Apolipoprotein E Markedly Facilitates Age-Dependent Cerebral Amyloid Angiopathy and Spontaneous Hemorrhage in Amyloid Precursor Protein Transgenic Mice

Aug 29, 2003The Journal of neuroscience : the official journal of the Society for Neuroscience

Apolipoprotein E greatly increases age-related brain blood vessel amyloid buildup and bleeding in mice with Alzheimer's-related protein

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Abstract

Both amyloid precursor protein mouse models showed an age-dependent increase in cerebral amyloid angiopathy (CAA) and associated microhemorrhage.

Cerebral amyloid angiopathy (CAA) is linked to increased risk of brain hemorrhage in the elderly and is prevalent in Alzheimer's disease.
The presence of the epsilon4 allele of apolipoprotein E (APOE) is associated with higher risk for CAA.
In APPsw mice, CAA developed earlier and more severely compared to PDAPP mice.
Breeding APPsw and PDAPP mice onto an Apoe-/- background resulted in no detectable CAA or microhemorrhage through 24 months.
Biochemical analysis indicated that the ratio of amyloid-beta 40 to 42 was elevated in CAA-affected cerebral vessels, similar to observations in humans.

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Cerebral amyloid angiopathy (CAA) is a common cause of brain hemorrhage in the elderly. It is found in the majority of patients with Alzheimer's disease (AD). The most common form of CAA is characterized by the deposition of the amyloid-beta (Abeta) peptide in the walls of cerebral vessels, and this deposition can lead to hemorrhage and infarction. As in AD, the epsilon4 allele of apolipoprotein E (APOE) is a risk factor for CAA. To determine the effect of apoE on CAA and associated hemorrhage in vivo, we used two amyloid precursor protein (APP) transgenic mouse models that develop age-dependent Abeta deposition: PDAPP and APPsw mice. We found that both models developed an age-dependent increase in CAA and associated microhemorrhage, with the APPsw model having an earlier and more severe phenotype; however, when APPsw and PDAPP mice were bred onto an Apoe-/- background, no CAA was detected through 24 months of age, and there was little to no evidence of microhemorrhage. Biochemical analysis of isolated cerebral vessels from both PDAPP and APPsw mice with CAA revealed that, as in human CAA, the ratio of Abeta 40:42 was elevated relative to brain parenchyma. In contrast, the ratio of Abeta 40:42 from cerebral vessels isolated from old PDAPP, Apoe-/- mice was extremely low. These findings demonstrate that murine apoE markedly promotes the formation of CAA and associated vessel damage and that the effect of apoE combined with the level of Abeta40 or the ratio of Abeta 40:42 facilitates this process.

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Apolipoprotein E Markedly Facilitates Age-Dependent Cerebral Amyloid Angiopathy and Spontaneous Hemorrhage in Amyloid Precursor Protein Transgenic Mice

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