Journal
JOURNAL OF NEUROSCIENCE
Volume 25, Issue 11, Pages 2803-2810Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5170-04.2005
Keywords
Alzheimer's disease; apolipoprotein E; cerebral amyloid angiopathy; amyloid-beta; ratio; transgenic models
Categories
Funding
- NIA NIH HHS [AG13956, AG05681, P50 AG005681, R01 AG013956, P01 AG011355, R37 AG013956] Funding Source: Medline
- NINDS NIH HHS [R37 NS034467, NS034467, R01 NS034467] Funding Source: Medline
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Alzheimer's disease (AD) is characterized by the aggregation and deposition of the normally soluble amyloid-beta (A beta) 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 epsilon 4 allele of the apolipoprotein E (apoE) gene (APOE) is a risk factor for CAA. To determine the effect of human apoE on CAA in vivo, we bred human APOE3 and APOE4 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 A beta 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 A beta 40:42 in brain extracellular pools and a lower 40:42 ratio in CSF, suggesting that apoE4 results in altered clearance and transport of A beta species within different brain compartments. These findings demonstrate that, once A beta fibrillogenesis occurs, apoE4 favors the formation of CAA over parenchymal plaques and suggest that molecules or treatments that increase the ratio of A beta 40:42 may favor the formation of CAA versus parenchymal plaques.
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