Human Apolipoprotein E4 Alters the Amyloid-β 40:42 Ratio and Promotes the Formation of Cerebral Amyloid Angiopathy in an Amyloid Precursor Protein Transgenic Model
Autor: | Steven M. Paul, Patrick Sullivan, Kelly R. Bales, Maia Parsadanian, David M. Holtzman, John D. Fryer, Kelly Simmons |
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Rok vydání: | 2005 |
Předmět: |
Apolipoprotein E
Genetically modified mouse Pathology medicine.medical_specialty Apolipoprotein E4 BACE1-AS Apolipoprotein E3 Enzyme-Linked Immunosorbent Assay Mice Transgenic Plaque Amyloid Alkenes Benzoates Amyloid beta-Protein Precursor Mice Apolipoproteins E Alzheimer Disease Neurobiology of Disease mental disorders Amyloid precursor protein medicine Extracellular Animals Humans cardiovascular diseases Senile plaques Amyloid beta-Peptides biology Chemistry General Neuroscience P3 peptide nutritional and metabolic diseases medicine.disease Peptide Fragments Mice Inbred C57BL Cerebral Amyloid Angiopathy Disease Models Animal Gene Expression Regulation biology.protein Blood Vessels lipids (amino acids peptides and proteins) Cerebral amyloid angiopathy |
Zdroj: | The Journal of Neuroscience. 25:2803-2810 |
ISSN: | 1529-2401 0270-6474 |
Popis: | Alzheimer's disease (AD) is characterized by the aggregation and deposition of the normally soluble amyloid-β (Aβ) peptide in the extracellular spaces of the brain as parenchymal plaques and in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA). CAA is a common cause of brain hemorrhage and is found in most patients with AD. As in AD, the ϵ4 allele of the apolipoprotein E (apoE) gene (APOE) is a risk factor for CAA. To determine the effect of human apoE on CAAin vivo, we bred humanAPOE3andAPOE4“knock-in” mice to a transgenic mouse model (Tg2576) that develops amyloid plaques as well as CAA. The expression of both human apoE isoforms resulted in a delay in Aβ deposition of several months relative to murine apoE. Tg2576 mice expressing the more fibrillogenic murine apoE develop parenchymal amyloid plaques and CAA by 9 months of age. At 15 months of age, the expression of human apoE4 led to substantial CAA with very few parenchymal plaques, whereas the expression of human apoE3 resulted in almost no CAA or parenchymal plaques. Additionally, young apoE4-expressing mice had an elevated ratio of Aβ 40:42 in brain extracellular pools and a lower 40:42 ratio in CSF, suggesting that apoE4 results in altered clearance and transport of Aβ species within different brain compartments. These findings demonstrate that, once Aβ fibrillogenesis occurs, apoE4 favors the formation of CAA over parenchymal plaques and suggest that molecules or treatments that increase the ratio of Aβ 40:42 may favor the formation of CAA versus parenchymal plaques. |
Databáze: | OpenAIRE |
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