Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease

Namba, Yoshio; Tomonaga, Masanori; Kawasaki, Hiroshi; Otomo, E; Ikeda, Kazuhiko

doi:10.1016/0006-8993(91)91092-f

Cited by 1,055 publications

(544 citation statements)

References 18 publications

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“…3E). Although multiple cells in AD brain, including microglia, have been shown to produce apoE, possibly underlying its increased expression in AD (43)(44)(45)(46)(47), our data suggest a means for increased expression by microglia at the site of A␤ deposits and perturbed neurons. In addition to enhancing cell growth, M-CSF also promoted BV-2 proliferation (Fig.…”

Section: Resultsmentioning

confidence: 67%

Amyloid-β peptide–Receptor for Advanced Glycation Endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease

Yan

Zhu²,

Fu³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

385

153

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In Alzheimer disease (AD), neurons are thought to be subjected to the deleterious cytotoxic effects of activated microglia. We demonstrate that binding of amyloidbeta peptide (A␤) to neuronal Receptor for Advanced Glycation Endproduct (RAGE), a cell surface receptor for A␤, induces macrophage-colony stimulating factor (M-CSF) by an oxidant sensitive, nuclear factor B-dependent pathway. AD brain shows increased neuronal expression of M-CSF in proximity to A␤ deposits, and in cerebrospinal fluid from AD patients there was Ϸ5-fold increased M-CSF antigen (P < 0.01), compared with age-matched controls. M-CSF released by A␤-stimulated neurons interacts with its cognate receptor, c-fms, on microglia, thereby triggering chemotaxis, cell proliferation, increased expression of the macrophage scavenger receptor and apolipoprotein E, and enhanced survival of microglia exposed to A␤, consistent with pathologic findings in AD. These data delineate an inflammatory pathway triggered by engagement of A␤ on neuronal RAGE. We suggest that M-CSF, thus generated, contributes to the pathogenesis of AD, and that M-CSF in cerebrospinal fluid might provide a means for monitoring neuronal perturbation at an early stage in AD.

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Section: Resultsmentioning

confidence: 67%

Amyloid-β peptide–Receptor for Advanced Glycation Endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease

Yan

Zhu²,

Fu³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

385

153

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“…Although the mechanism for these associations is still unknown, two general observations may be relevant for these associations. First, apoE and apoE-containing lipoproteins have been shown to interact with /3-amybid (A/3) both in vitro (Strittmatter et al, 1993a,b;LaDu et al, 1994LaDu et al, , 1995 and in vivo in the brains of AD patients (Namba et al, 1991;Naslund eta!., 1995) and after head trauma (Nicoll et al, 1995). Furthermore, apoE can influence the rate of A/3 fibril formation in vitro (Evans et a!., 1994;Wood eta!., 1996).…”

Section: Figmentioning

confidence: 99%

Nascent Astrocyte Particles Differ from Lipoproteins in CSF

LaDu

Gilligan

Lukens

et al. 1998

Journal of Neurochemistry

259

253

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Abstract:Little is known about lipid transport and metabolism in the brain. As a further step toward understanding the origin and function of CNS lipoproteins, we have characterized by size and density fractionation lipoprotein particles from human CSF and primary cultures of rat astrocytes. The fractions were analyzed for esterified and free cholesterol, triglyceride, phospholipid, albumin, and apolipoproteins (apo) E, Al, All, and J. As determined by lipid and apolipoprotein profiles, gel electrophoresis, and electron microscopy, nascent astrocyte particles contain little core lipid, are primarily discoidal in shape, and contain apoE and apoJ. In contrast, CSF lipoproteins are the size and density of plasma high-density lipoprotein, contain the core lipid, esterified cholesterol, and are spherical. CSF lipoproteins were heterogeneous in apolipoprotein content with apoE, the most abundant apolipoprotein, localized to the largest particles, apoAl and apoAll localized to progressively smaller particles, and apoJ distributed relatively evenly across particle size. There was substantial loss of protein from both CSF and astrocyte particles after density centrifugation compared with gel-filtration chromatography. The differences between lipoproteins secreted by astrocytes and present in CSF suggest that in addition to delivery of their constituents to cells, lipoprotein particles secreted within the brain by astrocytes may have the potential to participate in cholesterol clearance, developing a core of esterified cholesterol before reaching the CSF. Study of the functional properties of both astrocyte-secreted and CSF lipoproteins isolated by techniques that preserve native particle structure may also provide insight into the function of apoE in the pathophysiology of specific neurological diseases such as Alzheimer's disease. Key Words: Apolipoprotein E-Apolipoprotein J -Apolipoprotein Al -Alzheimer's disease-Cholesterol. J. Neurochem. 70, 2070Neurochem. 70, -2081Neurochem. 70, (1998.The intercellular transport of lipids through the aqueous circulatory system requires the packaging of these hydrophobic molecules into water-soluble carriers known as lipoproteins (high-density lipoprotein HDL; low-density lipoprotein LDL; and very-low-density lipoprotein, VLDL). Lipoproteins are macromolecular complexes composed of a phospholipid (PL) and free cholesterol (FC) shell surrounding a triglyceride (TG) and cholesteryl ester (CE) core (see Fig. 6A). Lipoproteins also contain apolipoproteins (apo), proteins that stabilize the surface of lipoproteins as they have both hydrophobic and hydrophilic domains. Apolipoproteins can also serve as cofactors for enzymatic reactions (Fielding et al., 1972) and ligands for cell surface receptors (Brown and Goldstein, 1986). In addition, alterations in apolipoproteins are associated with pathological conditions (Mahley, 1988). Whereas the regulation of lipoprotein metabolism and its effects on systemic lipid regulation have been studied extensively, much less is known about lipid tran...

