PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Ann N Y Acad Sci. Author manuscript; available in PMC Oct 1, 2011.
Published in final edited form as:
PMCID: PMC2958685
NIHMSID: NIHMS235744
Aging and cerebrovascular dysfunction: contribution of hypertension, cerebral amyloid angiopathy, and immunotherapy
Vitaly Vasilevko,1 Giselle Passos,1 Daniel Quiring,1 Elizabeth Head,1,2 Mark Fisher,2 and David H. Cribbs1,2*
1Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA
2Department of Neurology, University of California, Irvine, Irvine, CA
Correspondence: David H. Cribbs, Ph.D., Professor and Director of the ADRC Neuropathology Core, Department of Neurology, Institute for Memory Impairments and Neurological Disorder, 1111 Gillespie NRF, University of California, Irvine, Irvine CA 92697-4540, cribbs/at/uci.edu
Age-related cerebrovascular dysfunction contributes to ischemic stroke, intracerebral hemorrhages, microbleeds, cerebral amyloid angiopathy (CAA), and cognitive decline. Importantly, there is increasing recognition that this dysfunction plays a critical aging secondary role in many neurodegenerative diseases, including Alzheimer’s disease (AD). Atherosclerosis, hypertension, and CAA are the most common causes of blood brain barrier (BBB) lesions. The accumulation of amyloid beta (Aβ) in the cerebrovascular system is a significant risk factor for intracerebral hemorrhage (ICH), and has been linked to endothelial transport failure and blockage of perivascular drainage. Moreover, recent anti-Aβ immunotherapy clinical trials demonstrated efficient clearance of parenchymal amyloid deposits, but have been plagued by CAA-associated adverse events. While management of hypertension and atherosclerosis can reduce the incidence of ICH, there are currently no approved therapies for attenuating CAA. Thus, there is a critical need for new strategies that improve BBB function and limit the development of beta-amyloidosis in the cerebral vasculature.
Keywords: Alzheimer disease, cerebral amyloid angiopathy, blood brain barrier, immunotherapy, hypertension
The majority of elderly have brain pathology, and those with multiple brain pathologies have a greater risk of developing dementia [1, 2]. The common co-occurrence of Alzheimer’s disease (AD) and vascular pathology suggest that many vascular risk factors may also be risk factors for brain atrophy and dementia [3, 4]. Moreover, cerebral amyloid angiopathy (CAA) along with hypertension, are the two most common causes of intracerebral hemorrhage (ICH), and CAA has also been correlated with microbleeds in the elderly. Age-related alterations in transport across the BBB, as well as a reduction in the efficacy of the perivascular drainage pathway have been proposed to enhance accumulation of parenchymal and cerebrovascular amyloid deposits in the elderly [510]. Interestingly, modeling suggest that vessel pulsations provide the force to drive perivascular drainage, and age-related stiffening of arteries has been hypothesized to reduce flow thereby enhancing Aβ deposition in the perivascular space thereby further slowing the clearance of Aβ from the CNS [8, 9].
There is at least some hope for CAA-induced neuropathology because in a subset of patients with a diagnosis of CAA where there were clinical manifestations of the CAA-related inflammation there was significant clinical improvement following anti-inflammatory therapy. The clinical symptoms were subacute cognitive decline or seizure rather than hemorrhagic stroke. Of six inflammatory CAA patients with available follow-up information, five demonstrated clinical and radiographic improvement after immunosuppressive treatment [11]. Additional studies have found associations between CAA, inflammation and dementia [1214]. One conundrum of epidemiological studies linking anti-inflammatory drugs to favorable clinical outcomes [15] and studies of human diseases in animal models [16] is that they often fail in subsequent clinical trials. A likely critical factor in the success of anti-inflammatory drugs in treating diseases with associated inflammation is when the therapy is actually administered. For example, in a recent report where induction of autoimmune tolerance eliminated relapses, but failed to halt disease progression in a animal model of multiple sclerosis [17], suggesting that secondary disease processes were responsible for the continued decline in behavioral measures.
The remainder of this review we will focus on the pathological implications of CAA under normal aging conditions and in the presence of anti-Aβ immunotherapy in humans and in transgenic animal models. We will also discuss potential therapies to minimize the accumulation of CAA and reduce CAA-induced pathological complications.
CAA is a collective name for the several diseases of different etiology sharing similar pathology. They are characterized by congophilic deposition of amyloid formed by different peptides such as Aβ, cystatin C, gelsolin, prion protein, ABri and ADan within the walls of small and medium size cerebral blood vessels and sometimes in the microvasculature [1821]. However, the most frequent form of CAA is caused by cerebrovascular accumulation of Aβ in sporadic disorders in the elderly and is present in 80–100% of AD patients, and 100% of individuals with Down Syndrome [19, 2225]. The incidence of CAA in the elderly population without AD or other neuropathological abnormalities is age dependent and increases from 13.8% of people between 60 and 69 years to 44.8% of those 80 years and older [26]. CAA is not restricted to humans only and can be easily found in aged mammals: dogs and non-human primates [2729]. In humans hereditary CAA is often complemented by hemorrhages and stroke and initiated by vasculotropic autosomal dominant mutations in Aβ sequence of Dutch, Iowa, Flemish, Arctic and Italian types [12, 3033]. Other familial mutations associated with increased risk of CAA also connected with extra copies of APP as in French families with APP duplication [34], trisomy 21 [23], or APP processing-related enzymes presenelin-1 or −2 [3539].
CAA is, along with hypertension, the most common cause of ICH in the elderly. CAA-ICH is characterized by a high rate of recurrence, estimated at 21% at two years, with in-hospital mortality of 24% and six month mortality of 32% [40]. Given the high recurrence rates and devastating consequences of CAA-ICH, it is remarkable that there are currently no treatments available to prevent CAA-ICH. Clinical interventions usually consist of blood pressure control (i.e., hypertension treatment), as well as avoidance of medications that increase systemic hemorrhage risk (e.g. aspirin). However, there are currently no available treatments to specifically reduce the risk of CAA-ICH.
