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Cerebral amyloid angiopathy : new insights from transgenic mice

Herzig, Martin C.. Cerebral amyloid angiopathy : new insights from transgenic mice. 2004, PhD Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_7172


Cerebral amyloid angiopathy (CAA) is characterized by the deposition of congophilic material within the walls of small to medium-sized blood vessels of the brain and leptomeninges. The incidence of CAA increases with aging, and in its most severe stages, the vascular amyloid causes a breakdown of the blood vessel wall which results in spontaneous, often recurrent, lobar intracerebral hemorrhage. CAA is estimated to account for four to twenty percent of all nontraumatic intracerebral hemorrhages. Besides this major complication, extensive CAA has been associated with ischemic white matter damage with progressive dementia, perivascular inflammation, and secondary vasculitis. CAA occurs as a sporadic disorder in the elderly and in association with Alzheimer's disease (AD) with virtually all AD patients showing some degree of vascular amyloid in addition to parenchymal plaques. There are also familial forms of CAA such as hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D). The vascular amyloid in these disorders mainly consists of β -amyloid peptide (Aβ ) that is produced by proteolytic cleavage from its precursor, which is the β -amyloid precursor protein (APP). The major Aβ species that is deposited in the vasculature is Aβ 40, while parenchymal amyloid is mainly composed of Aβ 42. One major difficulty in studying CAA is that it can be definitely diagnosed only postmortem. Moreover, spontaneous CAA occurs only in old primates and dogs, both of which are not practical models to study the pathogenesis and therapy of CAA. Rodents do not spontaneously develop CAA. The purpose of this thesis was to provide useful model systems to study the pathomechanism of vascular amyloid formation and associated pathology. To this end we generated and used mice that are transgenic for human genes bearing mutations that are well known to cause either hereditary Aβ -CAA or classical familial AD. In a first study we analyzed CAA and CAA-associated pathological changes in APP23 transgenic mice. These mice overexpress human APP bearing the Swedish K670N/M671L double mutation, a typical early-onset AD-causing mutation, under the control of the neuron-specific Thy-1 promoter. In addition to parenchymal amyloid plaques, APP23 mice show consistent amyloid within leptomeningeal, neocortical, hippocampal, and thalamic vessel walls. Both CAA frequency and severity significantly increase with aging, demonstrating that not only more vessels are affected, but also that the amyloid burden of individual vessels increases with the progression of amyloid deposition. Cerebrovascular amyloid causes degeneration of vascular smooth muscle cells (SMCs). In severely affected vessels, SMCs are completely replaced by the amyloid. Similar to humans, amyloid depositing APP23 mice develop spontaneous hemorrhages, some of them being recurrent. The bleedings are associated with amyloid-laden vessels and therefore, their anatomical distribution appears very similar to that of CAA. In aged mice, a quantitative analysis revealed a positive correlation between hemorrhages and CAA. Interestingly, no significant relationship between hemorrhages and total amyloid load was observed. Occasionally, CAA-associated vasculitis is seen in animals with extensive vascular amyloid. In a second study, we generated transgenic mice that express human APP E693Q under the control of the same neuron-specific Thy-1 promoter (APPDutch mice) that has been used in APP23 mice. In HCHWA-D patients, the APP E693Q Dutch mutation causes severe CAA with recurrent cerebral hemorrhagic strokes often leading to death early in their fifties, or to dementia in patients that survive the strokes. In contrast to AD patients that show parenchymal amyloid plaques, HCHWA-D patients exhibit few parenchymal amyloid deposits. Similar to HCHWA-D, aged APPDutch mice show extensive Aβ deposits mainly within the walls of leptomeningeal vessels followed by cortical vessels. Parenchymal Aβ deposits are mostly absent. In severely affected vessels, the SMCs are completely displaced by the amyloid. In regions with CAA, fresh and old hemorrhages are observed, and activated perivascular microglia and reactive astrocytes are found. To examine the mechanism that leads to the almost exclusive vascular amyloid formation in APPDutch mice, we compared the mice with transgenic mice overexpressing wild-type (wt) human APP using the same neuronal promoter (APPwt mice). As they age, APPwt mice develop parenchymal plaques with limited vascular amyloid deposits. A biochemical analysis of Aβ 40 and Aβ 42 levels revealed significant higher Aβ 40:42 ratios in amyloid depositing and pre-depositing APPDutch mice compared to APPwt mice. To demonstrate that the high Aβ 40:42 ratio in APPDutch mice is linked to the almost exclusive vascular amyloid deposition, we crossed APPDutch mice with mice that overexpress human presenilin-1 bearing the G384A mutation (PS45 mice) that is known to dramatically increase the production of Aβ 42. Strikingly, young APPDutch/PS45 double-transgenic mice develop massive diffuse and compact parenchymal amyloid with only very little CAA. Thus, shifting the Aβ 40:42 ratio towards Aβ 42 is sufficient to redistribute the amyloid pathology from the vasculature to the parenchyma. A third series of experiments using neurografting techniques was performed to investigate the mechanisms involved in the initiation of cerebral amyloidosis in vivo . Cell suspensions of transgenic APP23 and wild-type B6 embryonic brain tissue were injected into the neocortex and hippocampus of both APP23 and B6 mice, respectively. In wild-type hosts, APP23 grafts did not show amyloid deposits up to 20 months after grafting. Interestingly, transgenic and wild-type grafts in young APP23 hosts develop amyloid plaques as early as three months after grafting. Although the majority of the amyloid is of the diffuse type, some compact and congophilic amyloid plaques are observed in the wild-type grafts. These congophilic amyloid lesions are surrounded by neuritic changes and gliosis, comparable to the amyloid-associated pathology that has previously been described in APP23 mice. These results support the importance of neuronally secreted Aβ for the development of cerebral amyloidosis which can be initiated distant from the site of Aβ production, a finding that supports the observation of the above mentioned APPDutch mouse model. In summary, we demonstrate that APP23 and APPDutch mice recapitulate CAA and CAAassociated pathology observed in humans and thus are valuable models for studying the human disease. Our results stress the importance of neuronally secreted Aβ for the development of CAA and emphasize the Aβ 40:42 ratio as an important factor in determining parenchymal versus vascular amyloid deposition. The understanding that different Aβ species can drive amyloid pathology in different cerebral compartments not only provides insights into the pathomechanism of sporadic and familial CAA but also has implications for current anti-amyloid therapeutic strategies.
Advisors:Reichert, Heinrich
Committee Members:Jucker, Mathias K.
Faculties and Departments:05 Faculty of Science > Departement Umweltwissenschaften > Zoologisches Institut
Item Type:Thesis
Thesis no:7172
Bibsysno:Link to catalogue
Number of Pages:111
Identification Number:
Last Modified:03 Oct 2013 16:10
Deposited On:13 Feb 2009 15:10

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