Amyloid: Vascular and Parenchymal

Amyloid: Vascular and Parenchymal 355

Amyloid: Vascular and Parenchymal R O Weller, R O Carare, and D Boche, University of Southampton School of Medicine, Southampton, UK ã 2009 Elsevier Ltd. All rights reserved.

Introduction Age brings many changes to the body and age is also a major risk factor for dementia. Alzheimer’s disease is one of the major forms of dementia in the elderly and is characterized by the accumulation of amyloid beta (Ab) peptides in the brain. Although there are no traditional lymphatics in the brain, interstitial fluid and solutes such as Ab are eliminated from brain tissue along the basement membranes in the walls of capillaries and cerebral arteries. Here we review how aging of the brain and cerebral arteries may lead to the failure of elimination of Ab from the brain and how this may contribute to the onset of dementia, particularly in Alzheimer’s disease. Immunotherapy for the removal of Ab from the brain is also briefly discussed.

Aging of the Brain and Cerebral Arteries Changes occur progressively in the brain and cerebral arteries with advancing age, and age is a major risk factor for Alzheimer’s disease and for cerebrovascular disease. Neurons in the brain are very long-lived cells, as they are established before birth and survive for the lifetime of the individual. With age, large neurons in the cerebral cortex and spinal cord accumulate waste products in the cytoplasm in the form of lipofuscin. Damaged mitochondria and membranes are broken down by lysosomal hydrolytic enzymes, and residual material accumulates in the cytoplasm of neurons as secondary lysosomes (lipofuscin). However, apart from a few familial disorders (lipofuscinoses), the lipofuscin in neurons does not seem to be a factor in dementia. Whereas cell organelles are broken down by lysosomes, cytoplasmic proteins are degraded by proteosomes. Damaged proteins become associated with ubiquitin and are delivered to proteosomes for degradation. As will be discussed later, there appears to be a failure of the ubiquitin–proteosomal system in dementias, particularly in Alzheimer’s disease. In addition to the changes that occur within aging neurons, astrocytosis is seen in the brain, with advancing age reflecting the damage that occurs throughout life from head injuries, episodes of viral encephalitis, and ischemia. Cerebral blood vessels and blood vessels elsewhere in the body change with age in a similar way. There is progressive stiffening of arterial walls, with an

increase in collagen in the tunica intima and in the tunica media. Major cerebral arteries, such as the vertebral, basilar, and middle cerebral arteries, show progressive dilatation and tortuosity due to fibrosis of the intima and media. Generalized thickening and stiffening of cerebral arteries (arteriosclerosis) is also accompanied by patchy thickening and the accumulation of cholesterol within atherosclerotic plaques of the major cerebral arteries. Occlusion of large or small cerebral arteries may result from emboli arising in the heart or from thrombi associated with atherosclerosis of the carotid arteries. Large infarcts resulting from occlusion of cerebral arteries may result in strokes, with focal neurological signs such as hemiparesis, whereas multiple small infarcts may produce no overt neurological signs but can result in vascular dementia (see Table 1).

Changes in the Brain Associated with Dementia Since the description in 1907 of the microscopic features in the brain in Alzheimer’s disease, many pathological changes associated with different types of dementia have been described. As shown in Table 1, the pathology of dementias is classified broadly based upon presence of intracellular protein inclusions mainly within neurons (tau, synuclein, ubiquitin, and huntingtin), extracellular deposits of amyloid proteins in the brain and in blood vessel walls (Ab, other amyloids, and prion protein), and small or large infarcts (multi-infarct or vascular dementia). (Lipofuscin has been included in Table 1, although excessive lipofuscin is a rare cause of dementia.)

