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  • ApoE is secreted from astrocytes glia into the

    2021-03-04

    ApoE is secreted from astrocytes/glia into the interstitial fluid and is important for metabolizing Aβ because of its propensity for binding Aβ as a cholesterol and phospholipid acceptor in reverse cholesterol transport [8]. Aβ oligomers show a direct toxicity to neurons, and ApoE inhibits oligomer formation of Aβ peptides in solution because of its ability to bind Aβ [9]. ApoE expression is transcriptionally induced through the action of the nuclear receptor, peroxisome proliferator-activated receptor-γ, and liver X receptors (LXRs) in coordination with retinoid x receptors [10]. Oral administration of retinoid x receptor agonists promotes the clearance of soluble Aβ and improves a variety of symptoms in mouse models of AD [11]. The lipidation of ApoE by the lipid transporter ATP-binding cassette transporter A1 (ABCA1), a major regulator of high-density lipoprotein metabolism, helps ApoE bind Aβ, while LXRs regulate the expression of both ABCA1 and ApoE and their activation increases the levels of lipidated ApoE [12]. The lack of ABCA1 causes a significant decrease in ApoE levels and a significant increase in amyloid deposition in the brains of ABCA1 knock-out mice, indicating that lipidated ApoE is essential for clearing amyloid deposition in the CGP 53353 australia [13]. The intracellular degradation of Aβ by microglia is principally carried out by neprilysin and related proteases [14] whose activity can be enhanced with ApoE. Thus, ApoE is essential for Aβ internalization into the microglia, the promotion of Aβ proteolytic degradation [15], [16], [17], [18], and the inhibition of Aβ toxicity in the brain. However, a recent report suggests that ApoE affects Aβ metabolism not by directly binding to Aβ in physiological fluids such as cerebrospinal fluid or interstitial fluid, but by creating competition for the same clearance pathways as Aβ, resulting in Aβ accumulation in the brain [19]. The beneficial effects of decreased ApoE expression that occur following AD treatment are supported by the fact that decreases in ApoE under haploinsufficiency of human ApoE results in less Aβ deposition in amyloid mouse models, which is independent of ApoE isoforms [20], [21]. Given that ApoE does appear to be involved in Aβ metabolism, ApoE metabolism may serve as a potential therapeutic target in the AD brain, although little is known about the fate of ApoE in the brain.
    Materials and methods
    Results
    Discussion A previous study showed that extracts from AD brain tissue demonstrate protease activity to ApoE at an acidic pH, which was inhibited by pepstatin A, suggesting that aspartic proteases are involved in the extracts [27]. Cathepsin D is also implicated in the pathogenesis and pathology of AD [28], [29], as it showed hydrolytic activity for both lipid-free and lipidated ApoE. In addition, the major ApoE fragment with cathepsin D had a similar molecular weight to that found in human brain lysates [30]. Furthermore, an immunohistochemical study revealed the colocalization of cathepsin D in neuritic plaques in brains with AD [31]. Other reports have suggested ApoE4 cleavage by a chymotrypsin-like protease, which is contained in human brain tissue or cultured neuronal cell lysates [32]. The hydrolytic activity of the chymotrypsin-like protease was inhibited only by phenylmethylsulfonyl fluoride, and not by other protease inhibitors including ethylene glycol tetraacetic acid, pepstatin, E-64, and iodoacetamide. These studies suggest that the key proteases in the extracts are serine proteases, and it might be a chymotrypsin-like protease, as determined by the substrate specificity of the protease with synthetic peptides [33]. However, these studies did not use the chymotrypsin-specific inhibitor, chymostatin. The involvement of metalloproteases in activated microglial cells has also been reported. Activated microglial cells secrete metalloproteases of 200kDa, which is different from the molecular weights of neutral endopeptidases and macrophage elastases, thus metalloproteases could degrade Aβ [34].