Cerebral Amyloid Angiopathy

Current project: 
Involment of proteolytic systems in the progression of Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is produced by the accumulation of β-amyloid protein within the meningeal and brain vessels. It is the second leading cause of cerebral hemorrhages. However, nowadays, factors related to brain bleedings following amyloid deposition are largely unknown. The understanding of the mollecular mechanisms that lead to cerebral hemorrhage may be the basis for future treatments.
Previous evidences of our group have shown that Matrix Metal•loproteinases (MMPs) are related to brain bleeding. Now, we aim to investigate the relationship between these proteolytic systems and the appearance of intracraneal hemorrages in CAA.

Our study includes:

1) The identification of both tissue and plasma biomarkers for the diagnosis and prognosis of CAA-related hemorrhages.

2) The search of the genetic markers related to proteolytic systems that could determine the risk of suffering a recurrence in CAA.

We are studying a cohort of probable CAA patients that have been recruited in Hospital Vall d’Hebron in collaboration with the Stroke Project of the Cerebrovascular Diseases Study Group (Spanish Society of Neurology).

3) The study of MMPs role in β-amyloid stimulated vascular cells in vitro.

Cultured cells of the neurovascular unit are challenged with different β-amyloid peptides and the implication of MMPs in β-amyloid cleavage and cell toxicity are studied using cellular and molecular biology methodology.

For this purpose, we use the human cerebral endothelial cell line hCMEC/D3, primary cultures of human leptomeningeal smooth muscle cells and rat/mouse glial and neuronal cultures.

Thioflavin-S staining of fibillar β-amyloid within brain vessels of CAA patient’s sections.

CAA team:

Mar Hernández Guillamon, PhD
Pilar Delgado, MD, PhD
Mireia Parés, PhD student

Related bibliography:

1)  Hernández-Guillamon M, Delgado P, Ortega L, Pares M, Rosell A, García-Bonilla  L, Fernández-Cadenas I, Borrell-Pagès M, Boada M, Montaner J. Neuronal TIMP-1 release accompanies astrocytic MMP-9 secretion and enhances astrocyte proliferation induced by beta-amyloid 25-35 fragment. J Neurosci Res. 2009 Jul;87(9):2115-25.

2) Rosell A, Ortega-Aznar A, Alvarez-Sabín J, Fernández-Cadenas I, Ribó M, Molina CA, Lo EH, Montaner J. Increased brain expression of matrix metalloproteinase-9 after ischemic and hemorrhagic human stroke. Stroke. 2006 Jun;37(6):1399-406.

3)  Alvarez-Sabín J, Delgado P, Abilleira S, Molina CA, Arenillas J, Ribó M, Santamarina E, Quintana M, Monasterio J, Montaner J. Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke. 2004 Jun;35(6):1316-22.

4) Montaner J, Molina CA, Monasterio J, Abilleira S, Arenillas JF, Ribó M, Quintana M, Alvarez-Sabín J. Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation. 2003 Feb 4;107(4):598-603.

Collaborations:
Mercè Boada
Fundació ACE, Barcelona, Spain.
www.fundacioace.com/

Jorge Ghiso and Agueda Rostagno
Pathology Dept. Langone Medical Center. NYU
New York, US.

Ignacio Romero
Life Science Dept. Open University.
Milton Keynes, UK.