Posted 15 April 2004

Cerebrovascular Disease Impedes the Drainage of Aβ from the Brain

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Our Hypothesis:

Why does Aβ accumulate in the brain in Alzheimer's disease? In familial AD, there is evidence that mutations in the APP or presenilin genes result in excessive or aberrant production of Aβ. But there is little evidence for overproduction of Aβ in sporadic Alzheimer's disease.

Perhaps there is a failure of elimination of Aβ from the brain in AD. The deposition of Aβ in the walls of arteries and capillaries in cerebral amyloid angiopathy (CAA) suggests that Aβ becomes entrapped in the perivascular pathways by which interstitial fluid (ISF) and solutes normally drain from the brain. If this is so, why does drainage of Aβ fail in the elderly but not in the young?

One major change that affects blood vessels with age is cerebrovascular disease. Arteriosclerosis brings with it a generalized, progressive thickening and fibrosis of artery walls, and the accompanying loss of elasticity would reduce the amplitude of vessel pulsations. We now have theoretical mathematical models suggesting that arterial pulsations generate the motive force behind the perivascular transport of ISF from the brain, and this happens in the reverse direction to the flow of blood through the vessel lumen. Furthermore, histological studies of serial sections show that thrombotic occlusion of cortical arteries results in failure of drainage of Aβ from the capillary bed leading to the site of occlusion.

These findings suggest that cerebrovascular disease could be a major factor in the failure of elimination of Aβ from the aging and Alzheimer brain. By this reasoning, enhancing the elimination of Aβ from the brain throughout life may be a strategy for future therapy for AD. This may involve regimes for reducing the development or progression of cerebrovascular disease; defining chaperone molecules for enhancing the perivascular drainage of Aβ; or improving the use of immunotherapy for the removal of Aβ from the brain.

Summary of Evidence

1. Arteries and capillaries in the brain have two major functions:

• Delivery of blood and nutrients
• Drainage of ISF from the brain, i.e., acting as lymphatics (1-3)

2. Injection of soluble fluorescent tracers of 3 kDa, which is approximately the size of Aβ, into gray matter of the mouse brain shows that, within five minutes, the tracers localize to the basement membranes of capillaries and artery walls. (Carare-Nnadi R & Weller R.O. 2004, unpublished observations)

3. The pattern of distribution of the soluble tracer is the same as the distribution of Aβ in vessel walls in CAA in the aging human and Alzheimer's brain, suggesting that Aβ drains from the brain along perivascular interstitial fluid drainage pathways (4,5).

4. Mathematical models suggest that arterial pulsations could be the motive force propelling Aβ and other soluble metabolites out of the brain along artery walls. (Schley D et al., 2004, submitted)

5. Age is a major risk factor for cerebrovascular disease and AD.

6. Cerebrovascular diseases (i.e., arteriosclerosis, atherosclerosis and thromboembolic occlusion) all result in reduced amplitude of arterial pulsations.

7. Evidence linking cerebrovascular disease to the failure of elimination of Aβ from the aging human brain is found in studies showing that thromboembolic occlusion of cortical arteries blocks the drainage of Aβ along blood vessel walls. (6,7,8). (Weller et al., 2004 in preparation)

8. Reduced vascular pulsations in cerebrovascular disease reduce the elimination of Aβ and other soluble metabolites from the aging human brain.

Conclusions
Cerebrovascular disease impedes the elimination of Aβ and probably other metabolites from the aging human brain. It contributes to the pathogenesis of AD as it results in the accumulation of soluble and insoluble Aβ and therefore alters the external neuronal environment in the aging and AD brain. Improving immunotherapy (9) may be one way forward for enhancing elimination of Aβ from the brain.

References:
1. Cserr HF, Knopf PM. Cervical lymphatics, the blood-brain barrier and the immunoreactivity of the brain: A new view. Immunology Today 1992,13:507-512. Abstract

2. Zhang ET, Richards HK, Kida S, Weller RO. Directional and compartmentalised drainage of interstitial fluid and cerebrospinal fluid from the rat brain. Acta Neuropathologica 1992,83:233-239. Abstract

3. Weller RO. Pathology of cerebrospinal fluid and interstitial fluid of the CNS: significance for Alzheimer disease, prion disorders and multiple sclerosis. J Neuropathol Exp Neurol 1998,57:885-94. Abstract

4. Weller RO, Massey A, Newman TA, Hutchings M, Kuo YM, Roher AE. Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am J Pathol 1998,153:725-33. Abstract

5. Preston S D, Steart PV, Wilkinson A, Nicoll JAR, Weller RO. Capillary and Arterial Amyloid Angiopathy: Delineation of the Perivascular Route for Elimination of Amyloid-beta from the Human Brain. Neuropathology and Applied Neurobiology 2003,29:106-117. Abstract

6. Weller RO, Yow HY, Preston SD, Mazanti I, Nicoll JAR. Cerebrovascular disease is a major factor in the failure of elimination of A-beta from the human brain: implications for therapy of Alzheimer's disease. Annals of the New York Academy of Sciences 2002,977:162-168. Abstract

7. Weller RO, Nicoll JAR. Cerebral Amyloid Angiopathy: Pathogenesis and effects on the aging and Alzheimer brain. Neurological Research 2003,25:611-616. Abstract

8. Nicoll JA, Yamada M, Fracoviak J, Mazur-Kolecka B, Weller RO. Cerebral Amyloid Angiopathy plays a direct role in the pathogenesis of Alzheimer's Disease. Neurobiology of Aging (in Press)

9. Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 2003,9:448-452. (See ARF related news story.)

Here is our position on the discussion topics suggested in the background text:

1. Why do AD and VaD overlap in their clinical symptoms, pathology, disease outcome, and treatment potential? Because cerebrovascular disease inhibits the drainage of Aß from the ageing brain. Treatment potential: Cholinesterase inhibitors may increase the amplitude of vascular pulsations and thus the drainage of interstitial fluid, Aβ etc. from the brain. (1. Beach TG, Kuo YM, Spiegel K, Emmerling MR, Sue LI, Kokjohn K, Roher AE. The cholinergic deficit coincides with Abeta deposition at the earliest histopathologic stages of Alzheimer disease. J Neuropathol Exp Neurol 2000,59:308-13.)

2. Does a vascular etiology explain the anatomical and cellular specificity of Alzheimer's pathology? Yes! It is related to perivascular interstitial fluid drainage territories.

3. If cerebral infarcts contribute independently to the risk of dementia, as asserted by Schneider et al., does this fact alone argue against Alzheimer's being a primary vascular disorder, or does the Schneider et al. study leave open the possibility that cerebral hypoperfusion is still the underlying cause of AD? Impaired perivascular interstitial fluid drainage is another underlying cause.

4. Why do cerebrovascular and heart disease (and about two dozen other reported risk factors) increase the risk of AD or VaD? Poor perfusion also means reduced amplitude of vessel pulsations, thus impairing the drainage of Aβ and other metabolites from the aging brain.

5. Is a vascular etiology incompatible with Alzheimer's being neurodegenerative? Can these two perspectives be united? Yes! Cerebrovascular disease results in poor perfusion and poor drainage of Aβ, etc., from the brain.

6. What new lines of investigation might bring about dramatic progress in AD? a) Consideration of AD as a vascular disorder, b) Improvement in cardiovascular state and cerebral circulation would improve vascular supply and drainage of interstitial fluid containing Aβ and other metabolites from the brain, and c) Search for chaperone molecules for Aβ to drain more efficiently along the walls of aging blood vessels.