Intracellular Protein Deposits Two major proteins, tau and synuclein, accumulate within neurons in dementia patients. Both proteins are associated with ubiquitin, which suggests that disposal of these proteins through the ubiquitin– proteosomal system may fail with age and dementia. Accumulation of Tau Protein

Tau protein (named after the Greek letter for ‘t’) is a microtubule-associated protein that is concerned with axoplasmic transport in normal neurons. Hyperphosphorylated tau accumulates with ubiquitin in aging neurons as the neurofibrillary tangles that were identified by Alzheimer and others by the use of silver stains (Figure 1). Examination of postmortem

356 Amyloid: Vascular and Parenchymal Table 1 Age changes in the brain associated with dementiaa Type of dementia

Intracellular inclusions in neurons

Extracellular deposits

Cerebral amyloid angiopathy

Infarcts

Aging brain

Lipofuscin þþþ Tau þ Lipofuscin þþþ Tau þ Lipofuscin þþþ Tau þþþ Lipofuscin þþþ Synuclein þþþ Tau þþ Lipofuscin þþþ in elderly Huntingtin þþþ Lipofuscin þþþ Tau þþþþ or ubiquitin only þþþ

Ab þ

Ab þ

þ

Ab þ

Ab þ

++++

Ab þþþþ

Ab þþþþ

þ/þþ

Ab þþ

Ab þþ

þ/þþ

Prion protein þþþþ Ab þ/ Ab þ/

þ/ (prion protein) þ/ (Ab) þ/ (Ab)

þ þ þ

Vascular dementia Alzheimer’s disease Dementia with Lewy bodies Creutzfeldt–Jakob disease Huntington’s disease Frontotemporal dementias

a

Intracellular inclusions, extracellular protein deposits, and vascular damage in the aging brain and in different major types of dementia. The features used as the pathological diagnostic criteria in the various dementias are in boldface type.

Neuron

Accumulation of Synuclein

Tau/ubiquitin fibrils (neurofibrillary tangles)

Neuritic Ab plaque Lipofuscin

RA

Axon Ab

DN

Drainage of Ab

MA

Ab Diffuse Ab plaque Ab

Artery Cerebral amyloid angiopathy Figure 1 Histopathological features of Alzheimer’s disease are characterized by the accumulation of neurofibrillary tangles composed of tau and ubiquitin within neurons, and by the deposition of amyloid beta (Ab) in brain parenchyma as amyloid plaques and in blood vessel walls as cerebral amyloid angiopathy. Ab in amyloid plaques is associated with microglial activation (MA) and reactive astrocytosis (RA). Swollen dystrophic neurons (DN) containing tau are associated with many of the amyloid plaques (neuritic plaques).

brains of aged patients with no impairment of cognition reveals some neurons with tau in their cytoplasm, particularly in the hippocampus. In Alzheimer’s disease, neurofibrillary tangles composed of hyperphosphorylated tau and ubiquitin complexes are more widespread and more numerous, especially in the temporal cortex, hippocampus, and frontal lobes. Mutations in the tau gene on chromosome 17 are associated with a familial dementia characterized by widespread accumulation, in neurons, of neurofibrillary tangles containing tau protein.

Synuclein is a protein associated with synapses in the brain; it accumulates with ubiquitin as spherical structures (Lewy bodies) within neurons, particularly of the substantia nigra and locus coeruleus in Parkinson’s disease. In dementia with Lewy bodies (see Table 1), synuclein and ubiquitin complexes (Lewy bodies) are observed in neurons of the cingulate gyrus, frontal and temporal cortices, and insula; synuclein also accumulates within neuronal processes, particularly in the hippocampus. There appears to be a failure in the ubiquitin–proteosomal system but the reasons for this are unclear in the majority of cases of dementia with Lewy bodies. Some familial cases of Parkinson’s disease or dementia with Lewy bodies are associated with mutations in the a-synuclein or parkin genes. Accumulation of Huntingtin

Inclusions of the protein huntingtin occur within nuclei of neurons in Huntington’s disease (see Table 1) in which there is expansion of triplet repeats in the gene encoding huntingtin, on chromosome 4.

