Mouse Model Of Cerebral Amyloid Angiopathy Research Articles

Abstract TMP115: White Matter Loss and Neurological Deficits Due to Chronic Global Hypoperfusion Are Worsened in a Mouse Model of Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is a disease of small and medium-sized vessels, characterized by amyloid deposition in the brain vasculature. The incidence of CAA increases with age and pathophysiological features (i.e., amyloid) overlap with that of Alzheimer’s Disease (AD). Cerebral hypoperfusion (CH) impairs the integrity of the blood brain barrier and contributes to cerebral atrophy and white matter loss. However, the link between hypoperfusion and vascular amyloid deposition remains understudied. We induced global CH with bilateral carotid artery stenosis (BCAS) in CAA mice of both sexes. We hypothesized that chronic CH accelerates cognitive decline in CAA, increases white matter damage, and induces gliotic changes in the brain. Using a mouse model of CAA (Tg-SwDI), male and female mice (12wks-old) were randomized to either BCAS (n=15) or sham (n=11) surgery. Cognitive (Y-maze (YM), NORT, Water Maze (WM)) and motor function (Open Field (OF)) testing was performed by a blinded investigator prior to surgery (baseline) and at regular intervals until tissue harvest 6 months post-BCAS. Brains were harvested for immunohistochemical (IHC) analysis (Kluver-Barrera (KB), Iba-1, GFAP, Myelin Basic Protein (MBP)) and flow cytometry. Sex-specific changes in spatial memory (YM) and learning (NORT/WM) were present in CAA BCAS mice, with females having an earlier onset of deficits than males. Female BCAS mice displayed deficits in cognition (NORT) at 3 (p=.003), 4 (YM, p=.0007), and 5-months (p=.01) after BCAS. Male BCAS mice demonstrated cognitive deficits 5 months post-BCAS (NORT, p=.001). Both female and male BCAS mice had poorer cognition (WM, p=.001) 6 months post-BCAS. IHC demonstrated increased demyelination (MBP, p=.004) and atrophy (KB) in the anterior corpus collosum (p=.04) and significant cortical gliosis (p=.02). The hippocampus contained higher numbers of NOX2-expressing (p= .051) and lipid-rich microglia in BCAS (p=.042) versus sham mice. Neuronal loss and increases in endothelial-cell amyloid levels were also found in BCAS CAA mice, using flow cytometry. Global CH accelerates cognitive deficits in a CAA model, an effect that is accelerated in female mice and led to gliosis, white matter damage, and lipid-accumulating microglia.

Abstract WP291: Cerebral Amyloid Angiopathy Induces Liver Inflammation in Aged Mice

Introduction: Cerebral amyloid angiopathy (CAA) is a chronic age-related neurodegenerative disease, identified by the presence of amyloid-beta (Aβ) deposition within the vasculature of the brain, leading to stroke and progressive cognitive decline. The liver is a key peripheral organ involved in the clearance of excess Aβ in the circulation. However, the role of the brain-liver axis in CAA is unknown. Here, we investigate inflammatory changes in the liver in a murine model of CAA. Methods: Aged (>23 months) male and female Tg-SwDI (CAA) mice harboring Swedish, Dutch, and Iowa mutations of the human amyloid precursor protein were used as a mouse model of CAA along with age-matched wild-type (WT) controls (n=3-7/grp). Hepatic inflammation was analyzed with histological and immunofluorescence imaging. Single cells from liver tissue were isolated and analyzed using flow cytometry. Total RNA was isolated to examine gene expression in the liver using real-time quantitative PCR. Results: Our data showed that CAA increases infiltration of immune cells proximal to liver sinusoids across both sexes compared to WT mice. We found increased macrophages (i.e., F4/80 + cells) in the liver of CAA mice compared to WT controls. Flow cytometry on the liver revealed that female CAA mice had a significant increase in dendritic cells (i.e., CD80 + CD45 + CD11c + cells, *** P <0.001) compared to WT females. Further, we found that Oatp2 , a membrane transporter which mediates hepatocytic uptake of toxic molecules (e.g., Aβ), is associated with sex-specific CAA pathophysiology in the liver. Conclusions: In this study, we found that sex differences may exist in CAA-induced liver inflammation. Further investigations are needed to study how vascular amyloidosis shapes the immune responses and peripheral Aβ clearance in the context of aging and CAA.