CAA may be an important predisposing factor for hemorrhagic complications of recombinant tissue-type plasminogen activator therapy for ischemic stroke [42]. Moreover, CAA is a well-described accompaniment of white matter disease of the elderly [50]; the latter is a near-universal accompaniment of aging and is regarded as a cerebrovascular disease variant. Another area of importance for CAA is its coexistence with ischemic stroke, ranging from large vessel occlusive disease to small vessel disease. In this setting, the clinician is faced with the highly problematic task of preventing brain infarction in a patient at high risk for brain hemorrhage. Ischemic stroke prevention almost always relies on pharmacotherapies that interfere with clotting pathways. Thus clinicians are faced with a profound dilemma in which prevention of ischemic stroke may exacerbate risk of hemorrhagic stroke.
Recently Schneider et al. [41] reported that the majority of elderly have brain pathology, however those that had multiple brain pathologies (AD, PD/LBD, or infarcts), had greatly increased odds (3 fold) for dementia. The common co-occurrence of AD and vascular pathology mesh with epidemiologic data showing that many vascular risk factors are also risk factors for brain atrophy and dementia [3, 4]. Thus, there is increasing recognition that dysfunction in the cerebral vasculature plays a critical role in many neurodegenerative diseases, including AD where approximately 80–95% of the cases have cerebral vascular pathology [42, 43]. Finally, Lippa and Knopman in an editorial on the Schneider et al. study proposed “that we may want to maximize medical management of vascular risk factors in the elderly, regardless of whether cognition is still normal [44].
While there are multiple forms of amyloid deposits found in AD brain parenchyma, which include dense core plaques, neuritic plaques, diffused plaques and pre-amyloid aggregates [45, 46], the amyloid deposits on the cerebral blood vessels are more uniform and always well organized and structured. Vascular amyloid deposits assembled in β-sheet structures and are easily stained with Thioflavin S (Figure 1) or Congo Red, which provides an additional name, “congophilic amyloid angiopathy”, for vascular deposits.
Figure 1
Figure 1
In canines fibrillar Aβ preferentially accumulates in the cerebral vasculature. (A) Prefrontal cortex of 15 years old border collie was stained with anti-Aβ antibodies. Aβ accumulates in the cerebral vessels as fibrillar Thioflavine (more ...)
Despite the fact that vascular deposits in humans, all other mammal species and APP/Tg mice and consists predominantly of Aβ40, CAA must be initiated, or “seeded”, by Aβ42. The pivotal role of Aβ42 in CAA formation was demonstrated in classical experiments by Todd Golde’s group using Tg mice selectively expressing only human Aβ40 or Aβ42 peptides in Bri-Aβ expressing cassette and crosses between those mice and Tg2576 [47, 48]. While mice expressing high levels of Aβ40 peptide did not develop parenchymal, nor vascular amyloid deposits, at the same time, mice expressing low levels of Aβ42 over time started to accumulate not only parenchymal compact plaques and diffused deposits, but also vascular, mainly leptomeningeal, deposits, resembling amyloid angiopathy in humans [47]. Additional support for a role for Aβ42 in seeding CAA comes from FAD mutations in presenelin-1 (PS-1), which alters cleavage of Aβ from the less amyloidogenic and more soluble Aβ40 towards aggregation prone Aβ42. Despite the shift in Aβ40/Aβ42 production towards Aβ42, which on average increased from 10% of total Aβ in wild type PS-1 to 20.6±9.6% in different PS-1 mutants [49, 50] and dramatic cotton wool, diffused and dense core amyloid deposition in parenchyma, individuals caring these mutations always have extensive CAA pathology [35, 38, 51]. It is important, that CAA Aβ is always organized in β-sheet Congo Red positive structures. In FAD of Dutch type Aβ accumulates predominantly in the small vessels of leptomeninges and cerebral cortex. It is deposited in the parenchyma mainly in the form of pre-amyloid Congo Red negative deposits, while mature neuritic plaques and neurofibrillary tangles, hallmark of AD, are characteristically absent [52, 53]. At the same time Congo Red positive Aβ deposits associated with cerebrovasculature remained consistent with the AD pathological features. Interestingly, in aged dogs parenchymal Aβ deposits are predominantly of Congo Red negative diffuse type, while canines develop congophilic angiopathy with age (Figure 1) [5456]. Also, in aged squirrel monkeys cerebrovascular amyloid is the most abundant form, even in the cases of severe cerebral amyloidosis [57]. APP transgenic mice we also found only Thioflavin S positive fibrillar amyloid deposits associated within the cerebral vasculature (Figure 1).
Ultrastructural analysis of CAA location revealed that in large leptomeningeal arteries amyloid deposits consists of clusters of fibrils in the outmost part of the basement membrane at the media-adventitia junction [58]. In small leptomeningeal arteries and arterioles amyloid found in the outer portion of the basement membrane, with smaller deposits surrounded by the intact smooth muscle cells (SMC), while the bigger, more advanced deposits are surrounded by degenerative SMC. In capillaries smaller deposits are also associated with abluminal basement membrane, which often abnormally folded and layered. Astrocytes foot processes and activated microglia is associated with such deposits [58]. Natte et al. using gold-labeled anti-Aβ40 and anti-Aβ42 specific antibodies on sections from hereditary cerebral hemorrhages with amyloidosis, Dutch type (HCHWA-Dutch) patients revealed possible molecular mechanism of CAA formation [59]. It starts with non-fibrillar Aβ42 deposits associated with reticular and electron dense structures on capillaries. Further, there were very few Aβ42+40- deposits of fibrillar structure, while the majority of deposits were larger and always fibrillar Aβ42+40+, often extended in the surrounding neuropil. Aβ40 was not detectable at the capillary basement membrane without Aβ42+ presence, suggesting that vascular amyloidosis as well as parenchymal plaques, is a nucleation-dependent phenomena and require fibrillar Aβ42+ as a seed [60]. Multiphoton microscopy analysis of CAA development in mouse AD model demonstrated a stereotypical pattern, with vessels over the dorsal surface of the brain showing an anterior-to-posterior and large-to-small vessel gradient of involvement. Higher magnification imaging showed that CAA began with a banding pattern determined by vascular smooth muscle cells. Later on, gaps between amyloid bands shrink and disappear, gradually reaching a confluent structure. Also CAA deposits are propagating by expansion of the already formed plaques rather than forming new “eyes” of the deposition [61, 62]. However, which factors promote Aβ42 adherence to the basement membrane and initiate the chain reaction of Aβ assembly and proliferation into fibrillar form remains to be investigated.
