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

Abstract

Alzheimer's disease (AD) is characterized by the aggregation and deposition of the normally soluble amyloid-␤ (A␤) 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 ⑀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␤ 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␤ 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␤ species within different brain compartments. These findings demonstrate that, once A␤ fibrillogenesis occurs, apoE4 favors the formation of CAA over parenchymal plaques and suggest that molecules or treatments that increase the ratio of A␤ 40:42 may favor the formation of CAA versus parenchymal plaques.

Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

“…A fifty percent reduction of ApoE also decreased CAA (45). In contrast, when human ApoE4 is overexpressed in Tg2576 mice, the distribution of amyloid pathology is altered in favor of vascular vs. parenchymal deposits (46). In the present study, we found that apocynin and, to a lesser degree, tempol decrease mouse ApoE levels-an effect that would be expected to decrease CAA formation to a far greater extent than neuritic plaques.…”

“…Taken together, these findings represent direct evidence that ROS play a causal role in the CV deficits induced by fibrillar Aβ in the form of CAA and that the source of the ROS is likely NADPH oxidase. In addition, we provide preliminary evidence that one mechanism by which ROS impact CAA pathogenesis is via an effect on ApoE-a factor known to promote CAA formation (45,46). Our findings have both mechanistic and therapeutic significance.…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…E2) Ito et al 2007;Deane et al 2008). In addition, apoE can influence the pathogenesis of CAA in an amyloid protein precursor (APP)-transgenic mouse model, with apoE4 increasing the amount of vascular plaques in comparison to apoE3 (Fryer et al 2005b In vitro and in vivo data including data in humans and animal models suggests that the physical interaction of apoE with Ab plays an important role in AD and CAA pathogenesis (Fig. 1).…”

“…In addition, the anatomical pattern of Ab deposition differs in the absence of apoE (Holtzman et al 2000a;Irizarry et al 2000). The expression of human apoE isoforms in either PDAPP or Tg2576 Tg mice resulted in a marked delay in the deposition of Ab and formation of neuritic plaques, compared with APP Tg mice expressing no apoE or mouse apoE Fryer et al 2005b). Importantly, expression of human apoE isoforms in APP Tg mice results in an isoform-specific effect on the amount of Ab accumulation as well as true amyloid deposits (E4 .…”

“…E2) (Holtzman et al 2000a;Fagan et al 2002;Fryer et al 2005b). In addition to the isoform-specific effects of human apoE on parenchymal Ab pathology, crossing human apoE knockin mice to Tg2576 mice resulted in a relative shift of Ab deposition from the brain parenchyma to arterioles in the form of CAA in apoE4 expressing mice relative to apoE3 or mouse apoE (Fryer et al 2005b). A similar effect of apoE4 predisposing to CAA is seen in humans.…”