Deposition of Amyloid in the Extracellular Spaces of the Brain A number of different proteins accumulate in the brains of elderly and demented patients as insoluble amyloid deposits in the extracellular spaces of gray matter, and, in many cases, in the walls of arteries as cerebral amyloid angiopathy. The most common of these proteins is amyloid beta (Ab), which may accumulate in the brains of elderly people who show no evidence of cognitive decline; Ab is deposited much more abundantly in the brain in Alzheimer’s disease.

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Other proteins, such as prion protein, accumulate in the gray matter in Creutzfeldt–Jakob disease, and a variety of other amyloid proteins, such as cystatin, transthyretin, and the British and Danish types of amyloid, accumulate in the extracellular spaces of the brain and in blood vessel walls in association with different types of familial dementia. In the following sections we explore the mechanisms by which amyloid proteins accumulate in the brain and blood vessel walls in elderly and demented patients, and in particular in Alzheimer’s disease.

Accumulation of Amyloid Proteins in the Brain in Alzheimer’s Disease Alzheimer’s disease is the commonest form of dementia in North America and Europe and has recently increased in incidence in many Asian countries. The disease is characterized pathologically by the accumulation of hyperphosphorylated tau within neurons and by the deposition of Ab in the extracellular spaces of gray matter in the brain and in the walls of cerebral arteries (Figure 1). Overproduction of Ab and failure of elimination of Ab from brain tissue appear to be the major reasons why Ab accumulates in the brain in old age and in Alzheimer’s disease. A number of familial dementias have been identified in which there is either an overproduction of Ab, particularly of the less soluble form, Ab1–42, or there is a production of a chemically aberrant form of Ab. Throughout life, Ab is produced by neurons and virtually all other cells in the body by the cleavage of a transmembrane protein, amyloid precursor protein (APP), encoded on chromosome 21. Three major secretases (a, b, and g) cleave APP to produce Ab in a number of forms that differ in the number of amino acids in the Ab peptide. The two major forms that accumulate in the brain and in the walls of arteries are Ab1–40 (40 amino acids long) and Ab1–42, which contains 42 amino acids and is less soluble than Ab1–40. Ab1–42 is mainly in the insoluble amyloid plaques within brain tissue and Ab1–40 predominates in the blood vessel walls in cerebral amyloid angiopathy. In the familial forms of Alzheimer’s disease, genetic mutations in the APP gene affect the cleavage sites of APP or the structure of Ab. Mutations in the presenilin 1 and 2 genes appear to affect the g-secretase cleavage of Ab from APP. In these types of familial Alzheimer’s disease, failure of elimination of the excessive amount of Ab from the aging brain appears to be a major factor in the pathogenesis of the dementia. Most cases of Alzheimer’s disease are sporadic, with familial cases accounting for less than 10% of all cases of Alzheimer’s disease. In the more common

sporadic form of Alzheimer’s disease, there is no firm evidence of overproduction of Ab, so it is probable that failure of elimination of Ab from the brain with advancing age is a major pathogenetic factor (Figure 1).

Elimination of Ab from the Brain Ab is produced throughout life in the brain and it is present at an average concentration of 2.75 ng g1 of cerebral cortex in clinically nondemented individuals; Ab is greatly increased in the brains of patients with Alzheimer’s disease. Studies in experimental mice and humans reveal a number of mechanisms by which Ab is eliminated from the normal brain. Ab is absorbed into the blood by several known pathways, such as that mediated by low-density lipoprotein receptorrelated protein-1 (LRP-1), and it is also degraded by peptidases such as neprilysin, in the parenchyma of the brain. In addition, Ab is eliminated from the brain with interstitial fluid along perivascular drainage pathways – effectively the lymphatics of the brain. Perivascular Route for the Elimination of Interstitial Fluid and Ab from the Brain