Abstract TP28: The Effects of Social Isolation on Cerebral Amyloid Angiopathy

Introduction: Cerebral amyloid angiopathy (CAA) is characterized by amyloid β (Aβ) deposition in the cortical and leptomeningeal vessels, and it is a largely untreatable cause of intracerebral hemorrhage and dementia. Studies estimate a 10-50% prevalence of CAA in the general elderly population, positioning it as one of the strongest vascular contributors to age-related cognitive impairment. With aging, the prevalence of social isolation (SI) also increases. Isolated individuals have an increased risk of Aβ-related cognitive decline and heightened inflammatory response to stress. Yet, whether and how SI exacerbates CAA-induced cognitive decline is unknown. Methods: TgSwDI mice harboring Swedish, Dutch, and Iowa mutations of human amyloid precursor protein were used as a mouse model of CAA. Male and female C57BL6 wildtype (WT) and CAA mice were randomly assigned to paired housing (PH) or SI at 3 months. Neurobehaviors were measured at baseline and every 3 months using the novel object recognition test (NORT), tail suspension test (TST), and fear conditioning (FC). At 12 months, microglia phenotype, vascular structure, and Aβ burden were assessed using flow cytometry and immunostaining. Results: Both WT and CAA isolated animals displayed significantly greater immobility in TST at 9 months post-SI, suggesting a depression-like behavior (n=10-15/grp, p<0.0001). Isolated CAA mice displayed exacerbated cognitive deficits in NORT and FC while WT mice showed intact cognition (n=10-15/grp, p<0.05). Specifically, SI-induced cognitive deficits were more prominent in the female CAA mice compared to males (n=5-8/grp, p<0.01). Sex differences were also observed in CAA mice in frequencies of Aβ-containing endothelial cells (CD31 + ) and vessel-associated microglia (VAM, CD45 int CD11b + CD31 + ) as well as in microglial phagocytosis of Aβ (n=3/grp, p<0.05). SI increased the frequency of Aβ-containing microglia in isolated CAA mice compared to their PH littermates. Conclusion: SI induced behavioral deficits in both WT and CAA mice but exacerbated cognitive decline only in the CAA SI mice. SI also influences microglial phagocytosis of Aβ. Further research is needed to determine the cellular and molecular mechanism underlying SI-induced changes in CAA.

Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy

BackgroundAlzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-β (Aβ) accumulation in the brain, although Aβ deposits mostly in the brain parenchyma in AD and in the cerebrovasculature in CAA. The presence of CAA can exacerbate clinical outcomes of AD patients by promoting spontaneous intracerebral hemorrhage and ischemia leading to CAA-associated cognitive decline. Genetically, AD and CAA share the ε4 allele of the apolipoprotein E (APOE) gene as the strongest genetic risk factor. Although tremendous efforts have focused on uncovering the role of APOE4 on parenchymal plaque pathogenesis in AD, mechanistic studies investigating the role of APOE4 on CAA are still lacking. Here, we addressed whether abolishing APOE4 generated by astrocytes, the major producers of APOE, is sufficient to ameliorate CAA and CAA-associated vessel damage.MethodsWe generated transgenic mice that deposited both CAA and plaques in which APOE4 expression can be selectively suppressed in astrocytes. At 2-months-of-age, a timepoint preceding CAA and plaque formation, APOE4 was removed from astrocytes of 5XFAD APOE4 knock-in mice. Mice were assessed at 10-months-of-age for Aβ plaque and CAA pathology, gliosis, and vascular integrity.ResultsReducing the levels of APOE4 in astrocytes shifted the deposition of fibrillar Aβ from the brain parenchyma to the cerebrovasculature. However, despite increased CAA, astrocytic APOE4 removal reduced overall Aβ-mediated gliosis and also led to increased cerebrovascular integrity and function in vessels containing CAA.ConclusionIn a mouse model of CAA, the reduction of APOE4 derived specifically from astrocytes, despite increased fibrillar Aβ deposition in the vasculature, is sufficient to reduce Aβ-mediated gliosis and cerebrovascular dysfunction.

