Progression Of Cerebral Amyloid Angiopathy Research Articles

Abstract WP144: Cerebral Amyloid Angiopathy Pathology Worsens Stroke Outcome and Has a Detrimental Effect on the Gut Microbiome in Mice

Background: Cerebral amyloid angiopathy (CAA) is associated with both ischemic and hemorrhagic stroke, is a known cause of vascular cognitive impairment (VCI), and predicts worsened outcome after stroke. A growing body of literature has highlighted the importance of the gut microbiome in stroke outcome and neurodegenerative diseases such as Alzheimerz’s. However, little is known about how changes in the microbiome can affect CAA progression. The gut-brain axis is highly involved in the systemic inflammatory response following stroke. Furthermore, the gut is a primary source of bacterial translocation resulting in cerebral inflammation which further may contribute to vascular pathology. Therefore, the cross talk between CAA, stroke, and gut function could be key in our understanding and treatment of stroke in patients with CAA. Methods: Symptomatic male Tg-SwDI (4 mths old) and C57BL/6 wild type (WT) mice underwent a 60 minute transient MCAO. Stroke was confirmed with cresyl violet staining and presence of amyloid β (Aβ) plaques were demonstrated with thioflavin. Post-stroke motor function was assessed at day 4 with open field-testing and results were compared to pre-stroke baseline and WT values and cognitive assessment was performed with the Y-maze test. Furthermore, PCR was used to identify the presence of Firmicutes and Bacteroidetes ratio (F:B) in both brain tissue and gut content. Results: We demonstrate a significant decrease in the total distance traveled in both open field and cognitive Y-maze (p<0.05 and p<0.01 respectively) at baseline of Tg-SwDI mice. This was associated with the presence of Aβ plaque in the brain. PCR did not reveal any conclusive evidence for bacterial translocation in the brain at day 4. However, there was a pathogenic shift in the gut F:B ratio following stroke in Tg-SwDI mice compared to sham Tg-SwDI or sham WT controls and this will be confirmed by 16S rRNA gene sequencing. Conclusion: Symptomatic CAA mice exhibit decreased motor and cognitive function compared to WT controls. Furthermore, 16S sequencing was performed to look at the bacterial translocation in detail from the gut to the brain. This is the first study to link CAA, stroke, and the gut brain axis, that may be crucial in understanding the complexity of stroke pathology.

Cerebral amyloid angiopathy and Alzheimer disease - one peptide, two pathways.

The shared role of amyloid-β (Aβ) deposition in cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD) is arguably the clearest instance of crosstalk between neurodegenerative and cerebrovascular processes. The pathogenic pathways of CAA and AD intersect at the levels of Aβ generation, its circulation within the interstitial fluid and perivascular drainage pathways and its brain clearance, but diverge in their mechanisms of brain injury and disease presentation. Here, we review the evidence for and the pathogenic implications of interactions between CAA and AD. Both pathologies seem to be driven by impaired Aβ clearance, creating conditions for a self-reinforcing cycle of increased vascular Aβ, reduced perivascular clearance and further CAA and AD progression. Despite the close relationship between vascular and plaque Aβ deposition, several factors favour one or the other, such as the carboxy-terminal site of the peptide and specific co-deposited proteins. Amyloid-related imaging abnormalities that have been seen in trials of anti-Aβ immunotherapy are another probable intersection between CAA and AD, representing overload of perivascular clearance pathways and the effects of removing Aβ from CAA-positive vessels. The intersections between CAA and AD point to a crucial role for improving vascular function in the treatment of both diseases and indicate the next steps necessary for identifying therapies.

