression in astrocytes or neurons demonstrated that high TGFb1 levels lead to vascular fibrosis [36, 48]. Whether these animal models accumulate murine Ab in the CAA pathology-like vascular plaques remains controversial, Brain Pathology 28 (2018) 495–506

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