Abstract 40: Gut Dysbiosis Exacerbates Neuroinflammation By Activation Of B Cells In A Mouse Model Of Cerebral Amyloid Angiopathy

Introduction: Cerebral amyloid angiopathy (CAA) is a debilitating disease that leads to intracerebral hemorrhage, white matter disease, and progressive cognitive decline in patients >50 years of age. Studies investigating the neuroimmune landscape in CAA are sparse. Here, we investigate the role of B cells in CAA. Methods: Pre-symptomatic (2 months) and symptomatic (10-13 months) male Tg-SwDI mice (CAA mice) harboring Swedish, Dutch, and Iowa mutations of human amyloid precursor protein (APP) were used as a mouse model of CAA. Single cells isolated from the brain were analyzed using flow cytometry to characterize neuroinflammation and cognitive impairment was assessed using fear conditioning. Fecal microbiota transplantation (FMT) of the microbiome from pre-symptomatic and symptomatic CAA mice into young wild-type (WT) recipient male mice (2 months) was performed to determine if CAA-induced gut dysbiosis contributes to brain B cell activation. Results: Cognitive assessment using fear conditioning indicated a significantly lower delta inactive state in symptomatic CAA mice (n=4/grp, * P <0.05) compared to pre-symptomatic CAA mice. Symptomatic CAA mice had a significantly lower relative frequency of microglia (CD45 int CD11b + , n=11-13/grp, ** P <0.01) and significant infiltration of lymphoid (CD45 high CD11b - , n=11-13/grp, *** P <0.001) cells in the brain, as compared to pre-symptomatic CAA mice. Symptomatic CAA mice had significantly higher B cells in the brain (n=10-13/grp, * P <0.05. Further, activated B cells as assessed by the expression level of CD11b showed that CD11b + B cells were significantly higher in the symptomatic CAA brain (n=10-13/grp, * P <0.05). Interestingly, this phenotype was recapitulated in young WT recipients reconstituted with pre-symptomatic CAA and CAA microbiome through FMT. Young WT recipients with CAA biome had significantly higher relative frequency of CD11b + B cells in the brain compared to young recipients with pre-CAA biome (n=7-9/grp, *** P <0.001). Conclusions: These results suggest that the aberrant activation of B cells in the brain may be influenced by CAA-induced gut dysbiosis. Further investigations upon the functional role of CD11b + B cells in the vascular deposition of Aβ are warranted.

