Human apoE Isoforms Differentially Regulate Brain Amyloid-β Peptide Clearance

Abstract

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer’s disease (AD). The APOE ε4 allele dramatically increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. In contrast, the APOE ε2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of Aβ42 peptide. However, the mechanism by which APOE alleles differentially modulate Aβ accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral Aβ deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aβ clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aβ accumulation later in life. Performing in vivo microdialysis in a mouse model of β-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aβ in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aβ deposition observed in aged PDAPP/TRE mice. Importantly, apoE isoform-dependent differences in soluble Aβ metabolism are observed not only in aged PDAPP/TRE mice but also in young PDAPP/TRE mice, well before the onset of Aβ deposition in amyloid plaques. Additionally, amyloidogenic processing of amyloid precursor protein and Aβ synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of Aβ from the brain, suggesting that Aβ clearance pathways may be useful therapeutic targets for AD prevention.

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

“…A major reason that appears to underlie this relationship is the fact that apoE isoforms result in differential onset of Ab accumulation in the brain with the onset E4 earlier than E3, which is earlier than E2. There is direct in vivo evidence that differences in Ab clearance is one factor that accounts for this (Castellano et al 2011), although effects of apoE on Ab aggregation independent of clearance may also be important. From a therapeutic standpoint, pathways that stimulate Ab clearance via apoE-dependent mechanisms are one possible approach to decrease Ab accumulation and its toxic effects.…”

“…1). A recent study shows that apoE isoforms do not differentially influence Ab production in vivo; however, apoE isoforms differentially affect Ab clearance before Ab deposition with E4 resulting in clearance that is slower than E3 and E2 (Castellano et al 2011). These results suggest the difference in Ab accumulation between apoE isoforms is likely because of isoform-specific differences in Ab clearance.…”

“…Strong evidence suggests a major mechanism by which apoE influences AD and cerebral amyloid angiopathy (CAA) is via its effects on Ab metabolism (Kim et al 2009a;Castellano et al 2011). Current understanding of apoE biology in the CNS and how apoE/Ab interactions are relevant to AD will be reviewed in the first section.…”

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

“…These receptors are not only implicated in adipocyte differentiation, but also regulate ApoE (Yue and Mazzone, 2009). ApoE is the main apolipoprotein in the brain, which facilitates the trafficking of lipids in the central nervous system, and has been also shown to modulate Aβ deposition and clearance in an isoformdependent manner (Castellano et al, 2011). Possession of an APOE ε4 allele is the strongest risk factor for sporadic AD, and has been linked to decreased efficiency of Aβ clearance (Castellano et al, 2011).…”

Neuronal activity regulates extracellular tau in vivo

“…The elimination of tau in brain lysates and ISF followed first-order kinetics. Thus t 1/2 for tau was calculated with the slope, k, of the linear regression (t 1/2 = 0.693/k, where k = 2.303k) as we previously reported (Castellano et al, 2011).…”