D-CAA (also known as hereditary cerebral haemorrhage with amyloidosis-Dutch type (HCHWA-D), or Katwijk’s disease) is an autosomal dominant disease caused by a point mutation in the amyloid precursor protein (APP) gene on chromosome 21. The mutation causes an amino acid substitution (E693Q) and is called the ‘Dutch mutation’. Amyloid-β (the APP cleavage product protein) is secreted into the extracellular space. Pathologically, the Dutch mutation results in amyloid-β accumulation around cerebral vessel walls, causing vessel wall integrity loss leading to haemorrhages. Investigating the effects of altered amyloid-β metabolism due to mutations like the Dutch mutation can also provide a better understanding of amyloid-β toxicity in more common diseases like sporadic cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD).
In the Neuro-D group we use a range of disease models including iPSC from D-CAA patients to create 2D neurons in a dish and sophisticated 3D brain organoid models, and D-CAA transgenic mice.
We use these models to study D-CAA pathology, investigate affected cell types, and test potential antisense oligonucleotide (AON)-based therapies.