There is no traditional lymphatic system in the brain. In other tissues, such as lung and skin, there are well-defined thin-walled lymphatic vessels along which interstitial fluid, solutes, and inflammatory cells drain to regional lymph nodes. Although there are no true lymphatics in the brain, studies in experimental animals have shown that solutes injected into the brain do drain to lymph nodes in the neck. Thus, when a soluble fluorescent tracer of molecular mass equivalent to that of Ab (4 kDa) is injected into gray matter of the brain, it initially spreads diffusely through the narrow extracellular spaces and rapidly enters basement membranes of capillary and artery walls, to drain out of the brain. It does appear that the perivascular route along basement membranes in the walls of capillaries and arteries is the pathway for lymphatic drainage of the brain. Ab is deposited in the walls of cerebral capillaries and arteries in aged humans and in Alzheimer’s disease in a pattern that suggests Ab also drains from the brain along basement membranes of capillary and artery walls. As Ab progressively accumulates in the artery walls, smooth muscle cells in the tunica media die, so that in severe cerebral amyloid angiopathy the whole thickness of the artery is replaced by amyloid, thus increasing the likelihood of intracerebral hemorrhage. Figure 2 summarizes the formation and elimination of interstitial fluid and metabolites from gray-matter

358 Amyloid: Vascular and Parenchymal Neuron

Metabolites Nutrients

Flow of interstitial fluid and Ab Capillary

Artery Flow of blood

Brain tissue

Figure 2 Perivascular drainage of interstitial fluid and metabolites from the brain. Experimental studies suggest that nutrients pass through the blood–brain barrier into capillary endothelial basement membranes and thence diffuse to neurons and other cells in the brain. Metabolites from these cells diffuse back to the capillary basement membranes through the narrow and restricted extracellular spaces of the cerebral cortex and other areas of gray matter in the brain. Once metabolites, including amyloid beta (Ab), have entered capillary basement membranes, they pass by relatively unrestricted bulk flow into the basement membranes of arteries and out of the brain. The lymphatic flow along artery walls is probably driven by the reflection waves arising from arterial pulsations. Stiffening of artery walls with age may reduce the amplitude of arterial pulsations and reflection waves, thus interfering with the perivascular elimination of metabolites, including Ab, from the brain.

areas of the brain. Nutrients pass through the blood– brain barrier into capillary basement membranes, which act as conduits or channels for the circulation of nutrients to neurons and other cells within the brain. Metabolites produced by cells in the brain pass through the very narrow extracellular spaces to drain out of the brain, with interstitial fluid, along basement membranes in the walls of capillaries and arteries. Data from experimental and human studies suggest that interstitial fluid and solutes from the brain drain along artery walls to cervical lymph nodes just under the base of the skull. It is unlikely that lymphocytes and other inflammatory cells can migrate from the brain to lymph nodes along the narrow basement membrane pathways followed by interstitial fluid and solutes. Such failure of lymphocyte migration from the brain may be a factor in the well-known ‘immunological privilege’ of the brain. The perivascular pathway for drainage of interstitial fluid and solutes from the brain is largely separate from the cerebrospinal fluid (CSF).

Pathways for the Drainage of CSF Drainage pathways for CSF have been extensively studied in both animals and humans. Tracers injected directly into the CSF of rodents drain largely through channels in the cribriform plate into lymphatics of the nasal mucosae and thence to cervical lymph

nodes. In humans, however, CSF drains directly back into the blood through arachnoid granulations and villi in the walls of intracranial and spinal venous sinuses, and the route through the cribriform plate plays a very minor role.

Failure of Elimination of Ab from the Brain with Advancing Age and Alzheimer’s Disease The various mechanisms and routes for the removal of Ab from the brain in young animals and young humans appear to fail with advancing age (Figure 3). In mice, degradation of Ab by neprilysin within the brain parenchyma, and absorption of Ab into the blood by the LRP-1-mediated mechanism, are reduced with increasing age. Accumulations of insoluble amyloid Ab in the interstitial fluid drainage pathways in artery walls in elderly individuals and in patients with Alzheimer’s disease suggest that the perivascular route for elimination of Ab also fails with age. Detailed observations in tracer studies have shown that solutes drain along capillary basement membranes and then along basement membranes between the smooth muscle cells of artery walls. Using these data, theoretical mathematical models indicate that pulsation of artery walls is the motive force for the perivascular drainage of interstitial fluid and solutes from the brain. The model predicts that fluid and solutes would be driven along the vascular basement

Amyloid: Vascular and Parenchymal 359

Ab

Failure of elimination results in deposition of Ab as insoluble plaques in brain tissue

Neprilysin

Aβ

Microglia and astrocytes

Ab Perivascular drainage of Ab

LRP-1

Ab Artery

Failure of perivascular elimination of Ab results in deposition of Ab in artery walls as cerebral amyloid angiopathy Figure 3 Pathways and mechanisms for the elimination of amyloid beta (Ab) from the brain fail with advancing age, resulting in the accumulation of Ab in brain parenchyma and in blood vessel walls. In the young, Ab is absorbed into the blood by a mechanism mediated by low-density lipoprotein receptor-related protein-1 (LRP-1) and is degraded in brain parenchyma by neprilysin and other enzymes. Ab also drains from the brain with interstitial fluid along capillary and artery walls. Failure of the LRP-1 mechanism and neprilysin with age and the failure of perivascular drainage of Ab along stiff, aged arteries are associated with deposition of insoluble Ab as plaques in brain parenchyma, and in blood vessel walls as cerebral amyloid angiopathy. Ultimately, levels of soluble Ab, and possibly other metabolites in the brain, rise, and this is associated with decline of cognitive function and dementia in Alzheimer’s disease.

membranes in the reverse direction to the blood flow during diastole by the reflection waves generated by the arterial pulse wave. The strength of the reflection waves driving the drainage of interstitial fluid and solutes from the brain would be proportional to the amplitude of the pulsations. Why then does the perivascular drainage of fluid and solutes such as Ab fail with age and in Alzheimer’s disease? Age is not only a risk factor for Alzheimer’s disease, it is also a risk factor for cerebrovascular disease in which there is fibrosis and stiffening of artery walls (arteriosclerosis), atherosclerotic plaque formation, and occlusion of arteries by thrombi or emboli. As cerebral arteries stiffen with age the amplitude of vessel pulsations would be reduced, and this would also reduce the strength of the reflection wave driving the interstitial fluid and solutes from the brain along the walls of arteries. Hypothetically, reduction in the motive force in stiffened arteries would lead to slowing of drainage of Ab and induce the precipitation of insoluble fibrils of Ab in the vessel walls. Such deposition would further impede the drainage of Ab and eventually lead to the accumulation of soluble and insoluble Ab and other metabolites in the brain. Direct evidence that cerebrovascular disease and stiffening of artery walls impedes the elimination of Ab along perivascular pathways is difficult to obtain.

Nevertheless, thrombotic occlusion of small cortical arteries with complete abolition of vascular pulsations is associated with deposition of Ab in the basement membrane of capillaries supplied by the occluded arteries. This suggests that once the pulsations in the vessel cease, Ab can no longer be propelled along the drainage pathway from capillaries basement membranes into artery walls.

Consequences of Amyloid Deposition in the Brain and Vessel Walls In cerebral amyloid angiopathy, there are two major complications of the deposition of Ab in the walls of cerebral arteries. The acute complication is intracerebral hemorrhage and the more long-term complication is related to the onset of dementia, particularly of Alzheimer’s disease. Soluble and insoluble forms of Ab accumulate in the cerebral cortex, and the fluid content in subcortical white matter is increased. Intracerebral Hemorrhage

There is a close association between intracerebral hemorrhage and cerebral amyloid angiopathy in the elderly. As increasing amounts of Ab are deposited in the basement membranes of artery walls, smooth muscle cells in the tunica media are destroyed and the vessel wall becomes a brittle tube of insoluble Ab,