Besides Aβ, which is the major component of senile plaques these lesions also accumulate other factors. The most common proteins detected in senile plaques, include proteoglycans [63], apolipoprotein E [64]; protease inhibitors α1-antichymotrypsin [65], α2-microglobulin [66]. Additionally Amyloid P, complement components C1q, C3d, C4d and membrane attack complex C5b-9, and complement inhibitors vitronectin, protectin and clusterin have also been reported to be in plaques [67, 68], growth factors and signaling molecules like cytokine-inducible adhesion molecule-1 [69]. Among the multiple proteins associated with senile plaques there is possibly a group of mainly inert molecules, while the majority of the proteins continue to be functionally active, thus attracting surrounding microglial cells and astrocytes and inducing their activation [68], which may occur independently of the chemoattractant and stimulatory properties of the fibrillar forms of Aβ.
Similar to the non-amyloid composition of senile plaques, there is robust presence of complement factors C1q, C3c, C4D and C5b-9 in the CAA [70, 71]. Verbeek et al. reported especially strong staining for C4d and C3c factors, while C1q was present in CAA with variable intensity [71]. Exceptionally strong staining of CAA was also detected for MAC C5b-9, compared with less intensive deposition in senile plaques, which suggests classical activation of the complement system and formation of membranolytic complex in CAA, and together with non sufficient complement inhibitory activities indicates extensive inflammation and degeneration of the vascular cells in CAA.
Analysis of the complement deposition in APP23 mouse AD model indicated a relatively weak complement response compared with AD, with similarly weak activation of microglia [72]. Antibodies against C1q, C3, C3d and C5 recognize parenchymal amyloid deposits weakly with more prominent cerebral vessels staining [72]. Microglial cells also express lower levels of complement CD11b receptor. In another AD mouse model TgSwDI with vasculotropic Aβ Dutch and Iowa mutations, with characteristic deposition of fibrillar Aβ in microvessels of the thalamus and hippocampus, and Thioflavin negative diffuse Aβ deposits throughout the frontal cortex [73], C1q, C3 and C4 were elevated in the regions of fibrillar Aβ deposits, e.g. thalamus and hippocampus, while the frontal cortex was free of complement deposition [74]. We found low levels of C1q and C3b complement factors associated with parenchymal plaques and vascular amyloid deposits in Tg2576 mice (Figure 2). Overall, in AD the strong deposition of complement and the co-localization of the membrane attack complex with damaged neurites and cerebral vasculature has led to speculation that complement activation is responsible for considerable neurodegeneration and cerebrovascular dysfunction [75].
Figure 2
Figure 2
Complement factors C1q and C3b are more strongly associated with vascular Aβ deposits than the parenchymal ones. Brain sections from 18 months old Tg2576 mice were immunostained with anti-C1q or C3b specific antibodies.
Experiments with mice deficient in complement components has produced mixed results regarding the possible role of complement in Aβ pathology and AD [76]. Inhibition of C3 activation with complement receptor-related protein significantly reduced reactive microgliosis, increased Aβ deposits in hAPP mice and was accompanied by a prominent accumulation of degenerating neurons [77]. Similar results were obtained in C3 deficient APP/C3−/− mice, which developed significantly increased total Aβ and amyloid plaque burden, significant loss of neuronal markers and differential activation of microglia towards the alternative phenotype [78]. APP mice deficient in C1q, APPQ−/−, also had strong reduction in glial activation biomarkers similar to APP/C3−/− mice, but they did show any differences in Aβ deposits [79]. Moreover, APPQ−/− mice demonstrated reduced neurodegeneration based on immunostaining for synaptophysin and MAP2 compared with their C1q sufficient APP counterparts.
Another important component of both CAA and parenchymal Aβ deposits is apolipoprotein E [64, 80, 81]. There are three allelic variants of ApoE in humans, ApoE2, ApoE3 and ApoE4, and individuals with one or two ApoE4 alleles have progressively higher risks and younger age of AD onset [82, 83]. The ApoE4 allele also increases the odds ratio for moderate or severe CAA by 2.9-fold if present as one allele, and 13.1-fold if present in two copies relative to the non-epsilon 4 carriers [84]. Individuals with ApoE4 alleles also have higher risks and earlier age of incidence for lobar hemorrhages [85]. ApoE4 genotype defines not only the risk of AD onset, but also the specific pathological feature of Aβ CAA deposits. Thal et al.[86] defined two forms of sporadic CAA. CAA-type1 is characterized by immunohistochemical detection of Aβ in cortical capillaries, leptomeningeal and cortical arteries, arterioles, veins and venules [86]. The CAA-type2 also exhibits Aβ deposits in leptomeningeal and cortical vessels, with the exception of cortical capillaries. The ratio of CAA-type1 and CAA-type2 were independent of severity of AD-related beta-amyloidosis, CAA-severity or increasing age, which suggested two different types of CAA pathology. At the same time, the ApoE4 allele constituted a 4-times higher risk of CAA-type1 and neuropil-associated vascular Aβ deposition in capillaries [86].