Long-Term Follow-Up of Cerebral Amyloid Angiopathy-Associated Intracranial Hemorrhage Reveals a High Prevalence of Atrial Fibrillation

Goal: Cerebral amyloid angiopathy (CAA) is the second-most common cause of nontraumatic intracerebral hemorrhages (ICH), surpassed only by uncontrolled hypertension. We characterized the percentage, risk factors, and comorbidities of patients suffering from CAA-related ICH in relation to long-term outcomes. Material and Methods: We performed retrospective analyses and clinical follow-ups of individuals suffering from ICH who were directly admitted to neurosurgery between 2002 and 2016. Findings: Seventy-four of 174 (42%) spontaneous nontraumatic lobar ICH cases leastwise satisfied the modified Boston criteria definition for at least “possible CAA.” Females suffered a higher risk of CAA-caused ICH (42 of 74, 56.8%, P= .035). Atrial fibrillation as a major comorbidity was observed in 19 patients (25.7%). Recovery (decrease of modified Rankin scale [mRS]) was highest during hospitalization in the acute clinic. One-year mortality was as follows: 14 of 25 patients (56%) with probable CAA without supporting pathology, 6 of 18, and 8 of 31 patients with supporting pathology and possible CAA, respectively. Only 10 of 74 (13.6%) had favorable long-term outcomes (mRS ≤2). Increasing numbers of lobar hemorrhages, low initial Glasgow Coma Scale, and subarachnoid hemorrhage were significantly associated with poor survivability, whereas statins, antithrombotic agents, an intraventricular hemorrhage, and midline shift played seemingly minor roles. Conclusions: Symptomatic ICH is a serious stage in CAA progression with high mortality. The high incidence of concurrent atrial fibrillation in these patients may support data on more widespread vascular pathology in CAA.

Early Aβ reduction prevents progression of cerebral amyloid angiopathy.

Clinical trials targeting β-amyloid peptides (Aβ) for Alzheimer disease (AD) failed for arguable reasons that include selecting the wrong stages of AD pathophysiology or Aβ being the wrong target. Targeting Aβ to prevent cerebral amyloid angiopathy (CAA) has not been rigorously followed, although the causal role of Aβ for CAA and related hemorrhages is undisputed. CAA occurs with normal aging and to various degrees in AD, where its impact and treatment is confounded by the presence of parenchymal Aβ deposition. APPDutch mice develop CAA in the absence of parenchymal amyloid, mimicking hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D). Mice were treated with a β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor. We used 3-dimensional ultramicroscopy and immunoassays for visualizing CAA and assessing Aβ in cerebrospinal fluid (CSF) and brain. CAA onset in mice was at 22 to 24 months, first in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. CSF Aβ increased with aging followed by a decrease of both Aβ40 and Aβ42 upon CAA onset, supporting the idea that combined reduction of CSF Aβ40 and Aβ42 is a specific biomarker for vascular amyloid. BACE1 inhibitor treatment starting at CAA onset and continuing for 4 months revealed a 90% Aβ reduction in CSF and largely prevented CAA progression and associated pathologies. This is the first study showing that Aβ reduction at early disease time points largely prevents CAA in the absence of parenchymal amyloid. Our observation provides a preclinical basis for Aβ-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D. ANN NEUROL 2019;86:561-571.

Abstract WP140: The Effect of Age-related Gut Dysbiosis on Microglial Function in Cerebral Amyloid Angiopathy

The role of “gut-immune-brain axis” across our lifespan is well recognized as a biologic variable. As our populations age, so does the prevalence of age-related illnesses including stroke and its sequelae. We examined how manipulating the microbiome alters the natural history of cerebral amyloid angiopathy (CAA), a major cause of recurring brain hemorrhages, stroke, and cognitive decline. Microglial phenotype changes with aging and deficits in microglial phagocytosis lead to increased amyloid burden in animal models of Alzheimer’s but it is not known if this occurs in CAA. We hypothesize that age-related dysbiosis accelerates initiation and progression of CAA and this effect is mediated by failure of microglial amyloid phagocytosis (MAP). We have investigated the effects of dysbiosis on MAP and cognitive decline in wild-type (WT) and Tg2576 transgenic mice. Gut microbiomes were altered in pre- and post-symptomatic transgenic mice via fecal microbiota transfer (FMT) from young and aged WT mice. Cognitive decline and microglial phenotype were assessed using behavioral tests and flow cytometry. Function of microglia using in vitro primary and ex vivo sorted cultures from CAA mice were also examined. Our preliminary data shows: 1) An increased Firmicutes:Bacteroidetes ratio, indicative of an aging microbiome, occurred in young recipients given aged donor FMT; conversely, the ratio decreased in aged mice given young biome(P<0.001, n=14); 2) Microglial phagocytosis was impaired in aged WT microglia (n=7/gp, P<0.01); and 3) Motor strength in both young and aged WT mice after FMT (n=17/gp) were dependent on the age of the donor microbiome rather than the age of the host (P<0.001). Our studies demonstrate an important role for the gut microbiome in modulating CAA pathogenesis and progression in the brain. Thus, manipulation of the gut microbiota could be an effective therapy to delay the onset and/or slow the progression of disease in CAA patients.