360 Amyloid: Vascular and Parenchymal

which makes it liable to rupture, causing an intracerebral hemorrhage. This complication occurs mainly in patients over the age of 75 years and can be fatal or may induce neurological deficits. Recent magnetic resonance imaging (MRI) studies have shown that the majority of intracerebral hemorrhages that have been attributed to cerebral amyloid angiopathy occur in the temporal and occipital lobes, supplied mainly by the posterior cerebral arteries. Dementia

The other major consequence of amyloid deposition in blood vessel walls is the failure of interstitial fluid drainage and the failure of elimination of Ab from the aging brain. The pathological diagnostic criteria for Alzheimer’s disease are mainly based upon the presence of neurofibrillary tangles within neurons and the severity of deposition of insoluble Ab as plaques in the cerebral cortex and hippocampus. As the elimination of Ab fails, it is deposited as insoluble plaques in gray-matter areas of the brain. The more compact plaques induce microglial activation and are associated with axonal damage and dystrophic neurites; the term ‘neuritic plaque’ is used for these structures (Figure 1). Other plaques of Ab are more diffuse and do not induce the same degree of brain tissue damage. Deposits of insoluble Ab in brain tissue impede the elimination of Ab and other metabolites from the brain. Before entering the drainage pathways in capillary and artery walls, interstitial fluid and metabolites diffuse through the narrow extracellular spaces of gray matter; Ab plaques block this diffusion. Eventually, drainage of solutes is severely restricted and levels of soluble Ab in gray matter rise. Recent studies have emphasized that a high level of soluble Ab in cerebral cortex and the severity of cerebral amyloid angiopathy correlate better with cognitive decline in patients with Alzheimer’s disease than does the number of insoluble plaques of Ab. Why the failure of elimination of soluble Ab results in dementia in Alzheimer’s disease is still not clear. Many studies suggest that the toxicity of Ab to neurons is not due to the accumulation of insoluble fibrils but rather is due to the presence of a soluble pool of Ab, particularly in its oligomeric form. In transgenic mice, dodecameric Ab assemblies are associated with an impairment of memory independently of Ab plaques or neuronal loss. Thus increased levels of soluble oligomeric Ab may be a factor inducing the onset of dementia in Alzheimer’s disease. However, it is also possible that other metabolites do not drain adequately from gray matter, resulting in their accumulation in the extracellular spaces, a change in neuronal environment, neuronal malfunction, and dementia.

Creutzfeldt–Jakob disease is another dementia that is characterized by the deposition of insoluble amyloid protein in the extracellular spaces of brain parenchyma, but, in this case, it is prion protein (see Table 1). As in Alzheimer’s disease and Ab, the mechanisms underlying the neurotoxicity of the prion protein are also unclear. Recent studies in experimental models suggest that the insoluble prion protein deposits in brain parenchyma are not toxic but that the conversion of the normal prion protein to disease-associated isoforms within neurons results in the neurotoxic form of the protein. Accumulation of the prion protein within blood vessel walls of the brain is less common than occurs with Ab. However, in some familial prion diseases and in animal models in which the protein has been truncated, prion protein is deposited within walls of the cerebrovasculature. Whether insoluble deposits of prion protein in brain parenchyma and in artery walls have the same effect of impairing interstitial fluid as do Ab deposits is not yet certain.

Fluid in Subcortical White Matter

Cerebral amyloid angiopathy has an effect not only on gray matter areas in the brain in Alzheimer’s disease, but also on the white matter. Accumulation of fluid in subcortical white matter is a frequent finding on MRI in patients with Alzheimer’s disease, and this correlates with the severity of cerebral amyloid angiopathy. Blood vessels supplying the subcortical white matter arise from the leptomeningeal arteries on the surface of the brain, and it appears that deposition of Ab in the walls of the leptomeningeal arteries impedes the drainage of fluid from subcortical white matter.

