Capillary cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances
Introduction
Cerebral amyloid angiopathy (CAA) is a vessel disorder which is frequently (80–100%) associated with Alzheimer's disease (AD) (Joachim et al., 1988, Revesz et al., 2005, Vinters, 1992). Although CAA can induce cerebral hemorrhage and infarction (Revesz et al., 2005, Vinters, 1992) its clinical impact on AD is not yet clear (Revesz et al., 2005, Vinters, 1992). The vascular amyloid deposits of CAA mainly consist of the amyloid β-protein (Aβ) similar to senile plaques in AD (Joachim et al., 1988, Revesz et al., 2005). Although the severity and extension of CAA into further brain regions is related to the pathological and clinical progression of AD (Jellinger, 2002, Revesz et al., 2005, Thal et al., 2003) it is not clear whether CAA in AD patients has additional impact on the AD-related degeneration of neurons besides tissue damage due to hemorrhage or infarction. The occurrence of CAA (Revesz et al., 2005, Vinters, 1992), its persistence and the development of cerebral hemorrhage after passive vaccination against Aβ (Nicoll et al., 2003, Pfeifer et al., 2002b, Racke et al., 2005) point to a critical role of CAA in the pathogenesis of AD and in its therapeutic management.
Mouse models for AD overexpressing APP exhibit senile plaques and CAA (Calhoun et al., 1999, Kawarabayashi et al., 2001). One of these models, the APP23 mouse, overexpresses human APP harboring the Swedish mutation (670/671 KM → NL) driven by a Thy-1 promoter (Sturchler-Pierrat et al., 1997). In 20-month-old APP23 mice vascular alterations with significant disturbances of cerebral blood flow were detected by magnetic resonance angiography (MRA) (Beckmann et al., 2003). However, a pathological correlative for these alterations has not been described so far. Other mouse models such as APP51/16 mice, overexpressing wild-type human APP driven by a Thy-1 promoter, do show only negligible CAA (Herzig et al., 2004). Hence, these mouse models are well suited to verify whether CAA has an impact on cerebral blood flow.
A decrease in capillary density has been reported in AD cases (Bouras et al., 2006, Buee et al., 1994, Wu et al., 2005) and in APP-transgenic mice (Lee et al., 2005). However, it is not clear whether CAA plays a role in the alteration of cerebral blood flow seen in AD (Foster et al., 1984, Johnson et al., 2005, Meguro et al., 1999) or in APP-transgenic mice (Beckmann et al., 2003). To address this question we studied a sample of APP23 mice, APP51/16 mice, and wild-type littermates at 25–26 months of age as well as human autopsy cases for an association of CAA with capillary pathology and disturbances in cerebral blood flow. Our results indicate that capillary CAA is associated with capillary occlusion in mice and humans, which is related to blood flow disturbances detected by MRA in mice.
Section snippets
Animals
APP23 and APP51/16 mice were generated as previously described (Herzig et al., 2004, Sturchler-Pierrat et al., 1997) and continuously back-crossed to C57BL/6 for more than 10 generations. An expression construct containing a murine Thy-1 promoter was used to drive neuron-specific expression of human mutant APP751 with the Swedish double mutation 670/671 KM → NL in APP23 mice and human wild-type APP in APP51/16 mice. Nine female heterozygous APP51/16 mice, 15 female heterozygous APP23 mice and 18
Occlusion of CAA-affected thalamic capillaries in APP23 mice
The thalamus was chosen to study CAA-related changes since vascular amyloid is very prominent in this brain region of APP23 mice. CAA and occlusion of CAA-affected capillaries was seen in the ventral posteromedial and posterolateral thalamic nuclei as well as in adjacent thalamic nuclei in coronal sections of APP23 mice (Fig. 1A–D). Capillaries not affected by CAA were not occluded. Brain stem capillaries were free of CAA and did not show occlusion in all investigated mice. In the APP23 mice up
Discussion
Our results show an association between CAA-related capillary occlusion with cerebral blood flow disturbances detected by MRA. Occlusion was restricted to CAA-affected capillaries and seen in the APP23 mouse model for AD and in human AD brain.
Disclosure statement
All animal experiments were performed in agreement with the Swiss and German laws on the use of laboratory animals for experimentation. Human autopsy tissue was studied according to the German law for using human tissue in agreement with the vote of the local ethical committee of the University of Bonn.
Acknowledgements
The authors gratefully acknowledge the technical assistance of N. Kolosnjaji and H.U. Klatt.
Matthias Staufenbiel, Stefan Zurbruegg, and Nicolau Beckmann are employees of the Novartis Institutes for Biomedical Research Basel. This study was supported by the University of Bonn (BONFOR-grant no. O-154.0041) and in part by the DFG (grant no. TH624/4-2) (DRT).
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Present address: Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA.