Insights into the pathogenesis and pathogenicity of cerebral amyloid angiopathy

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.

[O2–04–01]: Clearance of Beta‐amyloid Is Facilitated by Apolipoprotein E and Circulating High‐density Lipoproteins in Bioengineered Human Vessels

“…Finally, we observed that the presence of astrocytes induced expression of brain-specific tight junction proteins and transporters in tripartite vessels generated from ECs from a peripheral source, offering the potential to understand how vascular context may reprogram EC phenotype in future studies. Numerous studies have demonstrated that the accumulation and aggregation of Ab within the muscular layer of arteries and arterioles represents a key step in the development of CAA (Biffi and Greenberg, 2011;Love, 2009). We show that our platform can be used to investigate how human lipoproteins on each side of the BBB regulate vascular function and Ab transport and accumulation.…”

The development of cerebral amyloid angiopathy in cerebral vessels. A review with illustrations based upon own investigated post mortem cases

“…Other results indicate that β-amyloid 1-40 is mainly localized in leptomeningeal arteries, arterioles and small cortical vessels, while both β-amyloid 1-40 and β-amyloid 1-42 are presented and β-amyloid 1-42 dominates in capillaries [50,51].…”

Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum

“…Nevertheless, transgenic mouse models of cerebral amyloid deposition3 have provided the following insights (figure 2): (1) the major source of human Aβ is neuronal87 88; (2) an increased ratio of Aβ 40 :Aβ 42 in the brain results in a shift from brain parenchyma to the vasculature (perhaps by increasing the solubility of Aβ and thus its diffusion into the vessel wall)53; and (3) vascular Aβ deposition largely results from impaired clearance of Aβ (rather than overproduction), especially along perivascular drainage pathways 3 54 89. Impairment of perivascular drainage pathways has emerged as a key mechanism in sporadic CAA3 56 90: these efflux channels may be conceptualised as a cerebral ‘lymphatic system’, allowing interstitial fluid and solutes to drain out of the brain along basement membranes in the capillary walls, and between smooth muscle cells in the tunica media of small arteries (in the opposite direction to arterial blood flow) (figure 2).…”