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Cerebral amyloid angiopathy: pathogenetic mechanisms and link to dense amyloid plaques
Article first published online: 3 JAN 2008
DOI: 10.1111/j.1601-183X.2007.00380.x
2008 Blackwell Publishing Ltd
Additional Information
How to Cite
Kumar-Singh, S. (2008), Cerebral amyloid angiopathy: pathogenetic mechanisms and link to dense amyloid plaques. Genes, Brain and Behavior, 7: 67–82. doi: 10.1111/j.1601-183X.2007.00380.x
Publication History
- Issue published online: 3 JAN 2008
- Article first published online: 3 JAN 2008
- Received 24 August 2007, accepted for publication 24 October 2007
Keywords:
- Alzheimer’s disease;
- amyloid-β protein;
- CAA;
- cerebrovascular amyloidosis;
- dense-core plaques;
- pathogenesis;
- senile plaques;
- therapy;
- transgenic mice
Cerebral amyloid angiopathy (CAA) of the amyloid-β (Aβ) type is the most common form of sporadic CAA and is now also accepted as an early and integral part of Alzheimer’s disease (AD) pathogenesis. Cerebral amyloid angiopathy is a risk factor for haemorrhagic stroke and is believed to independently contribute to dementia. Rare forms of hereditary cerebral amyloidosis caused by mutations within the Aβ domain of amyloid precursor protein (APP) have been identified, where mutant Aβ preferably deposits in vessels because of a decreased fibrillogenic potential and/or increased vasotopicity. A review of factors involved in CAA caused by wild-type Aβ suggests that increased Aβ levels in brain without an increased Aβ42/Aβ40 ratio is one of the most important prerequisites for vascular amyloidosis. This is exemplified by CAA observed in APP duplication and Down’s syndrome patients, neprilysin polymorphism patients and knockout mice and Swedish APP (KM670/671NL) mice. Select presenilin mutations also lead to a prominent CAA, and importantly, presenilin mutations are shown to have varied effects on the production of Aβ40, the predominant amyloid found in CAA. Conversely, APP mutations such as Austrian APP (T714I) drastically decrease Aβ40 production and are deficient in CAA. Apolipoprotein E-ɛ4 is also shown to be a risk factor for CAA, and this might be because of its specific role in the aggregation of Aβ40. Recent data also suggest that dense-core senile plaques in humans and dense plaques in transgenic mice, composed predominantly of Aβ40, associate with vessels. This review highlights some of these aspects of genetics and biochemistry of CAA and pathological descriptions linked to a prominent CAA and/or dense plaques in humans and relevant mouse models and discusses how this knowledge has led to a better understanding of the processes involved in vascular amyloidosis, and in causing dementia, and thus has important therapeutic implications.