Attenuation of the Neurotoxic Effect of Aβ Amyloid Peptide by Apolipoprotein E

Whitson, J. S.; Mims, M. P.; Strittmatter, Warren J.; Yamaki, Takeshi; Morrisett, Joel D.; Appel, Stanley H.

doi:10.1006/bbrc.1994.1209

Cited by 68 publications

(42 citation statements)

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“…Membrane-associated mechanisms of A␤ neurotoxicity include membrane depolarization (36,37), membrane destabilization (46 -48), pore formation (66 -69), and membrane-associated free radical generation (70 -73). A membrane-mediated step could also be associated with the observed A␤-induced alterations in intracellular signaling (74 -76), ion channel function (77)(78)(79)(80), and calcium homeostasis (81)(82)(83)(84).…”

Section: Discussionmentioning

confidence: 99%

Reduction in Cholesterol and Sialic Acid Content Protects Cells from the Toxic Effects of β-Amyloid Peptides

Wang

Rymer

Good

2001

Journal of Biological Chemistry

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␤-Amyloid (A␤) is the primary protein component of senile plaques associated with Alzheimer's disease and has been implicated in the neurotoxicity associated with the disease. A variety of evidence points to the importance of A␤-membrane interactions in the mechanism of A␤ neurotoxicity and indicates that cholesterol and gangliosides are particularly important for A␤ aggregation and binding to membranes. We investigated the effects of cholesterol and sialic acid depletion on A␤-induced GTPase activity in cells, a step implicated in the mechanism of A␤ toxicity, and A␤-induced cell toxicity. Cholesterol reduction and depletion of membraneassociated sialic acid residues both significantly reduced the A␤-induced GTPase activity. In addition, cholesterol and membrane-associated sialic acid residue depletion or inhibition of cholesterol and ganglioside synthesis protected PC12 cells from A␤-induced toxicity. These results indicate the importance of A␤-membrane interactions in the mechanism of A␤ toxicity. In addition, these results suggest that control of cellular cholesterol and/or ganglioside content may prove useful in the prevention or treatment of Alzheimer's disease.An important pathological hallmark of Alzheimer's disease (AD) 1 is the formation and progressive deposition of insoluble amyloid fibrils within the cerebral cortex (1). The key constituent of these amyloid deposits has been identified as a 39 -43-amino acid long polypeptide, ␤-amyloid peptide (A␤), which is derived primarily from the proteolytic cleavage of a much larger amyloid precursor protein (2). Presenilin 1 and 2 are believed to be involved in the proteolytic processing of the A␤ fragment (3-6). Evidence for the causative role of A␤ in the pathogenesis of AD partly comes from genetic studies, which linked mutations in the amyloid precursor protein and in the presenilins to inheritable forms of AD (7-9). Further evidence originates from in vitro toxicity studies with synthetic A␤ peptides, which have shown that A␤, in an aggregated state (fibril, protofibril, low molecular weight oligomer, or diffusible, nonfibrillar ligand), is toxic to neurons in culture (10 -17). Although it seems certain that A␤ plays a role in neurotoxicity associated with AD, the molecular mechanism of A␤ neurotoxicity remains unclear.Increasing evidence indicates that the neuronal cell membrane is important in the mechanism of A␤ toxicity. Studies (18 -21) have indicated that membrane components such as cholesterol and gangliosides alter the affinity of A␤ for phospholipid membranes. Once associated with the membranes, negatively charged phospholipids, cholesterol, and gangliosides have been shown to increase the ␤-sheet content and/or rate of aggregation of A␤ (19,(21)(22)(23)(24). Both in vivo and in vitro, alterations in soluble cholesterol and/or cholesterol biosynthesis have also been shown to affect the normal processing of amyloid precursor protein (25)(26)(27). In these studies, the inhibition of cholesterol synthesis led to decreased A␤ formation (25,27). In...

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Section: Discussionmentioning

confidence: 99%

Reduction in Cholesterol and Sialic Acid Content Protects Cells from the Toxic Effects of β-Amyloid Peptides

Wang

Rymer

Good

2001

Journal of Biological Chemistry

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“…Recent attempts to construct transgenic mice that overexpress apoE4 and APP may have been misguided by the incorrect assumption that apoE4 promotes amyloid formation (30). It has been observed that low concentrations of apoE attenuate the neurotoxicity of ,B protein (31). This effect may be due to inhibition of amyloid nucleation by apoE, an activity that may have therapeutic benefit.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: implications for the pathogenesis and treatment of Alzheimer disease.

