The generation and function of soluble apoE receptors in the CNS

Department of Neuroscience, Georgetown University, Washington, DC, USA.
Molecular Neurodegeneration (Impact Factor: 6.56). 02/2006; 1(1):15. DOI: 10.1186/1750-1326-1-15
Source: PubMed


More than a decade has passed since apolipoprotein E4 (APOE-epsilon4) was identified as a primary risk factor for Alzheimer 's disease (AD), yet researchers are even now struggling to understand how the apolipoprotein system integrates into the puzzle of AD etiology. The specific pathological actions of apoE4, methods of modulating apolipoprotein E4-associated risk, and possible roles of apoE in normal synaptic function are still being debated. These critical questions will never be fully answered without a complete understanding of the life cycle of the apolipoprotein receptors that mediate the uptake, signaling, and degradation of apoE. The present review will focus on apoE receptors as modulators of apoE actions and, in particular, explore the functions of soluble apoE receptors, a field almost entirely overlooked until now.

Download full-text


Available from: PubMed Central · License: CC BY
  • Source
    • "The association of ApoE with ILVs and exosomes ascertains a new pathway of secretion for ApoE that would differ from its typical release as phospholipid discs (Kockx et al., 2008). The association of ApoE with ILVs would also extend the properties of exosomes as ApoE binds specific receptors for uptake and modulates the activity of soluble ApoE receptors (Rebeck et al., 2006). This association also prompts us to reconsider the respective roles of ApoE and exosomes in several pigment cell-associated pathologies such as age-related macular degeneration (Johnson et al., 2011; Wang et al., 2009) and melanoma metastasis (Peinado et al., 2012; Pencheva et al., 2012) where ApoE may endow signaling properties to exosomes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Accumulation of toxic amyloid oligomers is a key feature in the pathogenesis of amyloid-related diseases. Formation of mature amyloid fibrils is one defense mechanism to neutralize toxic prefibrillar oligomers. This mechanism is notably influenced by apolipoprotein E variants. Cells that produce mature amyloid fibrils to serve physiological functions must exploit specific mechanisms to avoid potential accumulation of toxic species. Pigment cells have tuned their endosomes to maximize the formation of functional amyloid from the protein PMEL. Here, we show that ApoE is associated with intraluminal vesicles (ILV) within endosomes and remain associated with ILVs when they are secreted as exosomes. ApoE functions in the ESCRT-independent sorting mechanism of PMEL onto ILVs and regulates the endosomal formation of PMEL amyloid fibrils in vitro and in vivo. This process secures the physiological formation of amyloid fibrils by exploiting ILVs as amyloid nucleating platforms.
    Full-text · Article · Sep 2015 · Cell Reports
  • Source
    • "During its journey to the cell surface, LRP undergoes sequential cleavage events due to different proteinases (reviewed in Rebeck et al., 2006). LRP is synthesized as a 600 kDa transmembrane glycoprotein, which later becomes cleaved by furin in the trans-Golgi network, thus producing a 515 kDa α-subunit and an 85 kDa β-subunit (Herz et al., 1990). "
    [Show abstract] [Hide abstract]
    ABSTRACT: As Giardia lamblia is unable to synthesize cholesterol de novo, this steroid might be obtained from the host's intestinal milieu by endocytosis of lipoproteins. In this work, we identified a putative Giardia lamblia low-density lipoprotein receptor-related proteins (GlLRP), a type I membrane protein, which shares the substrate N-terminal binding domain and a FXNPXY-type endocytic motif with human LRPs. Expression of tagged GlLRP showed that it was localized predominantly in the endoplasmic reticulum, lysosomal-like peripheral vacuoles and plasma membrane. However, the FXNPXY-deleted GlLRP was retained at the plasma membrane suggesting that it is abnormally transported and processed. The low-density lipoprotein and chylomicrons interacted with GlLRP, with this interaction being necessary for lipoprotein internalization and cell proliferation. Finally, we show that GlLRP binds directly to the medium subunit of Giardia adaptor protein 2, indicating that receptor-mediated internalization occurs through an adaptin mechanism.
    Full-text · Article · Mar 2011 · Molecular Microbiology
  • Source
    • "After age itself, ApoE is the second most important risk factor for LOAD and by far its single most important genetic factor (Ashford, 2004; Raber et al., 2004). ApoE is a secreted glycoprotein that associates with lipoproteins and mediates uptake of these lipid-rich particles into cells via receptor-mediated endocytosis by the LDL receptor family (Rebeck et al., 2006). In brain, ApoE is the primary transporter of endogenously produced brain lipids such as cholesterol and sulfatide (Dietschy and Turley, 2004; Poirier, 2003; Puglielli et al., 2003; Vos et al., 1994) that are essential for myelin production, function, and integrity (Dietschy and Turley, 2004; Marcus et al., 2006; Saher et al., 2005; Vos et al., 1994). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The amyloid hypothesis (AH) of Alzheimer's disease (AD) posits that the fundamental cause of AD is the accumulation of the peptide amyloid beta (Aβ) in the brain. This hypothesis has been supported by observations that genetic defects in amyloid precursor protein (APP) and presenilin increase Aβ production and cause familial AD (FAD). The AH is widely accepted but does not account for important phenomena including recent failures of clinical trials to impact dementia in humans even after successfully reducing Aβ deposits. Herein, the AH is viewed from the broader overarching perspective of the myelin model of the human brain that focuses on functioning brain circuits and encompasses white matter and myelin in addition to neurons and synapses. The model proposes that the recently evolved and extensive myelination of the human brain underlies both our unique abilities and susceptibility to highly prevalent age-related neuropsychiatric disorders such as late onset AD (LOAD). It regards oligodendrocytes and the myelin they produce as being both critical for circuit function and uniquely vulnerable to damage. This perspective reframes key observations such as axonal transport disruptions, formation of axonal swellings/sphenoids and neuritic plaques, and proteinaceous deposits such as Aβ and tau as by-products of homeostatic myelin repair processes. It delineates empirically testable mechanisms of action for genes underlying FAD and LOAD and provides "upstream" treatment targets. Such interventions could potentially treat multiple degenerative brain disorders by mitigating the effects of aging and associated changes in iron, cholesterol, and free radicals on oligodendrocytes and their myelin.
    Preview · Article · Sep 2009 · Neurobiology of aging
Show more