Abstract 105: Sex Differences In The Response To Global Cerebral Hypo-Perfusion In A Mouse Model Of Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is a disease of small and medium-sized vessels, characterized by amyloid deposition. The incidence of CAA increases with age and evidence reveals worsened cognition in females compared to males. Cerebral hypoperfusion, or a decrease in cerebral blood flow (CBF), changes the integrity of the blood brain barrier and contributes to microhemorrhages, cerebral atrophy, and white matter loss. However, the link between vascular amyloid deposition and hypoperfusion remains understudied. We induced global cerebral hypoperfusion with bilateral carotid artery stenosis (BCAS) in CAA mice of both sexes and examined cognitive deficits, white matter loss, and cerebral gliosis. We hypothesize that chronic cerebral hypoperfusion will accelerate cognitive decline in CAA, increase white matter damage, and induce gliotic changes in the brain.Using a mouse model of CAA (Tg-SwDI), male and female mice (3 months of age) were randomized to either BCAS (n=15) or sham (n=11) surgery using 0.18mm coils to induce global cerebral hypoperfusion. Cognitive (Y-maze (YM), NORT, Water Maze (WM)) and motor function (Open Field (OF)) testing was performed by a blinded investigator prior to surgery (baseline) and at regular intervals until tissue harvest 6 months post-BCAS (PB). The brain and brainstem were harvested for immunohistochemical (IHC) analysis (Kluver-Barrera (KB), Iba-1, GFAP, Myelin Basic Protein (MBP)).Sex-specific changes in spatial memory (YM) and learning (NORT/WM) were present in BCAS mice. Female BCAS mice displayed greater deficits in cognition (NORT) at 3 (p=.0028), 4 (YM, p=.0007), and 5-months PB (NORT, p=.0149). Male BCAS mice demonstrated similar cognitive deficits, but at a later timepoint of 5 months PB (NORT, p=.0007). Both female and male BCAS mice had poorer cognition (WM) and motor function (OF, p=.0011/.0055) 6 months PB. IHC demonstrated increased demyelination (MBP) (p=.0038) and atrophy (KB) in the anterior corpus collosum (p=.0447) and significant gliosis (p=.0230).This study shows that chronic global hypoperfusion accelerates cognitive deficits in a CAA model, an effect that is accelerated in female mice. BCAS led to gliotic changes and demyelination associated with white matter damage in the brain.

Three‐dimensional study on morphological changes of arterioles in Cerebral Amyloid Angiopathy

AbstractBackgroundThe accumulation of β‐amyloid plaques in the brain is a hallmark of Alzheimer’s disease. Vascular involvement is also common in the form of cerebral amyloid angiopathy (CAA), a vasculopathy that is produced when the β‐amyloid forms toxic deposits on vessels wall. The accumulation of β‐amyloid makes blood vessels stiff and increases the thickness of the vessel wall, reducing the blood flow and energy supply for the tissue. This predisposes to hemorrhage and contribute to cognitive decline and stroke.MethodWe used the CLARITY method to analyze tissue samples from patients with CAA to characterize changes to vessel morphology associated with vascular degeneration. The blood vessels were stained with isolectin, β‐amyloid with thiazine red, and proteins with primary antibodies associated with the vascular structure. We conducted 3D microscopy using a light sheet microscope and performed surface volume reconstruction to assess the morphology of rupturing vessel. We also measured arteriolar stiffness of vessels damaged using atomic force microscopy (AFM). Finally, we assessed cerebral blood flow and autoregulation in vivo in a novel mouse model of CAA using laser speckle flowetry.ResultVessels with CAA demonstrate an organized ring‐shaped deposits β‐amyloid. At sites, these rings are shattered and the vessel diameter increase. Degenerating vessels also demonstrate depletion of vascular smooth muscle, circumferential luminal dilation, and thickening of the vessel wall. Lysyl oxidase levels and markers of fibrosis are increased in vessels with degenerating features. We found that the arteriolar wall was more than 400% stiffer in CAA than in arterioles without CAA in the mice model. Finally, in a novel mouse model of CAA we are terming the VASC‐FAD model, resting cerebral blood flow and vasoreactivity are both reduced.ConclusionCombining the CLARITY technique associated with surface volume rendering and AFM we have a better overview of microhemorrhages to understand the vascular fragility and morphological changes, and accumulation of myofibroblast markers caused by the β‐amyloid deposition and stiffness. These features combine to alter the physiology of cerebral blood flow. Defining mechanism of microvascular degeneration in AD and CAA may lead to novel treatment targets to restore the ECM and vascular network integrity.

