Abstract
Amyloid is deposited in the walls of arteries and capillaries as cerebral amyloid angiopathy (CAA) in the brains of older individuals and of those with Alzheimer disease (AD). CAA in AD reflects an age-related failure of elimination of amyloid-beta (Aβ) from the brain along perivascular lymphatic drainage pathways. In the absence of conventional lymphatic vessel in the brain, interstitial fluid and solutes drain from the brain to cervical lymph nodes along narrow basement membranes in the walls of capillaries and arteries, a pathway that is largely separate from the cerebrospinal fluid. In this review we focus on the pathology and pathogenesis of CAA, its role in the aetiology of AD and its impact on immunotherapy for AD. The motive force for lymphatic drainage of the brain appears to be generated by arterial pulsations. Failure of elimination of Aβ along perivascular pathways coincides with a reduction in enzymic degradation of Aβ, reduced absorption of Aβ into the blood and age-related stiffening of artery walls that appears to reduce the motive force for lymphatic drainage. Reduced clearances of Aβ and CAA are associated with the accumulation of insoluble and soluble Aβs in the brain in AD and the probable loss of homeostasis of the neuronal environment due to retention of soluble metabolites within the brain. Tau metabolism may also be affected. Immunotherapy has been successful in removing insoluble plaques of Aβ from the brain in AD but with little effect on cognitive decline. One major problem is the increase in CAA in immunised patients that probably prevents the complete removal of Aβ from the brain. Increased knowledge of the physiology and structural and genetic aspects of the lymphatic drainage of Aβ from the brain will stimulate the development of therapeutic strategies for the prevention and treatment of AD.
Highlights
Deposition of amyloid-beta (Aβ) in the walls of cerebral arteries and capillaries as cerebral amyloid angiopathy (CAA) has a prevalence of 90% to 96% in patients with Alzheimer disease (AD) [1] and is present in 30% of non-demented individuals over the age of 60 years [2]
We focus on the pathology, pathogenesis and complications of CAA, its relationship to the aetiology of AD and how it affects the clinical outcome of immunotherapy for AD
15% of radioactive tracer injected into the interstitial fluid (ISF) is recoverable from the cerebrospinal fluid (CSF), and the majority of tracer drains to the cervical lymph nodes [9] at a rate equivalent to lymphatic drainage from other tissues [9]
Summary
Deposition of amyloid-beta (Aβ) in the walls of cerebral arteries and capillaries as cerebral amyloid angiopathy (CAA) has a prevalence of 90% to 96% in patients with Alzheimer disease (AD) [1] and is present in 30% of non-demented individuals over the age of 60 years [2]. Observations from tracer studies and from CAA (Figures 1-3) suggest that, as Aβ leaves the brain, it initially diffuses with ISF and other solutes through the narrow and tortuous extracellular spaces of the grey matter [3,33,38] (Figure 4) It enters the bulk drainage pathways in the 100- to 150-nm-thick endothelial basement membranes in the walls of capillaries [3,28,33] to drain out of the brain along basement membranes in the tunica media of cortical and leptomeningeal arteries [5]. Aβ is (i) produced by neurons and other cells in the brain and (ii) diffuses with interstitial fluid and other solutes through the narrow extracellular spaces (ECS) of the brain to (iii) the bulk flow lymphatic drainage pathways in the basement membranes of capillaries and in the tunica media of artery walls and (iv) out of the brain to cervical lymph nodes. The role of apoE in the elimination of Aβ from the brain is still not fully established, but the marked accumulation of apoE colocalising with Aβ in CAA following immunisation suggests that the elimination of Aβ may be chaperoned by apoE [45]
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