The question of how ApoE affects the risk of developing AD and how it contributes to Aβ deposition has been addressed with an ApoE knockout mouse model [87]. The cross between the PDAPP mouse AD model [88] with mice deficient in ApoE−/−, demonstrated that ApoE−/− mice had dramatically decreased immunoreactive Aβ deposits, which were present in the form of diffuse plaques, thus suggesting an important role of ApoE in facilitating Aβ peptide deposition [89]. Further analysis of these mice revealed a role for ApoE in the anatomical distribution of Aβ and APP processing. Lack of ApoE produced altered levels of full-length APP and elevated levels of Aβ in an age and region-dependent manner [90, 91]. Nilsson et al. demonstrated that ApoE facilitates both diffuse and fibrillar amyloid deposition and promotes cognitive impairment in PDAPP mice [92]. ApoE−/− mice were also crossed to another mouse model of AD, Tg2576 with a Swedish mutation [93, 94], which is known for an age-related progressive cerebral vascular amyloid accumulation in leptomeningeal and cortical vessels. Once again there was a robust reduction of parenchymal and vascular Aβ deposits, and in neuritic degeneration, thus further demonstrating the role of ApoE in pathological formation of not only neuritic but also CAA [95, 96]. In TgSwDI mice, substitution of the endogenous mouse ApoE for human ApoE3 or ApoE4 led to a strong shift from primarily microvascular fibrillar Aβ deposits towards parenchymal fibrillar deposition, however the ApoE4 isoform remained more vasculature-prone then the ApoE3 [97].
In 1999, Dale Schenk, and colleagues, at Elan reported that immunization of PDAPP transgenic mice with a vaccine containing fibrillar Aβ induced anti-Aβ antibodies that inhibited Aβ plaque deposition, dystrophic neurites and astrogliosis in the brains of the mice [114]. Importantly, when older mice that had already developed Aβ plaques were immunized with Aβ peptide, the amyloid plaques were cleared from the brain. Subsequently, other researchers showed that anti-Aβ immunotherapy improved behavioral measures in APP-transgenic mice [115]. Thus Anti-Aβ immunotherapy represents a potentially powerful strategy for reducing pathological forms of Aβ, and possibly aberrant forms of tau, in the brains of AD patients [98104]. Although results from the Phase I trial showed good safety and tolerability, the phase IIa portion of the AN1792 immunotherapy vaccine trial was halted because approximately 6% of the volunteers developed symptoms of an adverse inflammatory response in the brain [105]. Postmortem analysis of two cases with meningoencephalitis showed robust glial activation, T-cell infiltration and clearance of Aβ. Speculation on the cause of the meningoencephalitis has focused on Aβ-reactive T cells and adjuvant-induced inflammation in the brain [106, 107].
In addition, both active and passive immunotherapy increase the risk of adverse cerebral vascular events, including increased densities of cortical microhemorrhages and microvascular lesions, white matter abnormalities and vasogenic edema [103, 108112]. Interestingly, transgenic mouse models of Alzheimer’s disease amyloidosis have actually been good predictors of anti-Aβ immunotherapy-induced adverse events in the cerebral vasculature.
Overall, there was significant reduction in cortical Aβ plaque load and gliosis, and a reduction in dystrophic neurites in patients immunized with fibrillar Aβ. However, initial reports did not detect a change in neurofibrillary pathology in response to immunotherapy [101]. More recent analysis with a larger group of cases have reported a significant reduction in neuropil threads and dystrophic neurites in areas cleared of amyloid plaques, i.e. cerebral cortex, CA1 hippocampus, subiculum and enthorinal cortex [104, 113]. However, the phospho-tau accumulation in the neuronal cell bodies, contributing to neurofibrillary tangles, appeared not to be affected [104]. We previously reported a similar finding regarding the persistence of established tangles even with high titers of anti-Aβ antibodies in the 3xTgAD model [114]. Importantly, relatively high and chronic anti-Aβ antibodies titers appear to be required to maintain amyloid clearance in the brain [103].
As mentioned above, APP transgenic mice have proven to be good predictors of anti-Aβ immunotherapy-induced adverse events in the cerebral vasculature. In both mice and humans CAA for the most part has remained refractory to immunotherapy [98, 99, 103, 115117]. Moreover, the decrease of parenchymal Aβ plaques due to anti-Aβ immunization has been accompanied by a corresponding increase in vascular amyloid deposition. This has been interpreted to be due to immunotherapy-induced mobilization of Aβ in plaques, consisting of mostly Aβ42, which then travels with the flow of interstitial fluid to the basement membranes of cerebral capillaries and arteries where the Aβ accumulates [7]. Evidence in support of this hypothesis has come from further analysis of the CAA in patients that were vaccinated, which showed a prominent increase in the amount of Aβ42 in the cerebral vessels. Whether the immunotherapy-induced adverse cerebral vascular events can be clinically managed remains to be determined. For example, during the phase II stage of Elan’s Bapineuzumab (AAB-001) passive immunotherapy clinical trial 10 out of 12 patients that developed vasogenic edema were ApoE 4 positive, and ApoE 4 is found in 40% of the AD population, however lower dosing with the antibody appears to reduce the risk. Regarding the mechanism underlying the immunotherapy-mediated increase in CAA, Carare and colleagues have proposed that antibody-Aβ immune complexes may actually interfere with perivascular drainage when they are located specifically in the basement membranes, but at later time points perivascular drainage actually recovers due to clearance of immune complexes [Carare R et al., 9th International Alzheimer's Congress / Parkinson's Congress (AD/PD) 2009 Prague, Czech Republic]. Recent neuropathological data from the AN1792 clinical trial also provides support for the possibility that long-term immunotherapy may be able to clear Aβ from the cerebral vasculature. Analysis of two cases where the immunized patients lived for an extended period of time (four to five years) with the persistent presence of anti-Aβ antibodies had virtually complete absence of both plaques and CAA [103].
In old canines immunized with aggregated Aβ42 monthly for 25 months we were able to induce high levels of anti-Aβ antibodies. Immunotherapy initiated a robust reduction in parenchymal amyloid plaques in the absence of detectable CAA deposition, further supporting idea that the increase in CAA in response to immunotherapy may be transient [103, 118].