Abstract TP433: Structural, Molecular and Physiologic Alterations in Patients with Lobar Microbleeds

Background: Cerebral amyloid angiopathy (CAA) is diagnosed after a lobar intracerebral hemorrhage (L-ICH) but lobar microbleeds (LMB) are increasingly detected on MRIs of patients without L-ICH. We aimed to compare advanced imaging measures of structural brain damage, amyloid load, and cerebrovascular reactivity between CAA patients with L-ICH (CAA-ICH) and those with LMB (LMB-only). Methods: Standard MRI markers (LMB counts, cortical superficial siderosis [cSS], enlarged perivascular spaces [EPVS], white matter hyperintensity [WMH] patterns) and FreeSurfer based advanced volumetric analyses (calculated as percent of total intracranial volume) were obtained in 115 non-demented patients with either CAA-ICH or LMB-only. Pittsburgh compound B PET measures of amyloid deposition and fMRI measures of vascular reactivity (amplitude, time-to-peak, time-to-baseline) were also compared between the 2 groups. Results: LMB-only patients (n=37) presented with transient neurological symptoms or cognitive/gait complaints and stroke/neurodegenerative conditions were ruled out. Age, vascular risk factors, LMB counts, presence of cSS, EPVS counts and WMH patterns were not different between CAA-ICH and LMB-only (Table). Volume of WMH was significantly higher in CAA-ICH as compared to LMB-only patients in univariable and multivariable models (p=0.026). There was no difference in cortical thickness, WM volume, amyloid load/distribution and finally functional MRI markers of vascular reactivity between the two groups (Table). Conclusions: Our results indicate that measures of vascular physiology and amyloid load as well as structural damage of LMB-only patients are not different from CAA-ICH, except a lower WMH load. These data support the view that LMB-only patients represent a non-hemorrhagic stage of the disease and that they can be enrolled in clinical trials aimed at modifying the molecular/physiologic changes to reverse/prevent CAA progression.

Chronic treatment with five vascular risk factors causes cerebral amyloid angiopathy but no Alzheimer pathology in C57BL6 mice

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder and the most common form of dementia coming along with cerebral amyloid angiopathy (CAA) in more than 70% of all cases. However, CAA occurs also in pure form without AD pathology. Vascular life style risk factors such as obesity, hypertension, hypercholesterolemia, diabetes, stress or an old age play an important role in the progression of CAA. So far, no animal model for sporadic CAA has been reported, thus the aim of the present study was to create and characterize a new mouse model for sporadic CAA by treatment with different vascular risk factors. Healthy C57BL6 mice were treated with lifestyle vascular risk factors for 35 or 56 weeks: lipopolysaccharide, social stress, streptozotozin, high cholesterol diet and copper in the drinking water. Four behavioral tests (black-white box, classical maze, cheeseboard maze and plus-maze discriminative avoidance task) showed impaired learning, memory and executive functions as well as anxiety with increased age. The treated animals exhibited increased plasma levels of cortisol, insulin, interleukin-1ß, glucose and cholesterol, confirming the effectiveness of the treatment. Confocal microscopy analysis displayed severe vessel damage already after 35 weeks of treatment. IgG positive staining points to a severe blood-brain barrier (BBB) disruption and furthermore, cerebral bleedings were observed in a much higher amount in the treatment group. Importantly, inclusions of beta-amyloid in the vessels indicated the development of CAA, but no deposition of beta-amyloid plaques and tau pathology in the brains were seen. Taken together, we characterized a novel sporadic CAA mouse model, which offers a strategy to study the progression of the disease and therapeutic and diagnostic interventions.

