P2-353: Reducing the availability of soluble Aβ halts progression of cerebral amyloid angiopathy in transgenic mice

Abstract Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer’s disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-β isoform(s) (predominantly amyloid-β40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly. We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-β40 selective antibody, to attenuate amyloid-β accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-β accumulation both in leptomeningeal and brain vessels when measured by intravital multiphoton imaging and immunohistochemistry. By enriching for cerebral vascular elements, we also measured a significant reduction in the levels of soluble amyloid-β biochemically. We hypothesized that the reduction in vascular amyloid-β40 after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-β40 in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-β40 levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-β species that may otherwise be detrimental to normal vessel function.

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Cerebral Amyloid Angiopathy and Parenchymal Amyloid Deposition in Transgenic Mice Expressing the Danish Mutant Form of Human BRI2

Brain Pathology ◽

10.1111/j.1750-3639.2008.00164.x ◽

2009 ◽

Vol 19 (1) ◽

pp. 58-68 ◽

Cited By ~ 34

Author(s):

Ruben Vidal ◽

Ana G. Barbeito ◽

Leticia Miravalle ◽

Bernardino Ghetti

Keyword(s):

Transgenic Mice ◽

Cerebral Amyloid Angiopathy ◽

Amyloid Deposition ◽

Amyloid Angiopathy ◽

Mutant Form ◽

Cerebral Amyloid

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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

Journal of Neuroscience ◽

10.1523/jneurosci.4337-04.2005 ◽

2005 ◽

Vol 25 (3) ◽

pp. 629-636 ◽

Cited By ~ 206

Author(s):

M. M. Racke

Keyword(s):

Transgenic Mice ◽

Amyloid Precursor Protein ◽

Cerebral Amyloid Angiopathy ◽

Precursor Protein ◽

Amyloid Angiopathy ◽

Antibody Recognition ◽

Cerebral Amyloid

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

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.167.9 ◽

2008 ◽

Vol 22 (S1) ◽

Author(s):

Matthew P. Frosch ◽

Claudia M. Prada ◽

Monica Garci‐Alloza ◽

Rebecca A. Betensky ◽

Brian J. Bacskai ◽

...

Keyword(s):

Transgenic Mice ◽

Cerebral Amyloid Angiopathy ◽

Amyloid Angiopathy ◽

Cerebral Amyloid

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Abstract W MP94: Acute Inflammation Expands Cerebral Microbleeds in a Mouse Model of Cerebral Amyloid Angiopathy

Stroke ◽

10.1161/str.45.suppl_1.wmp94 ◽

2014 ◽

Vol 45 (suppl_1) ◽

Author(s):

Vitaly Vasilevko ◽

Mark J Fisher ◽

Kelley Kilday ◽

Giselle F Passos ◽

Shuo Liu ◽

...

Keyword(s):

Mouse Model ◽

Transgenic Mice ◽

Cerebral Amyloid Angiopathy ◽

Acute Inflammation ◽

Cerebral Microbleeds ◽

High Dose ◽

Amyloid Angiopathy ◽

Inflammatory Stimulus ◽

Cerebral Amyloid ◽

Average Size

Introduction: Cerebral microscopic hemorrhages are the pathologic substrate of cerebral microbleeds (CMB). Little is known about mechanisms of expansion of CMB. Here we studied the dynamics of CMB after acute inflammation, using a transgenic mouse model of cerebral amyloid angiopathy with spontaneous microscopic hemorrhages and endotoxin (lipopolysaccharide, LPS) as an inflammatory stimulus. Methods: 21-month old Tg2576 mice and wildtype littermates received a single dose of LPS, 100 or 1000 ug/kg i.p., or phosphate-buffered saline (PBS) as control. Mice were sacrificed 48 hours later and brains were collected for the analysis of microscopic hemorrhages, as well as edema formation, blood-brain barrier constituents and glial activation. Differences among groups were tested by anova and contrasts. Results: Hematoxylin and eosin staining demonstrated no freshly-formed microscopic hemorrhages in LPS-treated mice. Using Prussian blue staining, we found that total area, average size, and number of CMB differed significantly between PBS-treated wildtype and transgenic mice (p=0.03, p=.04 and p=.03 respectively). Acute inflammation did not significantly affect total area, average size, or number of CMB in wildtype animals. For transgenic mice, both doses of LPS significantly (p<.01) increased the total area of Prussian blue-positive lesions (2.2 to 2.9-fold increase), and higher LPS dose significantly (p<.01) increased average size of CMB by 2.6-fold; both average and total size of CMB increased in a dose-dependent manner. IgG and fibrinogen levels significantly increased after high dose LPS injection in both wildtype and transgenic mice (p<.05). Tight junction protein claudin-5 levels were also increased in high dose LPS-treated mice (p<0.05). LPS injection significantly increased expression of activated microglia markers CD45, CD14, and Iba1. Conclusions: In a mouse model of cerebral amyloid angiopathy, acute inflammatory stimulus induced expansion of CMB without producing fresh hemorrhage. Increased size of CMB was associated with indices of cerebral edema, alteration of tight junction constituents, and microglial activation. These findings suggest that cerebral edema may mediate expansion of cerebral microbleeds.

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