Genomes and Genes
Transgenic Model for Cerebral Amyloid Angiopathy
Principal Investigator: William Van Nostrand
Abstract: [unreadable] DESCRIPTION (provided by applicant): Cerebrovascular deposition of the amyloid [unreadable]-protein (A[unreadable]), a condition known as cerebral amyloid angiopathy (CAA), is a common pathological feature of patients with Alzheimer's disease (AD) and several related hereditary cerebral hemorrhage with amyloidosis (HCHWA) disorders. A[unreadable] is proteolytically derived from its parent molecule the amyloid [unreadable]-protein precursor (A[unreadable]PP). Apolipoprotein E (ApoE) genotype can facilitate both cerebrovascular A[unreadable] deposition and hemorrhagic stroke. It is significant that CAA accounts for up to 20% of cases of spontaneous primary intracerebral hemorrhage. Moreover, CAA is most severe in HCHWA patients often resulting in early recurrent and fatal intracerebral hemorrhages. The reason as to why there is preferential cerebrovascular A[unreadable] deposition in HCHWA disorders leading to hemorrhagic stroke and how ApoE may facilitate these pathological processes remains unresolved. [unreadable] [unreadable] We have shown that certain HCHWA mutant forms of A[unreadable], which exhibit a loss or change in charge at peptide residues 22 or 23, possess enhanced pathogenic properties towards cultured cerebrovascular cells. In addition, ApoE genotype can further influence the pathogenic effects of A[unreadable] in these in vitro paradigms. However, many of these issues can be better studied in valid in vivo models for CAA. Therefore, the overall hypotheses that forms the basis of this proposal is that expression of HCHWA mutant A[unreadable]PP in transgenic mice will lead to the preferential development of CAA and human ApoE genotype can further influence this pathology and promote cerebral hemorrhage. The broad objectives of this proposal are two-fold. First, we will compare the pathological consequences of neuronal over-expression of several human A[unreadable]PP forms yielding either wild-type or CAA mutant A[unreadable] with regards to the development of CAA. The CAA mutant forms A[unreadable]PP will contain either a single Dutch E22Q AB substitution or double Dutch/Iowa E22Q,D23N A[unreadable] substitutions. Second, the influence of human ApoE genotype on A[unreadable] deposition, the development of CAA, and cerebral hemorrhage will be investigated in these in vivo models. These proposed studies stem from our overall focus and continuing work on investigating the role of ABPP and its derived fragment A6 in the development of CAA, loss of vessel wall integrity, and hemorrhagic stroke. Completion of these specific aims will produce valuable models for both the further study of pathogenic mechanisms in CAA and in vivo systems to develop and test therapeutic strategies to mitigate cerebrovascular A[unreadable] deposition and the subsequent pathological consequence of hemorrhagic stroke. [unreadable] [unreadable]
Funding Period: 1998-05-01 - 2008-07-31
more information: NIH RePORT
- Human apolipoprotein E2 promotes parenchymal amyloid deposition and neuronal loss in vasculotropic mutant amyloid-β protein Tg-SwDI miceFeng Xu
Department of Neurosurgery and Medicine, Stony Brook University, Stony Brook, NY 11794 8122, USA
J Alzheimers Dis 31:359-69. 2012..These findings suggest that compared with human ApoE4, human ApoE2 does not beneficially influence the quantitative or spatial accumulation of human Dutch/Iowa CAA mutant amyloid or associated pathology in transgenic mice...
- Human apolipoprotein E redistributes fibrillar amyloid deposition in Tg-SwDI miceFeng Xu
Department of Medicine, Stony Brook University, Stony Brook, New York 11794 8153, USA
J Neurosci 28:5312-20. 2008....
- Experimental investigation of antibody-mediated clearance mechanisms of amyloid-beta in CNS of Tg-SwDI transgenic miceVitaly Vasilevko
The Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, California 92697 4540, USA
J Neurosci 27:13376-83. 2007..Thus, approaches that deliver immunotherapy to the brain may be more effective at clearing Abeta than immunization strategies in which the majority of the antibodies are in the periphery...
