Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype

Gibson, Gary E.; Haroutunian, Vahram; Zhang, H.; Park, L. C. H.; Shi, Qingli; Lesser, Martin; Mohs, Richard C.; Sheu, Rex K.-F.; Blass, John P.

doi:10.1002/1531-8249(200009)48:3<297::aid-ana3>3.0.co;2-z

Cited by 162 publications

(72 citation statements)

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“…However, mitochondrial dysfunction in AD appears to vary by APOE genotype, with greater dysfunction in APOE e4 carriers. 10 There is significant evidence that degradation fragments of the apoE4 protein have a greater neurotoxic effect on mitochondrial function over time compared to apoE3 or apoE2 fragments. [28][29][30][31] These fragments, found in cultured neuronal cells and AD brain, induce neurofibrillary tangle-like structures and cause neurotoxicity in vitro.…”

Section: Discussionmentioning

confidence: 99%

“…Declines in key brain mitochondrial TCA enzymatic activities in AD patients have been well documented and associated with APOE e4 status. 9,10 Insulin is critically important in peripheral and central energy metabolism and serves to regulate blood glucose levels. Insulin is transported across the blood/brain barrier and peripheral levels of insulin tend to correlate with levels in the CNS.…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease

et al. 2006

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Mild-to-moderate AD patients were randomized to placebo or rosiglitazone (RSG) 2, 4 or 8 mg. Primary end points at Week 24 were mean change from baseline in AD Assessment Scale-Cognitive (ADAS-Cog) and Clinician's Interview-Based Impression of Change Plus Caregiver Input global scores in the intention-to-treat population (N ¼ 511), and results were also stratified by apolipoprotein E (APOE) genotype (n ¼ 323). No statistically significant differences on primary end points were detected between placebo and any RSG dose. There was a significant interaction between APOE e4 allele status and ADAS-Cog (P ¼ 0.014). Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE e4-negative patients on 8 mg RSG (P ¼ 0.024; not corrected for multiplicity). APOE e4-positive patients did not show improvement and showed a decline at the lowest RSG dose (P ¼ 0.012; not corrected for multiplicity). Exploratory analyses suggested that APOE e4 non-carriers exhibited cognitive and functional improvement in response to RSG, whereas APOE e4 allele carriers showed no improvement and some decline was noted. These preliminary findings require confirmation in appropriate clinical studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease

et al. 2006

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“…Mitochondrial dysfunction was described in patients with AD, especially in those with the apoE4 genotype (143). Previously, we showed that apoE avidly binds to the ␣-and ␤-subunits of mitochondrial F1-ATPase (144), suggesting a possible role for apoE in intracellular transport within or between cell organelles.…”

Section: Apoe4 Neuropathology Independent Of A␤ Apoe Cleavage In Neurmentioning

confidence: 96%

“…4). It contains both the positively charged receptor binding region (amino acids [136][137][138][139][140][141][142][143][144][145][146][147][148][149][150] and the hydrophobic lipid binding region (amino acids 240-270). Mutagenesis of four conserved residues in the lipid binding region or three conserved positively charged residues in the receptor binding region abolished the neurotoxicity of apoE4 .…”

Section: Apoe4 Neuropathology Independent Of A␤ Apoe Cleavage In Neurmentioning

confidence: 99%

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.

827

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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“…The reduction in KGDHC activities in brains from AD patients bearing one apolipoprotein E4 allele is highly correlated to a clinical dementia rating (12). Reduced KGDHC activity is also found in fibroblasts from some AD patients (13).…”

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confidence: 92%

Reduction in the E2k Subunit of the α-Ketoglutarate Dehydrogenase Complex Has Effects Independent of Complex Activity

Shi

Chen

et al. 2005

Journal of Biological Chemistry

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The activity of the ␣-ketoglutarate dehydrogenase complex (KGDHC) declines in brains of patients with several neurodegenerative diseases. KGDHC consists of multiple copies of E1k, E2k, and E3. E1k and E2k are unique to KGDHC and may have functions independent of the complex. The present study tested the consequences of different levels of diminished E2k mRNA on protein levels of the subunits, KGDHC activity, and physiological responses. Human embryonic kidney cells were stably transfected with an E2k sense or antisense expression vector. Sense control (E2k-mRNA-100) was compared with two clones in which the mRNA was reduced to 67% of control (E2k-mRNA-67) or to 30% of control (E2k-mRNA-30). The levels of the E2k protein in clones paralleled the reduction in mRNA, and E3 proteins were unaltered. Unexpectedly, the clone with the greatest reduction in E2k protein (E2k-mRNA-30) had a 40% increase in E1k protein. The activity of the complex was only 52% of normal in E2k-mRNA-67 clone, but was near normal (90%) in E2k-mRNA-30 clone. Subsequent experiments tested whether the physiological consequences of a reduction in E2k mRNA correlated more closely to E2k protein or to KGDHC activity. Growth rate, increased DCF-detectable reactive oxygen species, and cell death in response to added oxidant were proportional to E2k proteins, but not complex activity. These results were not predicted because subunits unique to KGDHC have never been manipulated in mammalian cells. These results suggest that in addition to its essential role in metabolism, the E2k component of KGDHC may have other novel roles.

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Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype

Cited by 162 publications

References 50 publications

Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease

Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease

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

Reduction in the E2k Subunit of the α-Ketoglutarate Dehydrogenase Complex Has Effects Independent of Complex Activity

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