Sex differences in a murine model of Cerebral Amyloid Angiopathy

Cerebral amyloid angiopathy (CAA) is one of the common causes of lobar intracerebral hemorrhage and vascular cognitive impairment (VCI) in the aging population. Increased amyloid plaque deposition within cerebral blood vessels, specifically the smooth muscle layer, is linked to increased cerebral microbleeds (CMBs) and impaired cognition in CAA. Studies in Alzheimer’s disease (AD) have shown that amyloid plaque pathology is more prevalent in the brains of elderly women (2/3rd of the dementia population) compared with men, however, there is a paucity of studies on sex differences in CAA. The objective of this study was to discern the sexual dichotomies in CAA. We utilized male and female Tg-SwDI mice (mouse model of CAA) at 12–14 months of age for this study. We evaluated sex differences in CMBs, cognitive function and inflammation. Cognition was assessed using Y-maze (spatial working memory) and Fear Conditioning (contextual memory). CMBs were quantified by ex vivo brain MRI scans. Inflammatory cytokines in brain were quantified using ELISA. Our results demonstrated that aging Tg-SwDI female mice had a significantly higher burden of CMBs on MRI as compared to males. Interestingly, these aging Tg-SwDI female mice also had significantly impaired spatial and contextual memory on Y maze and Fear Conditioning respectively. Furthermore, female mice had significantly lower circulating inflammatory cytokines, IL-1α, IL-2, IL-9, and IFN-γ, as compared to males. Our results demonstrate that aging female Tg-SwDI mice are more cognitively impaired and have higher number of CMBs, as compared to males at 12–14 months of age. This may be secondary to reduced levels of neural repair cytokines (IL-1α, IL-2, IL-9 and IFN-γ) involved in sex specific inflammatory signaling in CAA.

Taxifolin: A Potential Therapeutic Agent for Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of β-amyloid (Aβ) in the walls of cerebral vessels, leading to complications such as intracerebral hemorrhage, convexity subarachnoid hemorrhage and cerebral microinfarcts. Patients with CAA-related intracerebral hemorrhage are more likely to develop dementia and strokes. Several pathological investigations have demonstrated that more than 90% of Alzheimer’s disease patients have concomitant CAA, suggesting common pathogenic mechanisms. Potential causes of CAA include impaired Aβ clearance from the brain through the intramural periarterial drainage (IPAD) system. Conversely, CAA causes restriction of IPAD, limiting clearance. Early intervention in CAA could thus prevent Alzheimer’s disease progression. Growing evidence has suggested Taxifolin (dihydroquercetin) could be used as an effective therapy for CAA. Taxifolin is a plant flavonoid, widely available as a health supplement product, which has been demonstrated to exhibit anti-oxidative and anti-inflammatory effects, and provide protection against advanced glycation end products and mitochondrial damage. It has also been shown to facilitate disassembly, prevent oligomer formation and increase clearance of Aβ in a mouse model of CAA. Disturbed cerebrovascular reactivity and spatial reference memory impairment in CAA are completely prevented by Taxifolin treatment. These results highlight the need for clinical trials on the efficacy and safety of Taxifolin in patients with CAA

Abstract WP397: Longitudinal Sex Differences in Cerebral Amyloid Angiopathy

Background: Cerebral amyloid angiopathy (CAA) is the most common cause of lobar intracerebral hemorrhage in the aging population. It is mostly a consequence of amyloid beta40 (Aβ40) deposition within the cerebral blood vessels. A recent study has shown that this amyloid plaque deposition is more prevalent in the brain of elderly women compared to men. The increase in amyloid plaque deposition is linked to increased cerebral microbleeds (CMBs) and reduced cognition. The major objective of this study to discern if a sexual dichotomy existed in CMBs and cognition using mouse model of CAA. Methods: We used the Tg-SwDI mouse (“CAA mouse”, harboring Swedish, Dutch, and Iowa mutations of human amyloid precursor protein) model that develops Aβ deposits and cognitive deficits at 3-4 months. Cognitive deficits were analyzed using Fear Conditioning (FC) in pre-symptomatic (3 month) and (12 month) old male and female mice. Briefly, mice were acclimated to the FC chamber for a 2 minute training trial to record baseline. After 1 hour rest, mice were placed back in the chamber for 2 minutes, where they received a 2 millisecond shock (1,000 u/amp). Day 2, activity was recorded for 3 minutes and this measure was compared to baseline to determine Mean Inactive State (MIS-seconds). Mice were euthanized following FC, and brains scanned ex vivo using a MRI T2 Star sequence to assess for CMBs. Results: FC showed a significant difference in MIS (p<0.05) between male (3 and 12 months old) and female (3 months only) mice, n=6/group, suggesting that aged females had significantly lower MIS (Figure 1). MRI showed that aged female mice had more CMBs compared to aged male mice (females, 15.3±7 vs. males 0.25 ±0.2, n= 3/group, p=0.05. Conclusion: In a mouse model of CAA, our results demonstrate that aged females have increased CMBs as compared to males, which may be contributing to decreased cognition as seen on FC. Ongoing studies are designed to further understand the etiology of this sex difference.