Another significant adverse event associated with immunotherapy and redistribution of Aβ from the parenchyma towards cerebral vasculature is the increased density of microhemorrhages, initially described in the mouse model of AD [115] and subsequently reported in AN1792 clinical trials [103, 119]. We also reported a significant increase in cerebrovascular microhemorrhages after active immunization of old Tg2576 mice [120], with involvement of leptomeningeal vessels and cortical arteries. Moreover, the concurrent increase in CAA and microhemorrhages was accompanied by significant co-localization of complement factors C1q and C3b at sites of CAA and microhemorrhages (Figure 3). Interestingly, in very old Tg2576 mice the cognitive benefits of immunotherapy persisted in spite of increased risks of CAA and microhemorrhages [121].
Figure 3
Figure 3
Anti-Aβ immunotherapy in very old Tg2576 mice is associated with the increased incidents of vascular failure. 18 months old Tg2576 mice were treated with mannan-Aβ28 conjugate vaccine, which significantly reduced amyloid load and gliosis, (more ...)
In preliminary studies we have tested the hypothesis that immunotherapy-induced microhemorrhages are caused by inflammation from antibody-Aβ immune complex formation at the sites of the CAA. In very old (20+ months) Tg2576 APP transgenic mice with substantial CAA we co-administered minocycline, which can suppress activation of microglia and monocytes, together with passive immunotherapy. While minocycline significantly attenuated microglial activation, it did not affect the number of microhemorrhages in the brains of the mice. However, minocycline did modestly decrease the size of microhemorrhages (Figure 4).
Figure 4
Figure 4
Preliminary studies with minocycline as an adjunct anti-inflammatory therapy to anti-Aβ immunotherapy in very old Tg2576. Twenty months old Tg2576 were injected weekly with anti-Aβ antibodies and supplemented with minocycline diet for (more ...)
Other approaches aimed at minimizing adverse events at sites of CAA include utilizing deglycosylation of the Fc portion of anti-Aβ immunoglobulins to reduce complement activation and Fc receptor-mediated inflammatory functions. APP transgenic mice that received the deglycosylated anti-Aβ (de-2H6) showed significant reductions in total Aβ immunochemistry and Congo red. Significantly fewer vascular amyloid deposits and microhemorrhages were observed in mice administered the de-2H6 antibody compared with mice receiving unmodified 2H6 antibody. Thus deglycosylated anti-Aβ antibodies may be preferable to unmodified IgG for anti-Aβ immunotherapy [122, 123]. Finally, intracerebroventricular delivery of low levels of anti- Aβ antibodies, as oppose to high doses delivered peripherally, reduces CAA and associated microhemorrhages, while preserving amyloid-clearing and behavior benefits in Tg2576 mice [124].
Recognition that cerebral vascular dysfunction plays a critical secondary role in many neurodegenerative diseases, and that the blood brain barrier appears to be particularly susceptible to age-related functional decline presents a significant challenge to researchers and clinicians. We envision two areas that should be targeted for future therapeutic intervention, endothelial cell transport and the perivascular drainage pathway, because both are involved in removing metabolic waste products from the brain. In this review we have focused on the clinical problems, such as intracerebral hemorrhage, deficits in endothelial transport, clogging of perivascular drainage, and increased microhemorrhages associated with the accumulation of one particular waste product, the Aβ peptide, which is the primary component of CAA in the vascular system. We also addressed the issue CAA-associated adverse events linked to anti-Aβ immunotherapy, and provided some examples of potential therapies to minimize the accumulation of CAA and reduce CAA-induced pathological complications.
Acknowledgements
The data presented in this review was funded in part by the following National Institutes of Health R01 Grants: NIA-AG020241, NIA-AG00538 and NINDS-NS50895 (DHC), and by an Alzheimer’s Association grant: IIRG 91822 (DHC). Brain tissue, antibodies and peptides were provided by the UCI-ADRC through funding from an NIH/NIA grant: P50 AG16573.
1. Kalaria RN. Linking cerebrovascular defense mechanisms in brain ageing and Alzheimer's disease. Neurobiol Aging. 2009;30:1512–1514. [PubMed]
2. Iadecola C, Park L, Capone C. Threats to the mind: aging, amyloid, and hypertension. Stroke. 2009;40:S40–S44. [PMC free article] [PubMed]
3. Knopman DS, et al. Cardiovascular risk factors and cerebral atrophy in a middle-aged cohort. Neurology. 2005;65:876–881. [PubMed]
4. Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer's disease: inflammation, cholesterol, and misfolded proteins. Lancet. 2004;363:1139–1146. [PubMed]
5. Deane R, et al. LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron. 2004;43:333–344. [PubMed]
6. Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57:178–201. [PubMed]
7. Carare RO, et al. Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology. Neuropathol Appl Neurobiol. 2008;34:131–144. [PubMed]
8. Weller RO, et al. Perivascular drainage of amyloid-beta peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathol. 2008;18:253–266. [PubMed]
9. Weller RO, et al. Cerebral amyloid angiopathy in the aetiology and immunotherapy of Alzheimer disease. Alzheimers Res Ther. 2009;1:6. [PMC free article] [PubMed]
10. Clapham R, et al. Cervical lymph nodes are found in direct relationship with the internal carotid artery: significance for the lymphatic drainage of the brain. Clin Anat. 23:43–47. [PubMed]