Evans

Berger

Cho

et al. 1995

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

334

242

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The apolipoprotein E4 (APOE4) allele is associated with an early age of onset of the nonfamilial form of Alzheimer disease (AD) and with increased 8 protein amyloid deposition in the brain. These two observations may both arise from an effect of the apoE family of proteins on the rate of in vivo amyloidogenesis. We report here that apoE3, the common apoE isoform, is an in vitro amyloid nucleation inhibitor at physiological concentrations. A significant delay in the onset of amyloid fibril formation by the ,3-amyloid protein of AD (181-40) was observed at a low apoE3 concentration (40 nM), corresponding to an apoE3/13 protein molar ratio of 1:1000. The inhibitory activity of a proteolytic fragment of apoE3, containing the N-terminal 191 amino acids, is comparable to the native protein, whereas the C-terminal fragment has no activity. ApoE4 is equipotent or slightly less potent than apoE3, which may be due to its inability to form a disulfide dimer, since the apoE3 dimer is a significantly more potent nucleation inhibitor than apoE4. Neither apoE3 nor apoE4 inhibits the seeded growth of amyloid or affects the solubility or structure of the amyloid fibrils, indicating that apoE is not a thermodynamic amyloid inhibitor. We propose that the linkage between the APOE4 allele and AD reflects the reduced ability of APOE4 homozygotes to suppress in vivo amyloid formation.Amyloid plaque is an ordered, fibrous protein aggregate that is characteristic of the Alzheimer disease (AD) brain. The acceleration of amyloid deposition may be a primary event in AD (1, 2). Thus, endogenous factors that affect the rate of amyloid formation could play a significant role in the pathogenesis of AD (3, 4). The apolipoprotein E genotype (APOE) has recently been recognized as a susceptibility factor for AD (5-8). Three isoforms of apoE occur in the human population. They differ by single amino acid changes. APOE3 is the most common allele (0.78), followed by APOE4 (0.14) and APOE2 (0.07) (9). ApoE4 and apoE3 differ with respect to lipoprotein binding (10), but the two proteins are indistinguishable with respect to low density lipoprotein receptor binding (11). ApoE3 and apoE4 are distinguished by a single point mutation in a sequence of 299 amino acids (apoE3, C112; apoE4, R112) (12).TheAPOE4 allele correlates with an earlier age of AD onset (5) and an increased amount of cerebral amyloid plaque (13) at the time of death relative to the common APOE3 allele. (/3,,). Once the nucleus has formed, association becomes favorable (Kg >> 1) and is not inhibited by apoE. Exogenous seed fibrils will bypass the lag time and result in rapid growth that is not inhibited by apoE (see Fig. 2).

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“…An enhanced burden of both ␤/A4-amyloid Strittmatter et al, 1993a,b;Czech et al, 1994;Gearing et al, 1995;Nagy et al, 1995;Ohm et al, 1995;Oyama et al, 1995) and NFT (Nagy et al, 1995;Ohm et al, 1995) was gene dose dependently seen in apoE ⑀4-carriers. Although isoform-specific interactions of apoE with both ␤/A4-amyloid (Strittmatter et al, 1993a,b;Wisniewski et al, 1993) and tau (Cotton et al, 1994;Strittmatter et al, 1994a,b;Whitson et al, 1994) have been reported, the mechanism behind the pathological effects of the apoE polymorphism remains unknown.…”

Section: Abstract: Alzheimer's Disease; Apolipoprotein E; Degeneratimentioning

confidence: 99%

“…It remains to be determined whether the molecular mechanisms behind these effects are related to genotype-specific alterations of apoE levels in the brain (Blennow et al, 1994;Bertrand et al, 1995), to isoform-specific differences in interactions with cellular proteins that mediate neurotrophic (Nathan et al, 1994;Bellosta et al, 1995;Holtzman et al, 1995) or cytotoxic (Crutcher et al, 1994;Clay et al, 1995) effects, or to molecular interactions with the ␤/A4-amyloid (Wisniewski and Frangione, 1992;Strittmatter et al, 1993b;Wisniewski et al, 1993;Gallo et al, 1994;Castano et al, 1995;Evans et al, 1995) or microtubule-associated proteins (Cotton et al, 1994;Huang et al, 1994Huang et al, , 1995Strittmatter et al, 1994a,b;Whitson et al, 1994).…”

Section: Apoe Genotype and Stage Dependency Of Reparative Capacitymentioning

confidence: 99%

Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele

Arendt¹,

Schindler²,

Brückner³

et al. 1997

J. Neurosci.

309

174

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A relationship between the apolipoprotein E (apoE) genotype and the risk to develop Alzheimer's disease has been established recently. Apolipoprotein synthesis is implicated in developmental processes and in neuronal repair of the adult nervous system.In the present study, we investigated the influence of the apolipoprotein polymorphism on the severity of neuronal degeneration and the extent of plastic dendritic remodeling in Alzheimer's disease. Changes in length and arborization of dendrites of Golgi-impregnated neurons in the basal nucleus of Meynert, locus coeruleus, raphe magnus nucleus, medial amygdaloid nucleus, pedunculopontine tegmental nucleus, and substantia nigra were analyzed after three-dimensional reconstruction. Patients with either one or two apoE ⑀4 alleles not only showed a more severe degeneration in all areas investigated than in patients lacking the apoE 4 allele but also revealed significantly less plastic dendritic changes. ApoE ⑀4 allele copy number, furthermore, had a significant effect on the pattern of dendritic arborization. Moreover, the relationship between the intensity of dendritic growth and both the extent of neuronal degeneration and the stage of the disease seen in patients lacking the apoE ⑀4 allele was very weak in the presence of one ⑀4 allele and completely lost in patients homozygous for the ⑀4 allele.The results provide direct evidence that neuronal reorganization is affected severely in patients with Alzheimer's disease carrying the apoE ⑀4 allele. This impairment of neuronal repair might lead to a more rapid functional decompensation, thereby contributing to an earlier onset and more rapid progression of the disease.

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Attenuation of the Neurotoxic Effect of Aβ Amyloid Peptide by Apolipoprotein E

Cited by 68 publications

References 0 publications

Reduction in Cholesterol and Sialic Acid Content Protects Cells from the Toxic Effects of β-Amyloid Peptides

Reduction in Cholesterol and Sialic Acid Content Protects Cells from the Toxic Effects of β-Amyloid Peptides

Apolipoprotein E is a kinetic but not a thermodynamic inhibitor of amyloid formation: implications for the pathogenesis and treatment of Alzheimer disease.

Plastic Neuronal Remodeling Is Impaired in Patients with Alzheimer’s Disease Carrying Apolipoprotein ε4 Allele

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