[Frontiers in Bioscience 14, 4778-4792, January 1, 2009]

Insights into the pathogenesis and pathogenicity of cerebral amyloid angiopathy

Seth Love, Scott Miners, Jen Palmer, Katy Chalmers, Patrick Kehoe

Dementia Research Group, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol BS16 1LE, UK

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Pathogenesis
3.1. Aβ40 predominates in CAA
3.2. Relationship between synthesis and accumulation of Aβ in sporadic CAA
3.3. Perivascular clearance of Aβ
3.4. Transport of Aβ from brain into blood
3.5. RAGE receptor-mediated transport of Aβ into the brain
3.6. TGFβ1, perivascular ECM and CAA
3.7. Several Aβ-degrading enzymes are present in the cerebral microvasculature and are deficient or less active in AD and CAA
3.8. Cerebrovascular ECE-1 is increased in AD
3.9. Involvement of other Aβ-degrading enzymes in AD and CAA
4. Genetic risk factors for CAA
4.1. APOE ε4 is associated with CAA, particularly in patients with AD and cerebral haemorrhage
4.2. Other genetic risk factors for CAA
5. Pathogenicity of CAA
5.1. CAA increases the risk of cerebral haemorrhage
5.2. CAA increases the risk of cerebral infarction and ischaemic leucoencephalopathy
5.3. In AD, CAA is associated with increased perivascular phospho-tau
5.4. CAA may be associated with perivascular inflammation and angiitis
6. Conclusion
7. Acknowledgments
8. References

1. ABSTRACT

Amyloid-beta (Abeta) cerebral amyloid angiopathy (CAA) affects most Alzheimer's disease (AD) patients and ~30% of otherwise-normal elderly people. APOE epsilon 4 is a major risk factor for CAA in AD. Neurons are probably the source of the vascular Abeta. CAA develops when Abeta is deposited in the vessel walls along or across which it normally passes into the CSF and bloodstream. Vascular deposition is facilitated by factors that increase Abeta40:Abeta42, impede perivascular passage of Abeta or raise its concentration. The levels of some Abeta-degrading enzymes are reduced in AD patients with CAA. However, angiotensin-converting enzyme activity is increased and may act via angiotensin II to increase transforming growth factor beta1, a potent inducer of ECM synthesis. CAA is a cause of intracerebral haemorrhage and cerebral ischaemic damage. In AD, neuritic degeneration is accentuated around Abeta-laden vessels. Rarely, CAA is associated with angiitis. The balance between parenchymal and cerebrovascular degradation of Abeta, and regulation of perivascular extracellular matrix production, are likely to be key determinants of Abeta distribution and pathogenicity within the brain.