Genetic Factors in Alzheimer’s Disease and Cerebral Amyloid Angiopathy Familial Alzheimer’s disease is associated with defined mutations in the APP and presenilin genes. Polymorphisms in apolipoprotein E (ApoE) are related to the development of cerebral amyloid angiopathy and sporadic Alzheimer’s disease. ApoE is an amyloidscavenging molecule regulating extracellular concentrations of Ab through ApoE receptor internalization via the endosomal/lysosomal pathway. ApoE–Ab complexes are transported from the interstitial fluid in the brain into blood through specific ApoE receptors present at the blood–brain barrier. However, co-localization of ApoE with Ab in brain parenchyma and in artery walls suggests that ApoE–Ab complexes are also transported with interstitial fluid along perivascular drainage pathways. In this way, ApoE may act as a chaperone molecule for Ab. ApoE exists in

Amyloid: Vascular and Parenchymal 361

three isoforms (e2, e3, and e4); the e4 isoform is the most important genetic risk factor for the development of sporadic Alzheimer’s disease and has a strong link with cerebral amyloid angiopathy.

Immunotherapy for Alzheimer’s Disease Alzheimer-like transgenic mice have been generated to reproduce Ab accumulation in brain parenchyma during their adult life in order to understand the mechanisms underlying Ab deposition and to test treatments that may remove the amyloid deposits. Immunotherapy studies in Alzheimer-like transgenic mice have shown that active immunization against Ab1–42 in young mice prevents the accumulation of Ab in brain parenchyma, and active immunization of older mice results in a decrease of Ab in brain parenchyma. Following the success of Ab immunotherapy in transgenic mice, a clinical trial was initiated in a cohort of patients affected with mild to moderate Alzheimer’s disease. Patients were actively immunized against Ab1–42 protein; however, the clinical trial was halted when 6% of the immunized patients developed a complication of what appeared to be meningoencephalitis. Postmortem examination of the first immunized cases shows that insoluble Ab plaques were removed from cortical areas by the antibody response generated following the immunization and by activated microglia. However, the tau pathology was not modified by Ab immunotherapy, with the exception of the dystrophic neurites, which disappeared as Ab plaques were removed. One of the consequences of Ab immunotherapy is an increase of the cerebral amyloid angiopathy. It appears, therefore, that removal of insoluble Ab plaques from brain parenchyma allows access of Ab to the perivascular drainage pathways. It is not clear whether this is the Ab removed from the brain by the immunotherapy or whether it is the Ab from the increased pool of soluble Ab in gray matter in Alzheimer’s disease. Whichever it is, it becomes entrapped in the perivascular drainage pathways. Such an increase in cerebral amyloid angiopathy also results in an increased frequency of microhemorrhages within the brains of the patients immunized against Ab; this was also observed in experimental transgenic mouse studies. The first year of clinical follow-up of the immunized patients has shown a beneficial effect, with slowing of the decline of cognitive function, and further follow-up studies will allow clinical data and neuropathological features to be correlated. To date, Ab42 immunotherapy has not induced harmful effects in the large majority of patients, and when there have been complications they have not been lethal. A second approach involving

passive immunization with specific antibody or peptide, to avoid the apparent meningoencephalitis, is currently in progress. However, it is still not known whether immunotherapy will be most useful as a means to prevent Ab plaque formation in familial Alzheimer’s disease and Down syndrome, or as a therapy in the established sporadic disease.

