Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-β peptides

Abstract

We have previously shown that apolipoprotein E (Apoe) promotes the formation of amyloid in brain and that astrocyte-specific expression of APOE markedly affects the deposition of amyloid-beta peptides (Abeta) in a mouse model of Alzheimer disease. Given the capacity of astrocytes to degrade Abeta, we investigated the potential role of Apoe in this astrocyte-mediated degradation. In contrast to cultured adult wild-type mouse astrocytes, adult Apoe(-/-) astrocytes do not degrade Abeta present in Abeta plaque-bearing brain sections in vitro. Coincubation with antibodies to either Apoe or Abeta, or with RAP, an antagonist of the low-density lipoprotein receptor family, effectively blocks Abeta degradation by astrocytes. Phase-contrast and confocal microscopy show that Apoe(-/-) astrocytes do not respond to or internalize Abeta deposits to the same extent as do wild-type astrocytes. Thus, Apoe seems to be important in the degradation and clearance of deposited Abeta species by astrocytes, a process that may be impaired in Alzheimer disease.

Apolipoprotein E region molecular signatures of Alzheimer's disease

“…In the brain, ApoE plays a role in astrocyte‐mediated amyloid‐beta degradation (Koistinaho et al., 2004), supporting the amyloid cascade hypothesis of AD development (Hardy & Higgins, 1992). However, some researchers contend that variants of other genes in the APOE region play a role in AD development.…”

Production and characterization of astrocyte-derived human apolipoprotein E isoforms from immortalized astrocytes and their interactions with amyloid-β

“…ApoE has been demonstrated to modulate Ah clearance and fibrillogenesis both in vitro (Beffert et al, 1999;Castano et al, 1995;Evans et al, 1994;Koistinaho et al, 2004;Ma et al, 1994;Yang et al, 1997Yang et al, , 1999 and in vivo (Bales et al, 1997;DeMattos et al, 2004;Holtzman et al, 2000;Shibata et al, 2000). In vivo, human apoE suppresses the onset of Ah deposition and subsequently results in an isoform-specific effect (E4 N E3 N E2) on the amount of Ah deposition, fibril formation, and neuritic plaque formation Holtzman et al, 2000).…”

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

“…Alternatively, apoE may modulate Ab removal from the brain to the systemic circulation by transport across the blood-brain barrier. Data from in vitro studies support the idea that apoE facilitates the binding and internalization of soluble Ab by cells or its clearance via enzymes such as neprilysn (Beffert et al 1998;Yang et al 1999;Cole and Ard 2000;Koistinaho et al 2004;Jiang et al 2008). Although in vitro studies suggest that apoE enhances cellular Ab uptake and degradation (Kim et al 2009a), there is in vivo evidence that apoE retards Ab clearance from the brain (DeMattos et al 2004;Bell et al 2007;Deane et al 2008), possibly via an effect at the blood -brain barrier (BBB) (Fig.…”

“…ApoE may also facilitate the cellular uptake of Ab through the endocytosis of a complex of apoE-containing lipoprotein particles bound to Ab in a manner that likely depends on the isoforms and its level of lipidation. Furthermore, apoE has been shown to directly enhance both the degradation of Ab within microglial cells and the ability of astrocytes to clear diffuse Ab deposits (Koistinaho et al 2004;Jiang et al 2008). Ab associated with apoEcontaining lipoprotein particles may also be retained within the CNS through their binding to heparin sulfate proteoglycan (HSPG) moieties present in the extracellular space (Mahley and Rall 2000).…”

“…A portion of Ab that is internalized by neurons, in particular oligomeric Ab42, accumulates in multivesicular bodies (MVBs)/late endosomes and lysosomes, and contributes to lysosomal dysfunction and neuronal toxicity. In contrast, receptormediated internalization of Ab by astrocytes (Koistinaho et al 2004) and microglia (Mandrekar et al 2009) is likely to represent a more functional pathway to clear and eventually degrade Ab.…”