Naslund, J. et al. Characterization of stable complexes involving apolipoprotein E and the amyloid peptide in Alzheimer's disease brain. Neuron 15, 219-228

Ludwig Institute for Cancer Research Biomedical Center S-751 24 Uppsala, Sweden
Neuron (Impact Factor: 15.05). 08/1995; 15(1):219-228. DOI: 10.1016/0896-6273(95)90079-9


Genetic evidence suggests a role for apolipoprotein E (apoE) in Alzheimer's disease (AD) amyloidogenesis. Here, amyloid-associated apoE from 32 AD patients was purified and characterized. We found that brain amyloid-associated apoE apparently exists not as free molecules but as complexes with polymers of the amyloid β peptide (Aβ). Brain Aβ-apoE complexes were detected irrespective of the apoE genotype, and similar complexes could be mimicked in vitro. The fine structure of purified Aβ-apoE complexes was fibrillar, and immunogold labeling revealed apoE immunoreactivity along the fibrils. Thus, we conclude that Aβ-apoE complexes are principal components of AD-associated brain amyloid and that the data presented here support a role for apoE in the pathogenesis of AD.

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    • "Individuals with one 4 allele have an increased risk for earlier development of AD by 2–3 fold; while, in people with two 4 alleles, the risk is about 12 fold higher [45] [18] [5]. Although several reasons may contribute to the ApoE isoform-specific effect on the risk of AD development, evidences suggest that interaction of ApoE4 with amyloid (A) plays an important role in AD pathogenesis [42] [35] [48]. In addition, there are some reports that demonstrated a positive relationship between density of the neurofibrillary tangles and hApoE 4 allele dosage [16] [21] [33]. "
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    ABSTRACT: The ε4 isoform of Apolipoprotein E (ApoE4) that is involved in neuron-glial lipid metabolism has been demonstrated as the main genetic risk factor in late-onset of Alzheimer's disease. However, the mechanism underlying ApoE4-mediated neurodegeneration remains unclear. We created a transgenic model of neurodegenerative disorder by expressing ε3 and ε4 isoforms of human ApoE in the Drosophila melanogaster. The genetic models exhibited progressive neurodegeneration, shortened lifespan and memory impairment. Genetic interaction studies between amyloid precursor protein and ApoE in axon pathology of the disease revealed that over expression of hApoE in Appl-expressing neurons of Drosophila brain causes neurodegeneration. Moreover, acute oxidative damage in the hApoE transgenic flies triggered a neuroprotective response of hApoE3 while chronic induction of oxidative damage accelerated the rate of neurodegeneration. This Drosophila model may facilitate analysis of the molecular and cellular events implicated in hApoE4 neurotoxicity.
    Full-text · Article · Dec 2015 · Behavioural Brain Research
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    • "Previous studies have revealed that apoE interacts with Aβ in vitro (Strittmatter et al., 1993b; LaDu et al., 1994) and in vivo, both in the cerebrospinal fluid (Strittmatter et al., 1993a) and in the brain (Näslund et al., 1995). However, because of the difficulty in monitoring Aβ oligomers specifically and quantitatively, whether apoE increases the levels of native Aβ oligomers remains unknown. "
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    ABSTRACT: Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid β peptide (Aβ) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component. The apolipoprotein E ε 4 (apoE ε4) allele is known to be a genetic risk factor for developing AD. However, it is still unknown how apoE impacts the process of Aβ oligomerization. Here, we found that the level of Aβ oligomers in APOE ε4/ε4 AD patient brains is 2.7 times higher than those in APOE ε3/ε3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of Aβ oligomers. To test this hypothesis, we examined the effect of apoE on Aβ oligomer formation. Using both synthetic Aβ and a split-luciferase method for monitoring Aβ oligomers, we observed that apoE increased the level of Aβ oligomers in an isoform-dependent manner (E2 < E3 < E4). This effect appears to be dependent on the ApoE C-terminal domain. Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of Aβ oligomers. Together, these data show that lipidated apoE, especially apoE4, increases Aβ oligomers in the brain. Higher levels of Aβ oligomers in the brains of APOE ε4/ε4 carriers compared with APOE ε3/ε3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD.
    Full-text · Article · Oct 2012 · The Journal of Neuroscience : The Official Journal of the Society for Neuroscience
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    • "The possibility that interaction with apoE modulated an Aβ clearance mechanism appeared to be supported by the finding that introduction of anti-Aβ antibodies or other Aβ-binding proteins such as gelsolin, led to a reduced amyloid load in the brain and rapidly improved cognition, with little evidence of Aβ-binding agents invading the brain parenchyma [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54]. We also introduced apoE itself into the circulation via parabiosis and found that it induced amyloid clearance without entering the brain in AD model mice [38]. "
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    ABSTRACT: The amyloid cascade hypothesis remains a robust model of AD neurodegeneration. However, amyloid deposits contain proteins besides A β , such as apolipoprotein E (apoE). Inheritance of the apoE4 allele is the strongest genetic risk factor for late-onset AD. However, there is no consensus on how different apoE isotypes contribute to AD pathogenesis. It has been hypothesized that apoE and apoE4 in particular is an amyloid catalyst or “pathological chaperone”. Alternatively it has been posited that apoE regulates A β clearance, with apoE4 been worse at this function compared to apoE3. These views seem fundamentally opposed. The former would indicate that removing apoE will reduce AD pathology, while the latter suggests increasing brain ApoE levels may be beneficial. Here we consider the scientific basis of these different models of apoE function and suggest that these seemingly opposing views can be reconciled. The optimal therapeutic target may be to inhibit the interaction of apoE with A β rather than altering apoE levels. Such an approach will not have detrimental effects on the many beneficial roles apoE plays in neurobiology. Furthermore, other A β binding proteins, including ACT and apo J can inhibit or promote A β oligomerization/polymerization depending on conditions and might be manipulated to effect AD treatment.
    Full-text · Article · Jul 2012 · International Journal of Alzheimer's Disease
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