Novel Therapeutic Potentials of Taxifolin for Amyloid-β-associated Neurodegenerative Diseases and Other Diseases: Recent Advances and Future Perspectives.

Amyloid-β (Aβ) has been closely implicated in the pathogenesis of cerebral amyloid angiopathy (CAA) and Alzheimer’s disease (AD), the major causes of dementia. Thus, Aβ could be a target for the treatment of these diseases, for which, currently, there are no established effective treatments. Taxifolin is a bioactive catechol-type flavonoid present in various plants, such as herbs, and it exhibits pleiotropic effects including anti-oxidant and anti-glycation activities. Recently, we have demonstrated that taxifolin inhibits Aβ fibril formation in vitro and have further shown that it improves cerebral blood flow, facilitating Aβ clearance in the brain and suppressing cognitive decline in a mouse model of CAA. These findings suggest the novel therapeutic potentials of taxifolin for CAA. Furthermore, recent extensive studies have reported several novel aspects of taxifolin supporting its potential as a therapeutic drug for AD and metabolic diseases with a high risk for dementia as well as for CAA. In this review, we have summarized the recent advances in taxifolin research based on in vitro, in vivo, and in silico approaches. Furthermore, we have discussed future research directions on the potential of taxifolin for use in novel therapeutic strategies for CAA, AD, and metabolic diseases with an increased risk for dementia.

Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) results from amyloid-β deposition in the cerebrovasculature. It is frequently accompanied by Alzheimer's disease and causes dementia. We recently demonstrated that in a mouse model of CAA, taxifolin improved cerebral blood flow, promoted amyloid-β removal from the brain, and prevented cognitive dysfunction when administered orally. Here we showed that taxifolin inhibited the intracerebral production of amyloid-β through suppressing the ApoE-ERK1/2-amyloid-β precursor protein axis, despite the low permeability of the blood-brain barrier to taxifolin. Higher expression levels of triggering receptor expressed on myeloid cell 2 (TREM2) were associated with the exacerbation of inflammation in the brain. Taxifolin suppressed inflammation, alleviating the accumulation of TREM2-expressing cells in the brain. It also mitigated glutamate levels and oxidative tissue damage and reduced brain levels of active caspases, indicative of apoptotic cell death. Thus, the oral administration of taxifolin had intracerebral pleiotropic neuroprotective effects on CAA through suppressing amyloid-β production and beneficially modulating proinflammatory microglial phenotypes.

Prolonged diet induced obesity has minimal effects towards brain pathology in mouse model of cerebral amyloid angiopathy: Implications for studying obesity–brain interactions in mice

Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer's disease (AD) and Down's syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we identify surprisingly that DIO does not significantly increase Aβ levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1β and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO has only modest effects towards Aβ in a mouse model of CAA, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with the majority of the existing literature in other models of Aβ pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in pathology within mouse models of Aβ pathogenesis, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed. This article is part of a Special Issue entitled: Animal Models of Disease.

