Disturbed balance in the expression of MMP9 and TIMP3 in cerebral amyloid angiopathy-related intracerebral haemorrhage

Abstract

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of the amyloid β (Aβ) protein in the cerebral vasculature and poses a major risk factor for the development of intracerebral haemorrhages (ICH). However, only a minority of patients with CAA develops ICH (CAA-ICH), and to date it is unclear which mechanisms determine why some patients with CAA are more susceptible to haemorrhage than others. We hypothesized that an imbalance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) contributes to vessel wall weakening. MMP9 plays a role in the degradation of various components of the extracellular matrix as well as of Aβ and increased MMP9 expression has been previously associated with CAA. TIMP3 is an inhibitor of MMP9 and increased TIMP3 expression in cerebral vessels has also been associated with CAA. In this study, we investigated the expression of MMP9 and TIMP3 in occipital brain tissue of CAA-ICH cases (n = 11) by immunohistochemistry and compared this to the expression in brain tissue of CAA cases without ICH (CAA-non-haemorrhagic, CAA-NH, n = 18). We showed that MMP9 expression is increased in CAA-ICH cases compared to CAA-NH cases. Furthermore, we showed that TIMP3 expression is increased in CAA cases compared to controls without CAA, and that TIMP3 expression is reduced in a subset of CAA-ICH cases compared to CAA-NH cases. In conclusion, in patients with CAA, a disbalance in cerebrovascular MMP9 and TIMP3 expression is associated with CAA-related ICH.

MFG-E8 (LACTADHERIN): a novel marker associated with cerebral amyloid angiopathy

“…Remarkably, we identified two proteins selectively associated with cerebrovascular Aβ, TIMP3 and MFG-E8. We focused our study on the MFG-E8 candidate since TIMP3 has been previously described in vessels from CAA patients [ 15 , 44 ]. Our proteomic results demonstrated that the LCM approach using an experimental transgenic model was a reliable tool that successfully validated candidates previously identified in other studies on humans.…”

Overlapping Protein Accumulation Profiles of CADASIL and CAA

“…In addition, tissue endogenous inhibitors (TIMPs) and matrix metalloproteinases (MMPs) are involved in regulation of the ECM, and dysregulation of these proteases can result in decreased turnover of ECM components and/or damage the integrity of the BBB, contributing to lobar hemorrhage. 65,77,78 MMP2 and MMP9 are enhanced in CAA with AD pathology, and matrix metalloproteinase inhibitor TIMP3 is enhanced in CAA both with and without underlying AD pathology. 40,70,78,79 MMP2 and MMP9 have also been shown to proteolyze various Ab peptides in AD.…”

Neurovascular Alterations in Vascular Dementia: Emphasis on Risk Factors

“…Upon ischemic stroke, MMP-9 is secreted by the cells forming the neurovascular unit via regulation of the extracellular signal-regulated kinase-(ERK)-1/2) and the signal transducer and activator of transcription (STAT)-3 pathways, leading to the degradation of basal lamina/extracellular matrix (ECM) proteins, and the recruitment and extravasation of peripheral immune cells (Nishikawa et al, 2018;Jäkel et al, 2020). Interestingly, human brain studies showed that MMP-9 is implicated in the degradation of type IV collagen at the basal lamina, resulting in hemorrhagic transformations (Rosell et al, 2006(Rosell et al, , 2008, enhanced leukocyte infiltration, and poor neurological outcomes (Kim et al, 2016).…”