11. Eng JA, et al. Clinical manifestations of cerebral amyloid angiopathy-related inflammation. Ann Neurol. 2004;55:250–256. [PubMed]
12. Grabowski TJ, et al. Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol. 2001;49:697–705. [PubMed]
13. Chui HC, et al. Cognitive impact of subcortical vascular and Alzheimer's disease pathology. Ann Neurol. 2006;60:677–687. [PMC free article] [PubMed]
14. Selnes OA, Vinters HV. Vascular cognitive impairment. Nat Clin Pract Neurol. 2006;2:538–547. [PubMed]
15. McGeer PL, Rogers J, McGeer EG. Inflammation, anti-inflammatory agents and Alzheimer disease: the last 12 years. J Alzheimers Dis. 2006;9:271–276. [PubMed]
16. Huang J, et al. Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein. Science. 1999;285:595–599. [PubMed]
17. Pryce G, et al. Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis. J Neuroimmunol. 2005;165:41–52. [PubMed]
18. Rostagno A, et al. Complement activation in chromosome 13 dementias. Similarities with Alzheimer's disease. J Biol Chem. 2002;277:49782–49790. [PubMed]
19. Revesz T, et al. Sporadic and familial cerebral amyloid angiopathies. Brain Pathol. 2002;12:343–357. [PubMed]
20. Holton JL, et al. Familial Danish dementia: a novel form of cerebral amyloidosis associated with deposition of both amyloid-Dan and amyloid-beta. J Neuropathol Exp Neurol. 2002;61:254–267. [PubMed]
21. Revesz T, et al. Cerebral amyloid angiopathies: a pathologic, biochemical, and genetic view. J Neuropathol Exp Neurol. 2003;62:885–898. [PubMed]
22. Esiri MM, Wilcock GK. Cerebral amyloid angiopathy in dementia and old age. J Neurol Neurosurg Psychiatry. 1986;49:1221–1226. [PMC free article] [PubMed]
23. Belza MG, Urich H. Cerebral amyloid angiopathy in Down's syndrome. Clin Neuropathol. 1986;5:257–260. [PubMed]
24. Premkumar DR, et al. Apolipoprotein E-epsilon4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology associated with Alzheimer's disease. Am J Pathol. 1996;148:2083–2095. [PubMed]
25. Chalmers K, Wilcock GK, Love S. APOE epsilon 4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of A beta protein. Neuropathol Appl Neurobiol. 2003;29:231–238. [PubMed]
26. Love S, et al. APOE and cerebral amyloid angiopathy in the elderly. Neuroreport. 2003;14:1535–1536. [PubMed]
27. Selkoe DJ, et al. Conservation of brain amyloid proteins in aged mammals and humans with Alzheimer's disease. Science. 1987;235:873–877. [PubMed]
28. Uchida K, Nakayama H, Goto N. Pathological studies on cerebral amyloid angiopathy, senile plaques and amyloid deposition in visceral organs in aged dogs. J Vet Med Sci. 1991;53:1037–1042. [PubMed]
29. Walker LC. Animal models of cerebral beta-amyloid angiopathy. Brain Res Brain Res Rev. 1997;25:70–84. [PubMed]
30. Hendriks L, et al. Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet. 1992;1:218–221. [PubMed]
31. Bornebroek M, Haan J, Roos RA. Hereditary cerebral hemorrhage with amyloidosis--Dutch type (HCHWA-D): a review of the variety in phenotypic expression. Amyloid. 1999;6:215–224. [PubMed]
32. Miravalle L, et al. Substitutions at codon 22 of Alzheimer's abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J Biol Chem. 2000;275:27110–27116. [PubMed]
33. Obici L, et al. A novel AbetaPP mutation exclusively associated with cerebral amyloid angiopathy. Ann Neurol. 2005;58:639–644. [PubMed]
34. Cabrejo L, et al. Phenotype associated with APP duplication in five families. Brain. 2006;129:2966–2976. [PubMed]
35. Yamada M, et al. Association of presenilin-1 polymorphism with cerebral amyloid angiopathy in the elderly. Stroke. 1997;28:2219–2221. [PubMed]
36. Mann DM, et al. Amyloid (Abeta) deposition in chromosome 1-linked Alzheimer's disease: the Volga German families. Ann Neurol. 1997;41:52–57. [PubMed]
37. Crook R, et al. A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med. 1998;4:452–455. [PubMed]
38. Houlden H, et al. Variant Alzheimer's disease with spastic paraparesis and cotton wool plaques is caused by PS-1 mutations that lead to exceptionally high amyloid-beta concentrations. Ann Neurol. 2000;48:806–808. [PubMed]
39. Yamada M. Cerebral amyloid angiopathy and gene polymorphisms. J Neurol Sci. 2004;226:41–44. [PubMed]
40. O'Donnell HC, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med. 2000;342:240–245. [PubMed]
41. Schneider JA, et al. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology. 2007;69:2197–2204. [PubMed]
42. Nicoll JA, et al. Cerebral amyloid angiopathy plays a direct role in the pathogenesis of Alzheimer's disease. Pro-CAA position statement. Neurobiol Aging. 2004;25:589–597. discussion 603-584. [PubMed]
43. Zlokovic BV. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 2005;28:202–208. [PubMed]
44. Lippa CF, Knopman DS. Dementia: many roads, but not built in a day. Neurology. 2007;69:2193–2194. [PubMed]
45. Yamaguchi H, et al. Immunoelectron microscopic localization of amyloid beta protein in the diffuse plaques of Alzheimer-type dementia. Brain Res. 1990;508:320–324. [PubMed]
46. Dickson DW. The pathogenesis of senile plaques. J Neuropathol Exp Neurol. 1997;56:321–339. [PubMed]
47. McGowan E, et al. Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron. 2005;47:191–199. [PMC free article] [PubMed]
48. Kim J, et al. Abeta40 inhibits amyloid deposition in vivo. J Neurosci. 2007;27:627–633. [PubMed]
49. Van Broeckhoven C. Presenilins and Alzheimer disease. Nat Genet. 1995;11:230–232. [PubMed]
50. Murayama O, et al. Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett. 1999;265:61–63. [PubMed]
51. Taddei K, et al. Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease. Neuroreport. 1998;9:3335–3339. [PubMed]
