Apolipoprotein (apo) E4 enhances amyloid β peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target

Ye, Shiming; Huang, Yadong; Müllendorff, Karin; Li, Dong; Giedt, Gretchen; Meng, Elaine C.; Cohen, Fred E.; Kuntz, Irwin D.; Weisgraber, Karl H.; Mahley, Robert W.

doi:10.1073/pnas.0508693102

Cited by 242 publications

(210 citation statements)

References 82 publications

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“…Replacing Arg-61 with Thr in apoE4, which abolishes domain interaction, completely inhibited apoE4-mediated stimulation of A␤ production (125). Excitingly, the apoE4 effect was abolished by treating the apoE4 with small molecules predicted to interact with the N-terminal region of apoE4 (but not apoE3) in the vicinity of Arg-61 and Arg-112 and disrupt domain interaction (125).…”

Section: Apoe4 Neuropathology In the Context Of A␤mentioning

confidence: 99%

“…Many studies have focused on the role of apoE in stimulating A␤ deposition or clearance (63,64,75,76). However, apoE4 also enhances A␤ production; apoE3 does so to a lesser extent (125). In rat neuroblastoma B103 cells stably transfected with human wild-type APP695, lipid-poor apoE4 stimulated A␤ production 60%, compared with only 30% by apoE3, and robustly stimulated APP recycling as well.…”

Section: Apoe4 Neuropathology In the Context Of A␤mentioning

confidence: 99%

“…In rat neuroblastoma B103 cells stably transfected with human wild-type APP695, lipid-poor apoE4 stimulated A␤ production 60%, compared with only 30% by apoE3, and robustly stimulated APP recycling as well. The latter effect was inhibited by blocking the LDL receptor-related protein pathway using the receptor-associated protein or LDL receptor-related protein siRNA (125), suggesting that this pathway is involved in APP recycling and A␤ production.…”

Section: Apoe4 Neuropathology In the Context Of A␤mentioning

confidence: 99%

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Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

Mahley

Weisgraber

Huang

2006

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

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826

801

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The premise of this review is that apolipoprotein (apo) E4 is much more than a contributing factor to neurodegeneration. ApoE has critical functions in redistributing lipids among CNS cells for normal lipid homeostasis, repairing injured neurons, maintaining synaptodendritic connections, and scavenging toxins. In multiple pathways affecting neuropathology, including Alzheimer's disease, apoE acts directly or in concert with age, head injury, oxidative stress, ischemia, inflammation, and excess amyloid ␤ peptide production to cause neurological disorders, accelerating progression, altering prognosis, or lowering age of onset. We envision that unique structural features of apoE4 are responsible for apoE4-associated neuropathology. Although the structures of apoE2, apoE3, and apoE4 are in dynamic equilibrium, apoE4, which is detrimental in a variety of neurological disorders, is more likely to assume a pathological conformation. Importantly, apoE4 displays domain interaction (an interaction between the N-and C-terminal domains of the protein that results in a compact structure) and molten globule formation (the formation of stable, reactive intermediates with potentially pathological activities). In response to CNS stress or injury, neurons can synthesize apoE. ApoE4 uniquely undergoes neuron-specific proteolysis, resulting in bioactive toxic fragments that enter the cytosol, alter the cytoskeleton, disrupt mitochondrial energy balance, and cause cell death. Our findings suggest potential therapeutic strategies, including the use of ''structure correctors'' to convert apoE4 to an ''apoE3-like'' molecule, protease inhibitors to prevent the generation of toxic apoE4 fragments, and ''mitochondrial protectors'' to prevent cellular energy disruption. mitochondria ͉ neurodegeneration ͉ cytoskeleton ͉ protein folding A polipoprotein (apo) E plays a fundamental role in the maintenance and repair of neurons, but its three isoforms differ in their abilities to accomplish these critical tasks (1-3). ApoE4 is associated with a wide variety of neuropathological processes. We hypothesize that different insults associated with a variety of disorders, in concert with apoE4, can lead to neuropathology. We believe that those processes are mediated by the cellular origin of apoE (astrocytes, neurons, or microglia), the nature of various injurious factors (''second hits''), and the structure of apoE4. Thus, understanding the structure and function of the apoE isoforms will yield new strategies for treating neuropathologies.Although apoE is involved in many neuropathologies, we will focus on its role in Alzheimer's disease (AD). We will consider the unique structural features that distinguish apoE4 from apoE3 and apoE2, the sites of synthesis and normal roles of apoE in the nervous system, and the pathological roles of apoE4 with or without amyloid ␤ (A␤) peptide. The evidence suggests that apoE4 is considerably more than a simple contributing factor in AD pathogenesis. ApoE and NeuropathologyApoE4's involvement in neuropathology is we...