Conclusions Ab is produced by the brain throughout life by the selective cleavage from amyloid precursor protein. The mechanisms for removal of Ab appear to fail in elderly humans, and if the failure is severe it is associated with Alzheimer’s disease. Failure of elimination of Ab along perivascular interstitial fluid drainage pathways may result from the stiffening of vessels that occurs with age and cerebrovascular disease in humans. If there is an increase in the production of Ab and particularly the more insoluble form in familial Alzheimer’s disease, the system of drainage may become overloaded and impeded at an early age. Understanding the mechanisms by which Ab is eliminated from the brain, the possible chaperone molecules that are involved, and the exact reasons why elimination of Ab fails is essential for the planning of future therapies for Alzheimer’s disease. Future research may center upon the factors that induce Ab to attach to vascular basement membranes. Prevention of such attachment may preserve the patency of the pathways for the drainage of interstitial fluid and solutes from the brain. See also: Aging of the Brain and Alzheimer’s Disease; Aging: Extracellular Space; Alzheimer’s Disease: An Overview; Alzheimer’s Disease: Molecular Genetics; Alzheimer’s Disease: Transgenic Mouse Models; Alzheimer’s Disease: MRI Studies; Animal Models of Alzheimer’s Disease; Axonal Transport and Alzheimer’s Disease; Axonal Transport and Huntington’s Disease; Axonal Transport and Neurodegenerative Diseases; Brain Glucose Metabolism: Age, Alzheimer’s Disease and ApoE Allele Effects; Dementia; Variant Creutzfeldt–Jakob Disease.

Further Reading Abbott NJ (2004) Evidence for bulk flow of brain interstitial fluid: Significance for physiology and pathology. Neurochemistry International 45: 545–552. Esiri MM, Lee VMY, and Trojanowski JQ (eds.) (2004) The Neuropathology of Dementia, 2nd edn. Cambridge: Cambridge University Press. Gallagher PJ and van der Wal AC (2007) Blood vessels. In: Mills SE (ed.) Histology for Pathologists, 3rd edn. pp. 218–238. Philadelphia: Lippincott Williams & Wilkins.

362 Amyloid: Vascular and Parenchymal Herzig MC, Van Nostrand WE, and Jucker M (2006) Mechanism of cerebral beta-amyloid angiopathy: Murine and cellular models. Brain Pathology 16: 40–54. Lue LF, Kuo YM, Roher AE, et al. (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. American Journal of Pathology 155: 853–862. Nicoll JA, Wilkinson D, Holmes C, et al. (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: A case report. Nature Medicine 9: 448–452. Preston SD, Steart PV, Wilkinson A, et al. (2003) Capillary and arterial amyloid angiopathy in Alzheimer’s disease: Defining the perivascular route for the elimination of amyloid beta from the human brain. Neuropathology and Applied Neurobiology 29: 106–117. Roher AE, Kuo Y-M, Esh C, et al. (2003) Cortical and leptomeningeal cerebrovascular amyloid and white matter pathology in Alzheimer’s disease. Molecular Medicine 9: 112–122. Schley D, Carare-Nnadi R, Please CP, et al. (2006) Mechanisms to explain the reverse perivascular transport of solutes out of the brain. Journal of Theoretical Biology 238: 962–974.

Shibata M, Yamada S, Kumar SR, et al. (2000) Clearance of Alzheimer’s amyloid-beta (1–40) peptide from brain by LDL receptor-related protein-1 at the blood–brain barrier. Journal of Clinical Investigation 106: 1489–1499. Weller RO (2005) Drainage pathways of CSF and interstitial fluid. In: Kalimo H (ed.) Pathology and Genetics. Cerebrovascular Diseases, pp. 50–55. Basel: ISN Neuropath Press. Weller RO and Nicoll JAR (2003) Cerebral amyloid angiopathy: Pathogenesis and effects on the ageing and Alzheimer brain. Neurological Research 25: 611–616. Weller RO and Nicoll JA (2005) Cerebral amyloid angiopathy: Both viper and maggot in the brain. Annals of Neurology 58: 348–350. Weller RO, Massey A, Newman TA, et al. (1998) Cerebral amyloid angiopathy: Amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer’s disease. American Journal of Pathology 153: 725–733. Wilcock DM, Rojiani A, Rosenthal A, et al. (2004) Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage. Journal of Neuroinflammation 1: 24.