52. Castano EM, et al. The length of amyloid-beta in hereditary cerebral hemorrhage with amyloidosis, Dutch type. Implications for the role of amyloid-beta 1–42 in Alzheimer's disease. J Biol Chem. 1996;271:32185–32191. [PubMed]
53. Frangione B, et al. Familial cerebral amyloid angiopathy related to stroke and dementia. Amyloid. 2001;8 Suppl 1:36–42. [PubMed]
54. Dahme E, Schroder B. [Congophilic angiopathy, cerebrovascular microaneurysms and cerebral hemorrhages in old dogs] Zentralbl Veterinarmed A. 1979;26:601–613. [PubMed]
55. Giaccone G, et al. Cerebral preamyloid deposits and congophilic angiopathy in aged dogs. Neurosci Lett. 1990;114:178–183. [PubMed]
56. Papaioannou N, et al. Immunohistochemical investigation of the brain of aged dogs. I. Detection of neurofibrillary tangles and of 4-hydroxynonenal protein, an oxidative damage product, in senile plaques. Amyloid. 2001;8:11–21. [PubMed]
57. Walker LC, et al. Amyloid in the brains of aged squirrel monkeys. Acta Neuropathol. 1990;80:381–387. [PubMed]
58. Yamaguchi H, et al. Beta amyloid is focally deposited within the outer basement membrane in the amyloid angiopathy of Alzheimer's disease. An immunoelectron microscopic study. Am J Pathol. 1992;141:249–259. [PubMed]
59. Natte R, et al. Ultrastructural evidence of early non-fibrillar Abeta42 in the capillary basement membrane of patients with hereditary cerebral hemorrhage with amyloidosis, Dutch type. Acta Neuropathol. 1999;98:577–582. [PubMed]
60. Jarrett JT, Berger EP, Lansbury PT., Jr The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer's disease. Biochemistry. 1993;32:4693–4697. [PubMed]
61. Kimchi EY, et al. Analysis of cerebral amyloid angiopathy in a transgenic mouse model of Alzheimer disease using in vivo multiphoton microscopy. J Neuropathol Exp Neurol. 2001;60:274–279. [PubMed]
62. Domnitz SB, et al. Progression of cerebral amyloid angiopathy in transgenic mouse models of Alzheimer disease. J Neuropathol Exp Neurol. 2005;64:588–594. [PubMed]
63. Snow AD, Willmer JP, Kisilevsky R. Sulfated glycosaminoglycans in Alzheimer's disease. Hum Pathol. 1987;18:506–510. [PubMed]
64. Namba Y, et al. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res. 1991;541:163–166. [PubMed]
65. Abraham CR, Selkoe DJ, Potter H. Immunochemical identification of the serine protease inhibitor alpha 1-antichymotrypsin in the brain amyloid deposits of Alzheimer's disease. Cell. 1988;52:487–501. [PubMed]
66. Bauer J, et al. Interleukin-6 and alpha-2-macroglobulin indicate an acute-phase state in Alzheimer's disease cortices. FEBS Lett. 1991;285:111–114. [PubMed]
67. McGeer PL, et al. Activation of the classical complement pathway in brain tissue of Alzheimer patients. Neurosci Lett. 1989;107:341–346. [PubMed]
68. McGeer PL, et al. Pathological proteins in senile plaques. Tohoku J Exp Med. 1994;174:269–277. [PubMed]
69. Verbeek MM, et al. Accumulation of intercellular adhesion molecule-1 in senile plaques in brain tissue of patients with Alzheimer's disease. Am J Pathol. 1994;144:104–116. [PubMed]
70. Verbeek MM, Eikelenboom P, de Waal RM. Differences between the pathogenesis of senile plaques and congophilic angiopathy in Alzheimer disease. J Neuropathol Exp Neurol. 1997;56:751–761. [PubMed]
71. Verbeek MM, et al. Distribution of A beta-associated proteins in cerebrovascular amyloid of Alzheimer's disease. Acta Neuropathol. 1998;96:628–636. [PubMed]
72. Schwab C, Hosokawa M, McGeer PL. Transgenic mice overexpressing amyloid beta protein are an incomplete model of Alzheimer disease. Exp Neurol. 2004;188:52–64. [PubMed]
73. Davis J, et al. Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursor. J Biol Chem. 2004;279:20296–20306. [PubMed]
74. Fan R, DeFilippis K, Van Nostrand WE. Induction of complement proteins in a mouse model for cerebral microvascular A beta deposition. J Neuroinflammation. 2007;4:22. [PMC free article] [PubMed]
75. McGeer PL, McGeer EG. Inflammation, autotoxicity and Alzheimer disease. Neurobiol Aging. 2001;22:799–809. [PubMed]
76. Tenner AJ. Complement in Alzheimer's disease: opportunities for modulating protective and pathogenic events. Neurobiol Aging. 2001;22:849–861. [PubMed]
77. Wyss-Coray T, et al. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. Proc Natl Acad Sci U S A. 2002;99:10837–10842. [PubMed]
78. Maier M, et al. Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci. 2008;28:6333–6341. [PMC free article] [PubMed]
79. Fonseca MI, et al. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J Neurosci. 2004;24:6457–6465. [PubMed]
80. Strittmatter WJ, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90:1977–1981. [PubMed]
81. Yamaguchi H, et al. Presence of apolipoprotein E on extracellular neurofibrillary tangles and on meningeal blood vessels precedes the Alzheimer beta-amyloid deposition. Acta Neuropathol. 1994;88:413–419. [PubMed]
82. Corder EH, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993;261:921–923. [PubMed]
83. Strittmatter WJ, Roses AD. Apolipoprotein E and Alzheimer disease. Proc Natl Acad Sci U S A. 1995;92:4725–4727. [PubMed]
84. Greenberg SM, et al. Apolipoprotein E epsilon 4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol. 1995;38:254–259. [PubMed]
85. Greenberg SM, et al. Apolipoprotein E epsilon 4 is associated with the presence and earlier onset of hemorrhage in cerebral amyloid angiopathy. Stroke. 1996;27:1333–1337. [PubMed]
86. Thal DR, et al. Two types of sporadic cerebral amyloid angiopathy. J Neuropathol Exp Neurol. 2002;61:282–293. [PubMed]
87. Zhang SH, et al. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science. 1992;258:468–471. [PubMed]
