PMC:2039847 / 4622-10166 JSONTXT

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In human brain, several members of this protein family are expressed, such as apolipoprotein E (ApoE), apolipoprotein J (ApoJ), and apolipoprotein D (apoD).\nApoE is a major determinant of lipid transport and metabolism and is expressed in brain by astrocytes, microglia, pericytes, and smooth muscle cells [14–18]. In human, three common isoforms are expressed: apoE2, apoE3, and apoE4 which are all products of alleles at a single gene locus [19, 20].\nThe ɛ4 allele of ApoE is the major genetic risk factor for AD, whereas the ɛ2 allele appears to be protective against AD [21–24]. As ApoE immunoreactivity was found in extracellular amyloid deposits in subjects with AD, it has been suggested that it affects amyloidogenesis [25, 26]. In vitro studies provided evidence for a direct interaction of ApoE with Aβ and the formation of stable complexes [27, 28]. Binding of ApoE to Aβ is, however, ApoE isoform-dependent (ɛ2\u003eɛ3\u003e\u003eɛ4) [29, 30] and depends on the degree of lipidation [29]. Lipidation of ApoE also seems a major factor in its effect on Aβ-mediated cellular toxicity [18]. In addition, ApoE4 promotes the conversion of soluble Aβ into β-sheet-rich amyloid more than ApoE3 [31–33].\nIn contrast to its effect on Aβ in vitro where a consistent accelerating effect of ApoE on Aβ aggregation is observed, the effect of ApoE on Aβ deposition in transgenic (Tg) mice studies is less equivocal. In early studies, both Aβ immunoreactivity and amyloid formation were reduced in ApoE knockout mice [31, 32]. In addition, CAA and associated microhemorrhages were also suppressed in ApoE knockout mice [34]. This effect might be due to the absence of ApoE/Aβ complexes [35]. In contrast to the effects of murine ApoE in the early studies, both human ApoE3 and ApoE4 suppressed Aβ deposition in Tg mice [36]. In addition, when these mice aged, ApoE4 induced a tenfold higher deposition of fibrillar Aβ than ApoE3 [37]. Consistent with these latter results, human ApoE4 accelerated Aβ deposition in APPSwe Tg mice relative to human ApoE3 [38]. In addition, when human ApoE3 or ApoE4 were knocked in in Tg mice, Aβ deposition was reduced compared to mice carrying endogenous ApoE at 9 months, and at 15 months, substantial CAA was observed in mice with human ApoE4, but not with human ApoE3, and, in either case, parenchymal Aβ was sparse [39]. Thus isoform- and species-specific differences in ApoE direct the aggregation or clearance of Aβ. Furthermore, it is suggested that the presence of ApoE facilitates internalization and degradation of Aβ from brain parenchyma by astrocytes [40] and human ApoE may reduce Aβ deposition in mouse brain by facilitating Aβ transport across the BBB [36]. Although these Tg mice studies seem contradictional, ApoE clearly affects conformational changes of Aβ and functions as an Aβ-transporter protein.\nBesides colocalization of ApoE with Aβ in AD brains, ApoE is also found within neurons containing NFTs [25] where it is able to interact directly with tau protein [41]. Furthermore, ApoE has an isoform-dependent effect on tau phosphorylation, as ApoE3 binds to tau in vitro, whereas ApoE4 fails to bind tau [42]. In addition, an ApoE4-dependent increase in phosphorylated tau has been observed [43–45].\nNeuroinflammation in AD comprises both activation of microglial cells and astrocytes and activation of the complement system. Aβ deposits in brain are associated with activated microglia and astrocytes, but also with elevated levels of complement [5, 6, 46]. ApoE may have an anti-inflammatory effect by suppressing microglial and astrocytic activation [47–50]. ApoE-deficient mice demonstrate increased levels of IL-6 and TNFα after LPS stimulation, suggesting a role of ApoE in inflammatory gene regulation [51]. In addition, ApoE isoform-dependent (ɛ2\u003cɛ3\u003cɛ4) differences in nitric oxide (NO) levels have been observed in microglia cells [52]. Transgenic mice expressing the ApoE4 protein isoform show a greater NO production than mice expressing the ApoE3 protein isoform. These data indicate that ApoE4 has a less efficient anti-inflammatory affect, and thus, may accelerate the development of AD.\nApolipoprotein J, also known as clusterin or SP-40/40, is a highly conserved heterodimeric secreted glycoprotein expressed in brain by epithelial and neuronal cells [53]. ApoJ colocalizes with fibrillar Aβ deposits, and it is suggested that it prevents misfolding and aggregation of soluble Aβ [54–56]. ApoD is a glycoprotein associated with high-density lipoproteins in human plasma and also has a high expression level in human brain [57], but neither its physiological role nor its ligand has been identified. ApoD levels are increased in the hippocampus of AD patients and in ApoE-deficient mice [58, 59].\nIn conclusion, ApoE and ApoJ can be regarded as amateur chaperones that regulate Aβ aggregation in vitro. By accelerating the Aβ aggregation process towards mature fibril formation, (human) ApoE prevents formation of toxic Aβ intermediates such as oligomers and protofibrils, and thus, may have a protective function towards development of AD. Moreover, ApoE protects against the development of AD by suppressing the inflammatory reactions associated with AD lesions. Besides its role in inducing conformational changes in Aβ, ApoE facilitates Aβ clearance from brain by serving as a transporter molecule of Aβ, which will be discussed in paragraph 4."}