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“…The NFTs are composed largely of the highly phosphorylated microtubule-associated protein tau (p-tau) (25) and, to a lesser extent, of phosphorylated neurofilaments (28,29). Both amyloid plaques and NFTs contain apoE (5,30,31); however, the role of apoE in the pathogenesis of these two lesions is uncertain. Histopathological and behavioral analyses of transgenic mice expressing different human apoE isoforms in the brain have revealed clear evidence for a dominant adverse effect of apoE4 (32)(33)(34), but the underlying mechanism is unknown.…”

mentioning

confidence: 99%

Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice

Harris

Brecht

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

305

365

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Apolipoprotein (apo) E4 increases the risk and accelerates the onset of Alzheimer's disease (AD). However, the underlying mechanisms remain to be determined. We previously found that apoE undergoes proteolytic cleavage in AD brains and in cultured neuronal cells, resulting in the accumulation of carboxyl-terminaltruncated fragments of apoE that are neurotoxic. Here we show that this fragmentation is caused by proteolysis of apoE by a chymotrypsin-like serine protease that cleaves apoE4 more efficiently than apoE3. Transgenic mice expressing the carboxylterminal-cleaved product, apoE4(⌬272-299), at high levels in the brain died at 2-4 months of age. The cortex and hippocampus of these mice displayed AD-like neurodegenerative alterations, including abnormally phosphorylated tau (p-tau) and Gallyas silverpositive neurons that contained cytosolic straight filaments with diameters of 15-20 nm, resembling preneurofibrillary tangles. Transgenic mice expressing lower levels of the truncated apoE4 survived longer but showed impaired learning and memory at 6 -7 months of age. Thus, carboxyl-terminal-truncated fragments of apoE4, which occur in AD brains, are sufficient to elicit AD-like neurodegeneration and behavioral deficits in vivo. Inhibiting their formation might inhibit apoE4-associated neuronal deficits.H uman apolipoprotein (apo) E, a 34-kDa protein composed of 299 amino acids, occurs as three major isoforms, apoE2, apoE3, and apoE4 (1-4). ApoE4 is a major risk or susceptibility factor for Alzheimer's disease (AD) (5-7). The apoE4 allele, which is found in 40-65% of cases of sporadic and familial AD, increases the occurrence and lowers the age of onset of the disease (7,8).Biochemical, cell biological, and transgenic animal studies have suggested several potential mechanisms to explain apoE4's contribution to the pathogenesis of AD. These include the modulation of the deposition and clearance of amyloid ␤ peptides and the formation of plaques (9-15), impairment of the antioxidative defense system (16), dysregulation of neuronal signaling pathways (17), disruption of cytoskeletal structure and function (18,19), and altered phosphorylation of tau and the formation of neurofibrillary tangles (NFTs) (20-23). However, the mechanisms of these apoE4-mediated detrimental effects are still largely unknown, and it is not known which are the primary effects and which are subsequent or downstream effects.The neuropathological hallmarks of AD include extracellular amyloid plaques and intracellular NFTs in the brain (24-27). The plaques consist primarily of amyloid ␤ peptides (24-26). The NFTs are composed largely of the highly phosphorylated microtubule-associated protein tau (p-tau) (25) and, to a lesser extent, of phosphorylated neurofilaments (28, 29). Both amyloid plaques and NFTs contain apoE (5, 30, 31); however, the role of apoE in the pathogenesis of these two lesions is uncertain. Histopathological and behavioral analyses of transgenic mice expressing different human apoE isoforms in the brain have revealed clear evi...

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Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease

Cited by 1,055 publications

References 18 publications

Amyloid-β peptide–Receptor for Advanced Glycation Endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease

Amyloid-β peptide–Receptor for Advanced Glycation Endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease

Nascent Astrocyte Particles Differ from Lipoproteins in CSF

Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice

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