Platelets isolated from an Alzheimer mouse damage healthy cortical vessels and cause inflammation in an organotypic ex vivo brain slice model

Platelets are anuclear blood cells and play a major role in hemostasis and thrombosis. Platelets express amyloid-precursor protein (APP), release beta-amyloid (Aβ) and are stimulated (pre-activated) in Alzheimer’s disease (AD). We hypothesize that such stimulated platelets severely damage brain vessels which subsequently leads to cerebrovascular damage in AD. In order to study this issue we isolated platelets from AD mice (expressing APP with the Swedish-Dutch-Iowa mutations), labeled them with the red fluorescent dye PKH26 and transcardially infused these freshly isolated platelets into the brains of anesthetized healthy C57BL6 wildtype mice. Brains were immediately taken, 110 µm thick organotypic brain slices prepared and cultured for 1 or 14 days. We observed that red PKH26+ fluorescent platelets were localized in collagen IV and Lectin-649 counterstained cortical brain vessels and that platelets from AD mice severely damaged cortical brain vessels in wildtype mice and entered the brain parenchyma. Confocal microscopy showed immunoreactivity for matrix metalloproteinases (MMP-2 and MMP-9) and beta-amyloid around these platelets. The effect was completely inhibited with an MMP inhibitor. Furthermore, isolated AD platelets caused inflammation and activated microglia around the site where platelets damaged cortical brain vessels. We conclude that AD-derived platelets more aggressively damage healthy vessels which may consequently play a role in the progression of cerebral amyloid angiopathy in AD.

Rapidly Sequential and Fatal Hemorrhaging in a Case of Cerebral Amyloid Angiopathy

Patient: Female, 63Final Diagnosis: Cerebral amyloid angiopathySymptoms: Altered mental state • aphasia • hemiplegiaMedication: —Clinical Procedure: —Specialty: NeurologyObjective:Unusual clinical courseBackground:Cerebral amyloid angiopathy (CAA) is an increasingly recognized cause of lobar intracerebral hemorrhage (ICH) and cognitive impairment in the aging population. Magnetic resonance imaging (MRI) of cerebral microbleeds is the most reliable option for clinical diagnosis of suspected CAA. The pathophysiology of microbleeds and ICH in CAA is not well understood, but it is thought to be the result of vessel weakening and rupture secondary to amyloid deposition. Little evidence has been established pertaining to the time course of recurrent CAA-related microbleeds or larger hemorrhages. Although several risk factors have been associated with an increased risk of ICH in CAA, there are no current treatment guidelines for recurrent hemorrhaging in CAA.Case Report:We present a rare case of rapidly sequential and fatal lobar hemorrhaging in the setting of suspected CAA, diagnosed by numerous microbleeds on MRI, compounded by the use of subcutaneous heparin in a 63-year-old female patient.Conclusions:This case broadens our understanding of a rarely identified progression of CAA and illustrates the need for further investigation of the use of subcutaneous heparin in the setting of probable CAA.

Longitudinal decrease in blood oxygenation level dependent response in cerebral amyloid angiopathy.

Lower blood oxygenation level dependent (BOLD) signal changes in response to a visual stimulus in functional magnetic resonance imaging (fMRI) have been observed in cross-sectional studies of cerebral amyloid angiopathy (CAA), and are presumed to reflect impaired vascular reactivity. We used fMRI to detect a longitudinal change in BOLD responses to a visual stimulus in CAA, and to determine any correlations between these changes and other established biomarkers of CAA progression. Data were acquired from 22 patients diagnosed with probable CAA (using the Boston Criteria) and 16 healthy controls at baseline and one year. BOLD data were generated from the 200 most active voxels of the primary visual cortex during the fMRI visual stimulus (passively viewing an alternating checkerboard pattern). In general, BOLD amplitudes were lower at one year compared to baseline in patients with CAA (p = 0.01) but were unchanged in controls (p = 0.18). The longitudinal difference in BOLD amplitudes was significantly lower in CAA compared to controls (p < 0.001). White matter hyperintensity (WMH) volumes and number of cerebral microbleeds, both presumed to reflect CAA-mediated vascular injury, increased over time in CAA (p = 0.007 and p = 0.001, respectively). Longitudinal increases in WMH (rs = 0.04, p = 0.86) or cerebral microbleeds (rs = − 0.18, p = 0.45) were not associated with the longitudinal decrease in BOLD amplitudes.

