Spontaneous Hemorrhagic Stroke in a Mouse Model of Cerebral Amyloid Angiopathy

Winkler, David T.; Bondolfi, Luca; Herzig, Martin C.; Jann, Lukas; Calhoun, Michael E.; Wiederhold, Karl‐Heinz; Tolnay, Markus; Staufenbiel, Matthias; Jucker, Mathias

doi:10.1523/jneurosci.21-05-01619.2001

Cited by 269 publications

(229 citation statements)

References 65 publications

(96 reference statements)

Supporting

Mentioning

213

Contrasting

Unclassified

Order By: Relevance

“…We found small knob-like structures on the casted vasculature, most pronounced on microvessels like capillaries at a time point when neither parenchymal nor vascular amyloid deposits were present (20,43,44). They could form two different structures, which we described as pompons and cubes, both extruding into endothelial cells and/or neuropil and staining positive for amyloid.…”

Section: Vascular Corrosion Casting Vascular Morphology and Networkmentioning

confidence: 79%

Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease

Meyer

Ulmann-Schuler

Staufenbiel

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

232

215

View full text Add to dashboard Cite

Substantial evidence from epidemiological, pathological, and clinical reports suggests that vascular factors are critical in the pathogenesis of Alzheimer's disease (AD), and changes in blood flow are currently the most reliable indicators of the disease. We previously reported that older APP23 transgenic (tg) mice have significant blood flow alterations correlated with structural modifications of blood vessels. For the present study, our objective was to analyze the age-dependent morphological and architectural changes of the cerebral vasculature of APP23 tg mice. To visualize the 3D arrangement of the entire brain vasculature, we used vascular corrosion casts. Already at young ages, when typically parenchymal amyloid plaques are not yet present, APP23 tg mice had significant alterations, particularly of the microvasculature, often accompanied by small deposits attached to the vessels. In older animals, vasculature abruptly ended at amyloid plaques, resulting in holes. Often, small deposits were sitting near or at the end of truncated vessels. Between such holes, the surrounding vascular array appeared more dense and showed features typical for angiogenesis. We propose that small amyloid aggregates associated with the microvasculature lead to morphological and architectural alterations of the vasculature, resulting in altered local blood flow. The characteristic early onset of vascular alterations suggests that imaging blood flow and/or vasculature architecture could be used as a tool for early diagnosis of the disease and to monitor therapies. amyloid precursor protein ͉ cerebral blood flow ͉ scanning electron microscopy ͉ vascular corrosion casting T he typical clinical picture of Alzheimer's disease (AD) includes a progressive decline of memory function, often accompanied by other clinical signs such as agitation, aggression, sleep disturbances, and social withdrawal. Nonetheless, brain autopsy is needed to positively confirm the diagnosis (1). A high density of neuritic plaques, neurofibrillary tangles, and vascular amyloid (A␤) is a characteristic neuropathological marker of AD (2, 3). Plaques and tangles in the neuropil may affect neuronal function and also contribute to the neuronal damage; however, it is unclear whether their incidence correlates with the clinical signs and symptoms of cognitive impairment characteristic of the disease (4). Evidence suggests that cerebrovascular pathologies, such as structural alterations (5), atherosclerotic lesions (6), and impaired hemodynamic responses (7), are early features of AD (for review, see ref. 8). Reduced blood flow has been reported as one of the most consistent physiological deficits in AD (9, 10); however, it remains unclear whether the reduced cerebral blood flow is a response to neuronal damage or a factor initiating the characteristic neuropathology. In vivo studies showed the effect of A␤ on cerebral blood flow and vessel architecture in a mouse model for AD (11,12). In other models, cerebrovascular regulatory mechanisms, such as endothelium-depende...

show abstract

Section: Vascular Corrosion Casting Vascular Morphology and Networkmentioning

confidence: 79%

Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease

Meyer

Ulmann-Schuler

Staufenbiel

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

232

215

View full text Add to dashboard Cite

show abstract

“…In contrast, APP transgenic mice with very severe VA␤ pathology (APP23 mice) develop spontaneous cerebral hemorrhage (Winkler et al, 2001), and, similar to human CAA patients, it is likely attributable to derangement and loss of smooth muscle cells (Winkler et al, 2001) and other destructive consequences of A␤-related toxicity (Christie et al, 2001). The degree of treatment-related effects such as microhemorrhage will probably vary depending on the severity of baseline VA␤ pathology.…”