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Section: Apoe4 Neuropathology In the Context Of A␤mentioning

confidence: 99%

Section: Apoe4 Neuropathology In the Context Of A␤mentioning

confidence: 99%

Section: Apoe4 Neuropathology In the Context Of A␤mentioning

confidence: 99%

See 1 more Smart Citation

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

Mahley

Weisgraber

Huang

2006

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

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826

801

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“…The linking of apoE4 domain interaction and astrocyte dysfunction represents a new paradigm for the association of apoE4 with neurodegenerative diseases and indicates that apoE4 domain interaction represents a viable therapeutic target. It was recently reported that disrupting domain interaction with small molecules abolishes the apoE4 enhanced Aβ production in cultured cells [51]. The relative contributions of molten globule formation and the lack of cysteine in apoE4 will await the generation of mice specific for these features, which are currently in progress.…”

Section: Reduced Cholesterolssecretionmentioning

confidence: 99%

Apolipoprotein E4 domain interaction: Synaptic and cognitive deficits in mice

Zhong

Scearce‐Levie

Ramaswamy

et al. 2008

Alzheimer's & Dementia

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BackgroundApolipoprotein E4 (apoE4), the major genetic risk factor for Alzheimer's disease (AD) and other neurodegenerative diseases, has three structural and biophysical properties that distinguish it from the other isoforms—domain interaction, reduced stability, and lack of cysteine. Assessing their relative contributions to effects of apoE4‐associated pathogenesis in AD is important from a mechanistic and therapeutic perspective, that is not possible using human apoE transgene or knock‐in models.MethodsWe analyzed Arg‐61 apoE mice, a gene‐targeted model that selectively displays domain interaction.ResultsThe mice displayed age‐dependent loss of the synaptic protein synaptophysin in neocortex and hippocampus and had lower levels of the postsynaptic neuroligin‐1. Activation of dentate gyrus granule neurons increased Arc expression 3.5‐fold in wildtype mice but only 2.3‐fold in Arg‐61 mice. The losses of synaptic proteins caused a mild memory deficit in Arg‐61 mice in the water‐maze test. Since synaptic integrity requires efficient glutamate uptake, we measured astrocyte glutamate transporter 1 in the hippocampus. The level was reduced in Arg‐61 mice, suggesting that inefficient glutamate uptake by astrocytes causes chronic excitotoxicity. Consistent with the reduced secretion of Arg‐61 apoE by astrocytes in this model, cholesterol secretion was also reduced 34%. This reduction could also contribute to the synaptic deficits by limiting the availability of cholesterol for neuronal repair.ConclusionsDomain interaction in the absence of other structural characteristics of apoE4 is sufficient to cause synaptic pathology and functional synaptic deficits, potentially associated with astrocyte dysfunction and impaired maintenance of neurons. Therapeutic targeting of domain interaction might blunt effects of apoE4 in neurodegenerative disease.

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“…Binding (19) ) showing amino acid residues that distinguish between the isoforms. Arg112 facilitates bridge formation (Arg61-Glu255) leading to domain interaction in the apoE4 isoform.…”

Section: Arg158mentioning

confidence: 99%

ApoE genotype: from geographic distribution to function and responsiveness to dietary factors

2012

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ApoE is a key protein in lipid metabolism with three major isoforms. ApoE allele frequencies show non-random global distribution especially in Europe with high apoE e3 frequency in the Mediterranean area, whereas the apoE e4 genotype is enriched in Northern Europe. The apoE e4 genotype is one of the most important genetic risk factors for age-dependent chronic diseases, including CVD and Alzheimer's disease (AD). The apoE polymorphism has been shown to impact on blood lipids, biomarkers of oxidative stress and chronic inflammation, which all may contribute to the isoform-dependent disease risk. Studies in mice and human subjects indicate that the apoE e3 but not the apoE e4 genotype may significantly benefit from dietary flavonoids (e.g. quercetin) and n-3 fatty acids. Metabolism of lipid soluble vitamins E and D is likewise differentially affected by the apoE genotype. Epidemiological and experimental evidence suggest a better vitamin D status in apoE e4 than e3 subjects indicating a certain advantage of e4 over e3. The present review aims at evaluation of current data available on interactions between apoE polymorphism and dietary responsiveness to flavonoids, fat soluble vitamins and n-3 fatty acids. Likewise, distinct geographic distribution and chronic disease risk of the different apoE isoforms are addressed.

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Apolipoprotein (apo) E4 enhances amyloid β peptide production in cultured neuronal cells: ApoE structure as a potential therapeutic target

Cited by 242 publications

References 82 publications

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

Apolipoprotein E4 domain interaction: Synaptic and cognitive deficits in mice

ApoE genotype: from geographic distribution to function and responsiveness to dietary factors

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