Deposition of amyloid β in the walls of human leptomeningeal arteries in relation to perivascular drainage pathways in cerebral amyloid angiopathy

Deposition of amyloid β (Aβ) in the walls of cerebral arteries as cerebral amyloid angiopathy (CAA) suggests an age-related failure of perivascular drainage of soluble Aβ from the brain. As CAA is associated with Alzheimer's disease and with intracerebral haemorrhage, the present study determines the unique sequence of changes that occur as Aβ accumulates in artery walls. Paraffin sections of post-mortem human occipital cortex were immunostained for collagen IV, fibronectin, nidogen 2, Aβ and smooth muscle actin and the immunostaining was analysed using Image J and confocal microscopy. Results showed that nidogen 2 (entactin) increases with age and decreases in CAA. Confocal microscopy revealed stages in the progression of CAA: Aβ initially deposits in basement membranes in the tunica media, replaces first the smooth muscle cells and then the connective tissue elements to leave artery walls completely or focally replaced by Aβ. The pattern of development of CAA in the human brain suggests expansion of Aβ from the basement membranes to progressively replace all tissue elements in the artery wall. Establishing this full picture of the development of CAA is pivotal in understanding the clinical presentation of CAA and for developing therapies to prevent accumulation of Aβ in artery walls. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.

Iron transport across the blood-brain barrier: development, neurovascular regulation and cerebral amyloid angiopathy.

There are two barriers for iron entry into the brain: (1) the brain-cerebrospinal fluid (CSF) barrier and (2) the blood-brain barrier (BBB). Here, we review the literature on developmental iron accumulation by the brain, focusing on the transport of iron through the brain microvascular endothelial cells (BMVEC) of the BBB. We review the iron trafficking proteins which may be involved in the iron flux across BMVEC and discuss the plausible mechanisms of BMVEC iron uptake and efflux. We suggest a model for how BMVEC iron uptake and efflux are regulated and a mechanism by which the majority of iron is trafficked across the developing BBB under the direct guidance of neighboring astrocytes. Thus, we place brain iron uptake in the context of the neurovascular unit of the adult brain. Last, we propose that BMVEC iron is involved in the aggregation of amyloid-β peptides leading to the progression of cerebral amyloid angiopathy which often occurs prior to dementia and the onset of Alzheimer's disease.

The Cerebrovascular Basement Membrane: Role in the Clearance of β-amyloid and Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA), the accumulation of β-amyloid (Aβ) peptides in the walls of cerebral blood vessels, is observed in the majority of Alzheimer’s disease (AD) brains and is thought to be due to a failure of the aging brain to clear Aβ. Perivascular drainage of Aβ along cerebrovascular basement membranes (CVBMs) is one of the mechanisms by which Aβ is removed from the brain. CVBMs are specialized sheets of extracellular matrix that provide structural and functional support for cerebral blood vessels. Changes in CVBM composition and structure are observed in the aged and AD brain and may contribute to the development and progression of CAA. This review summarizes the properties of the CVBM, its role in mediating clearance of interstitial fluids and solutes from the brain, and evidence supporting a role for CVBM in the etiology of CAA.