Matrix metalloproteinase–19 expressed in cerebral amyloid angiopathy

Background. Cerebral amyloid angiopathy (CAA) is a frequent finding in the brains of patients with Alzheimer's disease (AD). CAA may be complicated with CAA-associated intracerebral haemorrhage (CAAH). Previous studies have revealed matrix metalloproteinase (MMP) expression in a mouse model of CAA and in human intracerebral haemorrhage. Here we studied the involvement of MMPs in human CAA and CAAH.Material and methods. To investigate the putative expression of MMPs in human CAA and CAAH (Step 1), immunohistochemistry (IHC) against MMPs-1, -2, -7, -9, -19 and -26 was applied on tissue microarray (TMA) constructed of cerebral samples from 29 individuals with AD, 15 with CAAH and 2 controls. The findings in TMA were confirmed (Step 2) in tissue samples from 64 individuals, 45 presenting with CAA (including 36 with CAAH) and 19 without CAA (including 11 with hypertensive cerebral haemorrhage).Results. In Step 1, immunoreactivity against MMPs-19 and -26 was detected in cerebral blood vessels in CAA. The results were confirmed in Step 2, where CAA (p<0.001) and intracerebral haemorrhage (p=0.045) were associated with vascular immunoreactivity against MMP-19. Multivariate analysis showed that the association between vascular MMP-19 and intracerebral haemorrhage was dependent from CAA. MMP-26 associated with CAA (p=0.021) but not with intracerebral haemorrhage.Conclusion. This is the first human study showing local MMP-19 immunoreactivity in the Aβ-amyloid-laden blood vessels in CAA, suggesting that MMPs may be involved in CAA.

Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of the amyloid beta-protein (A beta) within cerebral vessels. The involvement of different brain areas in CAA follows a hierarchical sequence similar to that of Alzheimer-related senile plaques. Alzheimer's disease patients frequently exhibit CAA. The expansion of CAA in AD often shows the pattern of full-blown CAA. The deposition of A beta within capillaries distinguishes two types of CAA. One with capillary A beta-deposition is characterized by a strong association with the apolipoprotein E (APOE) epsilon 4 allele and by its frequent occurrence in Alzheimer's disease cases whereas the other one lacking capillary A beta-deposits is not associated with APOE epsilon 4. Capillary CAA can be seen in every stage of CAA or AD-related A beta-deposition. AD cases with capillary CAA show more widespread capillary A beta-deposition than non-demented cases as well as capillary occlusion. In a mouse model of CAA, capillary CAA was associated with capillary occlusion and cerebral blood flow disturbances. Thus, blood flow alterations with subsequent hypoperfusion induced by CAA-related capillary occlusion presumably point to a second mechanism in which A beta adversely affects the brain in AD in addition to its direct neurotoxic effects.

Matrix metalloproteinase-9 in cerebral-amyloid-angiopathy-related hemorrhage

Spontaneous intracerebral hemorrhage (ICH) is one of the most recognized complications of cerebral amyloid angiopathy (CAA), but little is known about the molecular pathogenesis of this life-threatening complication. In this review, we present preliminary evidence which suggests that the extracellular-matrix-degrading protease, matrix metalloproteinase-9 (MMP-9), may play a role in the development of spontaneous ICH resulting from CAA. The amyloid-beta peptide (Aβ) induced the synthesis, cellular release, and activation of MMP-9 in murine cerebral endothelial cells (CECs), resulting in increased extracellular matrix (ECM) degradation. Furthermore, in a mouse model of CAA (APPsw transgenic mice), MMP-9 immunoreactivity was observed in amyloid-laden cerebral vessels in aged APPsw mice but not in young APPsw or aged wild-type mice. More extensive MMP-9 immunostaining was present in amyloid-laden vessels with evidence of microhemorrhage. These results suggest that increased vascular MMP-9 expression, stimulated by Aβ, may play a role in the pathogenesis of spontaneous intracerebral hemorrhage (ICH) in patients with CAA.