Brain, Vol. 124, No. 12, 2383-2392,
December 2001
© 2001 Oxford University Press
Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease due to a novel presenilin 1 mutation
1 Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, 2 Laboratory of Neurobiology and 3 Neuropathology, Department of Medicine, 4 Department of Neurology, General Hospital Middelheim, Born-Bunge Foundation, University of Antwerp, Antwerpen and 5 Laboratory of Neuropathology, University of Leuven, Faculty of Medicine, Leuven, Belgium
Correspondence to:
Professor Dr Christine Van Broeckhoven, Department of Molecular Genetics, University of Antwerp (UIA), Department of Biochemistry, Universiteitsplein 1, B-2610 Antwerpen, Belgium E-mail: cvbroeck{at}uia.ua.ac.be
The dense-cored plaques are considered the pathogenic type of amyloid deposition in Alzheimer's disease brains because of their predominant association with dystrophic neurites. Nevertheless, in >90% of cases of Alzheimer's disease amyloid is also deposited in cerebral blood vessel walls (congophilic amyloid angiopathy; CAA) but its role in Alzheimer's disease pathogenesis remains enigmatic. Here, we report a family (family GB) in which early-onset Alzheimer's disease was caused by a novel presenilin 1 mutation (L282V). This was unusually severe CAA reminiscent of the Flemish amyloid precursor protein (A692G) mutation we reported previously, which causes Alzheimer's disease and/or cerebral haemorrhages. In family GB, however, the disease presented as typical progressive Alzheimer's disease in the absence of strokes or stroke-like episodes. Similarly, neuroimaging studies and neuropathological examination favoured a degenerative over a vascular dementia. Interestingly, an immunohistochemical study revealed that, similar to causing dense-cored amyloid plaques, CAA also appeared capable of instigating a strong local dystrophic and inflammatory reaction. This was suggested by the observed neuronal loss, the presence of tau- and ubiquitin-positive neurites, micro- and astrogliosis, and complement activation. Together, these data suggest that, like the dense-cored neuritic plaques, CAA might represent a pathogenic lesion that contributes significantly to the progressive neurodegeneration that occurs in Alzheimer's disease.
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