Section: Discussionmentioning

confidence: 99%

Immunotherapy Reduces Vascular Amyloid- in PDAPP Mice

Schroeter¹,

Khan²,

Barbour³

et al. 2008

Journal of Neuroscience

117

View full text Add to dashboard Cite

In addition to parenchymal amyloid-␤ (A␤) plaques, Alzheimer's disease (AD) is characterized by A␤ in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in the majority of patients. Recent studies investigating vascular A␤ (VA␤) in amyloid precursor protein transgenic mice have suggested that passive immunization with anti-A␤ antibodies may clear parenchymal amyloid but increase VA␤ and the incidence of microhemorrhage. However, the influences of antibody specificity and exposure levels on VA␤ and microhemorrhage rates have not been well established, nor has any clear causal relationship been identified. This report examines the effects of chronic, passive immunization on VA␤ and microhemorrhage in PDAPP mice by comparing antibodies with different A␤ epitopes (3D6, A␤ 1-5 ; 266, A␤ 16 -23 ) and performing a 3D6 dose-response study. VA␤ and microhemorrhage were assessed using concomitant A␤ immunohistochemistry and hemosiderin detection. 3D6 prevented or cleared VA␤ in a dose-dependent manner, whereas 266 was without effect. Essentially complete absence of VA␤ was observed at the highest 3D6 dose, whereas altered morphology suggestive of ongoing clearance was seen at lower doses. The incidence of microhemorrhage was increased in the high-dose 3D6 group and limited to focal, perivascular sites. These colocalized with A␤ deposits having altered morphology and apparent clearance in the lower-dose 3D6 group. Our results suggest that passive immunization can reduce VA␤ levels, and modulating antibody dose can significantly mitigate the incidence of microhemorrhage while still preventing or reducing VA␤. These observations raise the possibility that A␤ immunotherapy can potentially slow or halt the course of CAA development in AD that is implicated in vascular dysfunction.

show abstract

“…9,38 No specific disease has been attributed to medin amyloid deposits. However, as it has been shown that amyloids of other biochemical nature found in the vasculature may cause a weakening of the vessel wall, [27][28][29] it is reasonable to believe that medin is deleterious to the surrounding tissue and is also involved in conditions such as thoracic aortic dissections and aneurysms.…”

Section: Discussionmentioning

confidence: 99%

“…27,28 It has been shown in a mouse model of Ab cerebral amyloid angiopathy that the amyloid deposits are associated with disorganized medial smooth muscle cells and a substantial loss of these cells. 29,30 Therefore, it is logical to believe that the sometimes widely spread medin amyloid deposits in the thoracic aorta are associated with aortic wall weakening. In this study, we have studied the prevalence of medin in aortic tissues of patients suffering from sporadic thoracic aortic dissection and aneurysm.…”

mentioning

confidence: 99%

Role of aggregated medin in the pathogenesis of thoracic aortic aneurysm and dissection

Peng

Larsson

Wassberg

et al. 2007

Laboratory Investigation

View full text Add to dashboard Cite

The pathogenesis of sporadic thoracic aortic aneurysm and dissection, which may lead to rupture of the aorta, remains largely unknown. Amyloid deposits, formed from the medin peptide, are very prevalent in the media of the thoracic aorta. We have studied the occurrence of medin-derived amyloid in specimens from patients with thoracic aortic aneurysm, aortic dissection type A and normal dimensioned aorta. Surprisingly, the amount of amyloid was significantly lower in the aneurysm and dissection groups (0.63±0.13 and 0.36±0.24 amyloid particles per mm 2 , respectively) compared to the control material (2.37 ± 0.58). However, focal medin immunoreactivity not associated with amyloid was found more conspicuously in the media of the two diseased groups. Recent amyloid research indicates that prefibrillar oligomeric aggregates, rather than mature amyloid fibrils, are toxic to the surrounding cells. The non-amyloid medin immunoreactivity observed may represent such toxic oligomers. This is supported by the fact that aggregated medin induced death of aortic smooth muscle cells in vitro. In addition, cells incubated together with medin increased the production of matrix metalloproteinase-2, a protease that degrades elastin and collagen and subsequently weakens the vessel wall. We therefore propose that medin oligomers are involved in the degeneration process of sporadic thoracic aortic aneurysm and dissection.

show abstract

Spontaneous Hemorrhagic Stroke in a Mouse Model of Cerebral Amyloid Angiopathy

Cited by 269 publications

References 65 publications

Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease

Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease

Immunotherapy Reduces Vascular Amyloid- in PDAPP Mice

Role of aggregated medin in the pathogenesis of thoracic aortic aneurysm and dissection

Contact Info

Product

Resources

About