Reducing Available Soluble β-Amyloid Prevents Progression of Cerebral Amyloid Angiopathy in Transgenic Mice

Cerebral amyloid angiopathy (CAA), the accumulation of β-amyloid (Aβ) in the walls of leptomeningeal and cortical blood vessels of the brain, is a major cause of intracerebral hemorrhage and cognitive impairment and is commonly associated with Alzheimer disease. The progression of CAA, as measured in transgenic mice by longitudinal imaging with multiphoton microscopy, occurs in a predictable linear manner. The dynamics of Aβ deposition in and clearance from vascular walls and their relationship to the concentration of Aβ in the brain are poorly understood. We manipulated Aβ levels in the brain using 2 approaches: peripheral clearance via administration of the amyloid binding "peripheral sink" protein gelsolin and direct inhibition of its formation via administration of LY-411575, a small-molecule γ-secretase inhibitor. We found that gelsolin and LY-411575 both reduced the rate of CAA progression in Tg2576 mice from untreated rates of 0.58% ± 0.15% and 0.52% ± 0.09% to 0.11% ± 0.18% (p = 0.04) and -0.17% ± 0.09% (p < 0.001) of affected vessel per day, respectively, in the absence of an immune response. The progression of CAA was also halted when gelsolin was combined with LY-411575 (-0.004% ± 0.10%, p < 0.003). These data suggest that CAA progression can be prevented with non-immune approaches that may reduce the availability of soluble Aβ but without evidence of substantial amyloid clearance from vessels.

Tissue transglutaminase colocalizes with extracellular matrix proteins in cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is a key histopathological hallmark of Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). CAA is characterized by amyloid-beta (Aβ) depositions and remodeling of the extracellular matrix (ECM) in brain vessels and plays an important role in the development and progression of both AD and HCHWA-D. Tissue transglutaminase (tTG) modulates the ECM by molecular cross-linking of ECM proteins. Here, we investigated the distribution pattern, cellular source, and activity of tTG in CAA in control, AD, and HCHWA-D cases. We observed increased tTG immunoreactivity and colocalization with Aβ in the vessel wall in early stage CAA, whereas in later CAA stages, tTG and its cross-links were present in halos enclosing the Aβ deposition. In CAA, tTG and its cross-links at the abluminal side of the vessel were demonstrated to be either of astrocytic origin in parenchymal vessels, of fibroblastic origin in leptomeningeal vessels, and of endothelial origin at the luminal side of the deposited Aβ. Furthermore, the ECM proteins fibronectin and laminin colocalized with the tTG-positive halos surrounding the deposited Aβ in CAA. However, we observed that in situ tTG activity was present throughout the vessel wall in late stage CAA. Together, our data suggest that tTG and its activity might play a differential role in the development and progression of CAA, possibly evolving from direct modulation of Aβ aggregation to cross-linking of ECM proteins resulting in ECM restructuring.

Amyloid-β Contributes to Blood–Brain Barrier Leakage in Transgenic Human Amyloid Precursor Protein Mice and in Humans With Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is a degenerative disorder characterized by amyloid-β (Aβ) deposition in the blood-brain barrier (BBB). CAA contributes to injuries of the neurovasculature including lobar hemorrhages, cortical microbleeds, ischemia, and superficial hemosiderosis. We postulate that CAA pathology is partially due to Aβ compromising the BBB. We characterized 19 patients with acute stroke with "probable CAA" for neurovascular pathology based on MRI and clinical findings. Also, we studied the effect of Aβ on the expression of tight junction proteins and matrix metalloproteases (MMPs) in isolated rat brain microvessels. Two of 19 patients with CAA had asymptomatic BBB leakage and posterior reversible encephalopathic syndrome indicating increased BBB permeability. In addition to white matter changes, diffusion abnormality suggesting lacunar ischemia was found in 4 of 19 patients with CAA; superficial hemosiderosis was observed in 7 of 9 patients. Aβ(40) decreased expression of the tight junction proteins claudin-1 and claudin-5 and increased expression of MMP-2 and MMP-9. Analysis of brain microvessels from transgenic mice overexpressing human amyloid precursor protein revealed the same expression pattern for tight junction and MMP proteins. Consistent with reduced tight junction and increased MMP expression and activity, permeability was increased in brain microvessels from human amyloid precursor protein mice compared with microvessels from wild-type controls. Our findings indicate that Aβ contributes to changes in brain microvessel tight junction and MMP expression, which compromises BBB integrity. We conclude that Aβ causes BBB leakage and that assessing BBB permeability could potentially help characterize CAA progression and be a surrogate marker for treatment response.

