Hereditary cerebral hemorrhage with amyloidosis–Dutch type (HCHWA-D) is an early onset hereditary form of Cerebral amyloid angiopathy (CAA) caused by a point mutation of the Amyloid Precursor protein (APP). CAA refers to the accumulation of Amyloid β (Aβ) peptide, resulting from APP protein cleavage, in intracerebral vessels. CAA pathology is present in the majority of Alzheimer’s Disease (AD) brains and is associated with intracerebral hemorrhages in the elderly. The general aim of this thesis is to decipher the molecular pathogenesis of HCHWA-D. Since no proven therapeutic treatment exists to prevent or even delay the disease onset, the understanding of underlying pathomechanisms in HCHWA-D is important. It may help discovering new therapeutic targets and biomarkers that can be used to assess the efficacy of candidate drugs in treatment trials. The main finding of this thesis is that Transforming growth factor β (TGFβ) deregulation plays a central role in HCHWA-D pathogenesis. In the final chapter, the beneficial and detrimental aspects of TGFβ on the vascular and parenchymal brain components are reviewed and the possible causes of TGFβ activation in HCHWA-D as well as its implication for future studies and therapeutic intervention are discussed.Bontius Stichting (Leiden, Netherlands), the Dutch CAA Foundation (Rotterdam, Netherlands) and the Netherlands Organization for Scientific Research (NWO, The Hague, Netherlands), under research program VIDI, project “Amyloid and Vessels,” number 864.13.014LUMC / Geneeskund
