Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model - PubMed (original) (raw)

Comparative Study

Human apolipoprotein E4 alters the amyloid-beta 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model

John D Fryer et al. J Neurosci. 2005.

Abstract

Alzheimer's disease (AD) is characterized by the aggregation and deposition of the normally soluble amyloid-beta (Abeta) 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 epsilon4 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 Abeta 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 Abeta 40:42 in brain extracellular pools and a lower 40:42 ratio in CSF, suggesting that apoE4 results in altered clearance and transport of Abeta species within different brain compartments. These findings demonstrate that, once Abeta fibrillogenesis occurs, apoE4 favors the formation of CAA over parenchymal plaques and suggest that molecules or treatments that increase the ratio of Abeta 40:42 may favor the formation of CAA versus parenchymal plaques.

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Figures

Figure 1.

Figure 1.

Ex vivo image of an APPsw brain demonstrating extensive CAA. A, A 15-month-old (15 m.o.) APPsw mouse brain stained with X-34 and imaged with UV epifluorescence to denote fibrillar amyloid. Extensive CAA in leptomeningeal vessels can be seen on the cortical surface (arrows) as well as on plaques near the cortical surface (arrowheads). B, A 15-month-old non-transgenic (non-Tg) mouse brain stained with X-34, demonstrating the specificity of the stain.

Figure 2.

Figure 2.

Expression of human apoE3 or apoE4 delays deposition compared with murine apoE in the APPsw model at 12 months of age. A, D, Anti-Aβ immunostaining with monoclonal antibody m3D6 (A) or X-34 staining (D) to denote fibrillar amyloid of APPsw mice expressing endogenous murine apoE demonstrating CAA (arrows) and parenchymal plaques (arrowheads). However, 12-month-old (12 m.o.) APPsw mice expressing human apoE3 (B, E) or apoE4 (C, F) had little or no detectable plaques.

Figure 3.

Figure 3.

Expression of apoE determines the level of CAA and parenchymal plaque pathology in an isoform-dependent manner in the 15-month-old (15 m.o.) APPsw model. A-F, Anti-Aβ immunostaining with m3D6 antibody (A-C) or X-34 staining (D-F) to visualize fibrillar Aβ deposits demonstrates CAA (arrows) and parenchymal plaques (arrowheads). A, D, APP swmice expressing endogenous murine apoE had both CAA and parenchymal plaques. B, C, E, F, APPsw mice expressing human apoE3 (B, E) had only occasional Aβ deposits, whereas APPsw mice expressing human apoE4 (C, F) had extensive CAA with infrequent parenchymal plaques.

Figure 4.

Figure 4.

Stereological quantitation of CAA and fibrillar plaque load. A-C, In 15-month-old APPsw mice, expression of human apoE4 (hApoE) and murine apoE (mApoE) resulted in significantly greater CAA load in leptomeningeal vessels (A), penetrating cortical vessels (B), and total cortical vessels (C) and parenchymal plaque load compared with mice expressing human apoE3. B-D, Expression of murine apoE also resulted in significantly higher levels of penetrating (B), total CAA (C), and parenchymal plaque load (D) compared with expression of human apoE4. D, Expression of both human apoE3 and apoE4 resulted in a dramatic reduction in parenchymal amyloid plaque load compared with mice expressing murine apoE. Error bars represent SEM.

Figure 5.

Figure 5.

Fifteen-month-old APPsw mice expressing human apoE4 (hApoE4) had dramatically more deposition of Aβ incerebral vessels than mice expressing human apoE3. A, B, Human apoE3-expressing mice deposited 21.26 ± 5.097 ng/mg Aβ1-40 and 25.58 ± 9.282 ng/mg Aβ1-42 in cerebral vessels, whereas human apoE4-expressing mice deposited 21,040 ± 13,530 ng/mg Aβ1-40 and 4535 ± 2094 ng/mg Aβ1-42 in cerebral vessels. C, D, Additionally, human apoE3-expressing mice deposited 8.493 ± 1.918 ng/mg Aβ1-40 and 5.827 ± 1.421 ng/mg Aβ1-42 in brain parenchymal tissue, whereas human apoE4-expressing mice deposited 60.89 ± 20.53 ng/mg Aβ1-40 and 57.38 ± 17.48 ng/mg Aβ1-42 in brain parenchymal tissue. Error bars represent SEM.

Figure 6.

Figure 6.

Expression of human apoE4 (hApoE4) alters the ratio of Aβ 40:42 in extracellular pools of the CNS. A, The level of Aβ1-40 in PBS-soluble brain extracts was significantly higher in APPsw mice expressing human apoE4 compared with mice expressing murine apoE (mApoE). Aβ1-42 levels were slightly, but not significantly, lower in APPsw mice expressing human apoE4 compared with mice expressing murine apoE. B, The level of Aβ1-40 in the CSF was slightly, but not significantly, lower in APPsw mice expressing human apoE4 compared with mice expressing murine apoE. Also, Aβ1-42 levels were slightly, but not significantly, higher in APPsw mice expressing human apoE4 compared with mice expressing murine apoE. C, The Aβ 40:42 ratio in PBS-soluble extracts was significantly higher in APPsw mice expressing human apoE4 compared with murine apoE. D, However, the Aβ 40:42 ratio in the CSF was significantly lower in APPsw mice expressing human apoE4 compared with mice expressing human apoE3 or murine apoE. Error bars represent SEM.

Figure 7.

Figure 7.

Expression of murine apoE (mApoE) or human apoE3 (hApoE3) or apoE4 (hApoE4) does not alter apoE levels or total brain cholesterol. A, B, Levels of human apoE were not significantly different in PBS-soluble brain extracts of cortical tissue (A) or in CSF (B). C, Additionally, the level of hippocampal cholesterol did not significantly differ among mice expressing murine apoE, human apoE3, or human apoE4. Error bars represent SEM.

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