88. Games D, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature. 1995;373:523–527. [PubMed]
89. Bales KR, et al. Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nat Genet. 1997;17:263–264. [PubMed]
90. Irizarry MC, et al. Apolipoprotein E affects the amount, form, and anatomical distribution of amyloid beta-peptide deposition in homozygous APP(V717F) transgenic mice. Acta Neuropathol. 2000;100:451–458. [PubMed]
91. Dodart JC, et al. Apolipoprotein E alters the processing of the beta-amyloid precursor protein in APP(V717F) transgenic mice. Brain Res. 2002;955:191–199. [PubMed]
92. Nilsson LN, et al. Cognitive impairment in PDAPP mice depends on ApoE and ACT-catalyzed amyloid formation. Neurobiol Aging. 2004;25:1153–1167. [PubMed]
93. Hsiao K, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996;274:99–102. [PubMed]
94. Irizarry MC, et al. APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1. J Neuropathol Exp Neurol. 1997;56:965–973. [PubMed]
95. Holtzman DM, et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2000;97:2892–2897. [PubMed]
96. Fagan AM, et al. Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer's disease. Neurobiol Dis. 2002;9:305–318. [PubMed]
97. Xu F, et al. Human apolipoprotein E redistributes fibrillar amyloid deposition in Tg-SwDI mice. J Neurosci. 2008;28:5312–5320. [PMC free article] [PubMed]
98. Nicoll JA, et al. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003;9:448–452. [PubMed]
99. Ferrer I, et al. Neuropathology and pathogenesis of encephalitis following amyloid-beta immunization in Alzheimer's disease. Brain Pathol. 2004;14:11–20. [PubMed]
100. Masliah E, et al. Abeta vaccination effects on plaque pathology in the absence of encephalitis in Alzheimer disease. Neurology. 2005;64:129–131. [PubMed]
101. Nicoll JA, et al. Abeta species removal after abeta42 immunization. J Neuropathol Exp Neurol. 2006;65:1040–1048. [PubMed]
102. Holmes C, et al. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008;372:216–223. [PubMed]
103. Boche D, et al. Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain. Brain. 2008;131:3299–3310. [PubMed]
104. Boche D, et al. Reduction of aggregated Tau in neuronal processes but not in the cell bodies after Abeta42 immunisation in Alzheimer's disease. Acta Neuropathol. 120:13–20. [PubMed]
105. Orgogozo JM, et al. Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology. 2003;61:46–54. [PubMed]
106. Cribbs DH, et al. Adjuvant-dependent modulation of Th1 and Th2 responses to immunization with beta-amyloid. Int Immunol. 2003;15:505–514. [PMC free article] [PubMed]
107. Cribbs DH. Abeta DNA vaccination for Alzheimer's disease: focus on disease prevention. CNS Neurol Disord Drug Targets. 9:207–216. [PMC free article] [PubMed]
108. Weller RO, Boche D, Nicoll JA. Microvasculature changes and cerebral amyloid angiopathy in Alzheimer's disease and their potential impact on therapy. Acta Neuropathol. 2009;118:87–102. [PubMed]
109. Boche D, et al. Neuropathology after active Abeta42 immunotherapy: implications for Alzheimer's disease pathogenesis. Acta Neuropathol. 120:369–384. [PubMed]
110. Uro-Coste E, et al. Cerebral amyloid angiopathy and microhemorrhages after amyloid beta vaccination: case report and brief review. Clin Neuropathol. 29:209–216. [PubMed]
111. Black RS, et al. A single ascending dose study of bapineuzumab in patients with Alzheimer disease. Alzheimer Dis Assoc Disord. 24:198–203. [PMC free article] [PubMed]
112. Salloway S, et al. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73:2061–2070. [PMC free article] [PubMed]
113. Serrano-Pozo A, et al. Beneficial effect of human anti-amyloid-{beta} active immunization on neurite morphology and tau pathology. Brain [PMC free article] [PubMed]
114. Oddo S, et al. Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron. 2004;43:321–332. [PubMed]
115. Pfeifer M, et al. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science. 2002;298:1379. [PubMed]
116. Racke MM, et al. Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci. 2005;25:629–636. [PubMed]
117. Wilcock DM, et al. Amyloid-beta vaccination, but not nitro-nonsteroidal anti-inflammatory drug treatment, increases vascular amyloid and microhemorrhage while both reduce parenchymal amyloid. Neuroscience. 2007;144:950–960. [PMC free article] [PubMed]
118. Head E, et al. A two-year study with fibrillar beta-amyloid (Abeta) immunization in aged canines: effects on cognitive function and brain Abeta. J Neurosci. 2008;28:3555–3566. [PubMed]
119. Patton RL, et al. Amyloid-beta peptide remnants in AN-1792-immunized Alzheimer's disease patients: a biochemical analysis. Am J Pathol. 2006;169:1048–1063. [PubMed]
120. Petrushina I, et al. Mannan-Abeta28 conjugate prevents Abeta-plaque deposition, but increases microhemorrhages in the brains of vaccinated Tg2576 (APPsw) mice. J Neuroinflammation. 2008;5:42. [PMC free article] [PubMed]
121. Wilcock DM, et al. 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. J Neuroinflammation. 2004;1:24. [PMC free article] [PubMed]
122. Wilcock DM, et al. Deglycosylated anti-amyloid-beta antibodies eliminate cognitive deficits and reduce parenchymal amyloid with minimal vascular consequences in aged amyloid precursor protein transgenic mice. J Neurosci. 2006;26:5340–5346. [PubMed]
123. Karlnoski RA, et al. Deglycosylated anti-Abeta antibody dose-response effects on pathology and memory in APP transgenic mice. J Neuroimmune Pharmacol. 2008;3:187–197. [PubMed]
124. Thakker DR, et al. Intracerebroventricular amyloid-beta antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice. Proc Natl Acad Sci U S A. 2009;106:4501–4506. [PubMed]