Matrix metalloproteinase inhibition reduces oxidative stress associated with cerebral amyloid angiopathy in vivo in transgenic mice

Cerebral amyloid angiopathy (CAA), characterized by extracellular beta-amyloid peptide (Abeta) deposits in vessel walls, is present in the majority of cases of Alzheimer's disease and is a major cause of hemorrhagic stroke. Although the molecular pathways activated by vascular Abeta are poorly understood, extracellular matrix metalloproteinases (MMP) and Abeta-induced oxidative stress appear to play important roles. We adapted fluorogenic assays for MMP activity and reactive oxygen species generation for use in vivo. Using multiphoton microscopy in APPswe/PS1dE9 and Tg-2576 transgenic mice, we observed strong associations between MMP activation, oxidative stress, and CAA deposition in leptomeningeal vessels. Antioxidant treatment with alpha-phenyl-N-tert-butyl-nitrone reduced oxidative stress associated with CAA (approximately 50% reduction) without affecting MMP activation. Conversely, a selection of agents that inhibit MMP by different mechanisms of action, including minocycline, simvastatin, and GM6001, reduced not only CAA-associated MMP activation (approximately 30-40% reduction) but also oxidative stress (approximately 40% reduction). The inhibitors of MMP did not have direct antioxidant effects. Treatment of animals with alpha-phenyl-N-tert-butyl-nitrone or minocycline did not have a significant effect on CAA progression rates. These data suggest a close association between Abeta-related MMP activation and oxidative stress in vivo and raise the possibility that treatment with MMP inhibitors may have beneficial effects by indirectly reducing the oxidative stress associated with CAA.

Effect of Gelsolin on Cerebral Amyloid Angiopathy (CAA) in Transgenic Mice

Cerebral amyloid angiopathy (CAA), the deposition of cerebrovascular β‐amyloid (Aβ), is a cause of hemorrhagic stroke and is present in most cases of Alzheimer disease. We have previously developed a quantitative approach to measure CAA progression in mice and have shown that CAA can be reversed by passive immunotherapy. We now report the effect of peripheral administration of gelsolin, an agent with the ability to bind Aβ in the plasma and that may thus act as a peripheral sink for Aβ, on the rate of CAA progression. Cranial windows were placed in 11 month old mice, an age at which CAA deposition follows a mixed‐effects linear model. Seven days post‐craniotomy, mice were randomized to intraperitonal administration of either gelsolin (0.6 mg/kg) or vehicle every 2 days for 3 weeks. CAA in leptomeningeal arteries was imaged on day 0, 7, 14 and 21 post‐craniotomy using methoxy‐X04, with angiograms used to facilitate vessel alignment. Between day 0 and day 7 (prior to start of treatment) there was CAA progression as expected. Peripherally administrated gelsolin resulted in mild regression of CAA deposits. The effect of the peripherally administrated gelsolin was evident within a week after initial administration and this effect was sustained until day 21 (last imaging session). These data demonstrate that gelsolin, an agent with a peripherally acting effect on Aβ can cause regression of CAA in Tg2576. In addition, these data also suggest that plasma/brain Aβ dynamics may play a crucial role in the progression of CAA. Supported by NIH AG020570, EB00768 and AG21084, Caja Madrid fellowship (MG‐A), Lefler fellowship (CMP) and the Harvard NeuroDiscovery Center (RAB).

Effect of passive immunotherapy on the rate of progression of cerebral amyloid angiopathy (caa) in transgenic mice

Effect of passive immunotherapy on the rate of progression of cerebral amyloid angiopathy (caa) in transgenic mice

P4-292: Effect of immunotherapy on the rate of progression of cerebral amyloid angiopathy (CAA) in transgenic mice

P4-292: Effect of immunotherapy on the rate of progression of cerebral amyloid angiopathy (CAA) in transgenic mice