- Induction of complement proteins in a mouse model for cerebral microvascular A beta depositionRong Fan
Department of Medicine, Stony Brook University, Stony Brook, NY 11794 USA
J Neuroinflammation 4:22. 2007..Our findings demonstrate that Tg-SwDI mice exhibit elevated complement protein expression in response to fibrillar vascular A beta deposition that is observed in patients with familial CAA...
- Increased severity of hemorrhage in transgenic mice expressing cerebral protease nexin-2/amyloid beta-protein precursorFeng Xu
Stroke 38:2598-601. 2007..Although little is known of its physiological function, the potent inhibition of certain prothrombotic proteinases by PN2/AbetaPP suggests that it may function to regulate cerebral thrombosis during vascular injury events...
- Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloidRong Fan
Department of Medicine, Stony Brook University, Stony Brook, New York 11794, USA
J Neurosci 27:3057-63. 2007..These finding suggest that anti-inflammatory treatment targeted for cerebral microvascular amyloid-induced microglial activation can improve cognitive deficits without altering the accumulation and distribution of Abeta...
- Early-onset subicular microvascular amyloid and neuroinflammation correlate with behavioral deficits in vasculotropic mutant amyloid beta-protein precursor transgenic miceF Xu
Department of Medicine, Health Sciences Center T 15 083, Stony Brook University, Stony Brook, NY 11794 8153, USA
Neuroscience 146:98-107. 2007..These findings indicate that early-onset accumulation of subicular microvascular amyloid and accompanying neuroinflammation correlates with impaired performance in the learning and memory task in Tg-SwDI mice...
- Metallothionein-I and -III expression in animal models of Alzheimer diseaseJ Carrasco
Institute of Neurosciences, Department of Cellular Biology, Physiology and Immunology, Animal Physiology Unit, Faculty of Sciences, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain 08193
Neuroscience 143:911-22. 2006..In contrast to MT-I, MT-III mRNA expression was not significantly altered in any of the models examined suggesting that the various MT isoforms may have different roles in these experimental systems, and perhaps also in human AD...
- Mechanism of cerebral beta-amyloid angiopathy: murine and cellular modelsMartin C Herzig
Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tubingen, Germany
Brain Pathol 16:40-54. 2006....
- Protease nexin-2/amyloid beta-protein precursor limits cerebral thrombosisFeng Xu
Department of Medicine, Stony Brook University, NY 11794, USA
Proc Natl Acad Sci U S A 102:18135-40. 2005..These findings indicate that PN2/AbetaPP plays a significant role in regulating cerebral thrombosis and that modest increases in this protein can profoundly enhance cerebral hemorrhage...
- The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer diseaseVeronica Hirsch-Reinshagen
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V4Z 5H5, Canada
J Biol Chem 280:43243-56. 2005..These data suggested that ABCA1-mediated effects on apoE levels and lipidation influenced amyloidogenesis in vivo...
- Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa Double A beta in human A betaPP transgenic miceJudianne Davis
Department of Medicine, Health Sciences Center, Stony Brook University, HSC T 15 083, Stony Brook, NY 11794 8153, USA
Neurobiol Aging 27:946-54. 2006....
- Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor proteinJianting Miao
Department of Medicine, HSC, Stony Brook University, Stony Brook, NY 11794 8153, USA
Am J Pathol 167:505-15. 2005..Together, these studies identify the Tg-SwDI mouse as a unique model to investigate selective accumulation of cerebral microvascular amyloid and the associated neuroinflammation...
- Reducing cerebral microvascular amyloid-beta protein deposition diminishes regional neuroinflammation in vasculotropic mutant amyloid precursor protein transgenic miceJianting Miao
Department of Medicine, Stony Brook University, Stony Brook, New York 11794 8153, USA
J Neurosci 25:6271-7. 2005....