Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity

Chang, Shengjun; Ma, Tian ran; Miranda, R. Dennis; Balestra, Maureen E.; Mahley, Robert W.; Huang, Yadong

doi:10.1073/pnas.0508254102

Cited by 321Alzheimer's disease research and treatmentsMitochondrial Function and PathologyDementia and Cognitive Impairment Research

Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity

Open access

Chang, Shengjun, Ma, Tian ran, Miranda, R. Dennis, Balestra, Maureen E., Mahley, Robert W., Huang, Yadong·2005·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0508254102PMC PMC1311737

Open this paper in CoChat — free account

Abstract

Apolipoprotein (apo) E4, a 299-aa protein and a major risk factor for Alzheimer's disease, can be cleaved to generate C-terminal-truncated fragments that cause neurotoxicity in vitro and neurodegeneration and behavioral deficits in transgenic mice. To investigate this neurotoxicity, we expressed apoE4 with C- or N-terminal truncations or mutations in transfected Neuro-2a cells. ApoE4 (1-272) was neurotoxic, but full-length apoE4(1-299) and apoE4(1-240) were not, suggesting that the lipid-binding region (amino acids 241-272) mediates the neurotoxicity and that amino acids 273-299 are protective. A quadruple mutation in the lipid-binding region (I250A, F257A, W264R, and V269A) abolished the neurotoxicity of apoE4(1-272), and single mutations in the region of amino acids 273-299 (L279Q, K282A, or Q284A) made full-length apoE4 neurotoxic. Immunofluorescence staining showed that apoE4(1-272) formed filamentous inclusions containing phosphorylated tau in some cells and interacted with mitochondria in others, leading to mitochondrial dysfunction as determined by MitoTracker staining and flow cytometry. ApoE4(241-272) did not cause mitochondrial dysfunction or neurotoxicity, suggesting that the lipid-binding region alone is insufficient for neurotoxicity. Truncation of N-terminal sequences (amino acids 1-170) containing the receptor-binding region (amino acids 135-150) and triple mutations within that region (R142A, K146A, and R147A) abolished the mitochondrial interaction and neurotoxicity of apoE4(1-272). Further analysis showed that the receptor-binding region is required for escape from the secretory pathway and that the lipid-binding region mediates mitochondrial interaction. Thus, the lipid- and receptor-binding regions in apoE4 fragments act together to cause mitochondrial dysfunction and neurotoxicity, which may be important in Alzheimer's disease pathogenesis.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1073/pnas.0508254102

Cites

72 of 72 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

APOE4 increases the sensitivity of cells to oxidative stress.
“APOE4 increases the sensitivity of cells to oxidative stress”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [13]
The Abstract lists impairment of the antioxidative defense system among proposed apoE4-related mechanisms, which is consistent with greater vulnerability to oxidative stress. But the paper does not report a test showing that APOE4 increases cells’ sensitivity to oxidative stress; its cell experiments assess neurotoxicity and mitochondrial function, not responses to an oxidative challenge. (LLM, conf=0.78)
Experimental — accuracy not yet measured
APOE4 expression generates a toxic C-terminal fragment of apoE4 that can directly target electron transport chain (ETC) complexes in mitochondria.
“the generation of a toxic C-terminal fragment of apoE4 that can directly target electron transport chain (ETC) complexes in the mitochondria25–27”
From APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice (2020) · cites this paper as [25]
The Results report that apoE4(1-272) fragments localize to mitochondria in Neuro-2a cells and impair mitochondrial function, as measured by MitoTracker fluorescence (Figs. 2 and 5). They do not show direct targeting of electron transport chain complexes. The paper describes the toxic fragment as C-terminal-truncated apoE4, not an isolated C-terminal fragment. (LLM, conf=0.88)
Experimental — accuracy not yet measured
ApoE4 is associated with aggravated Alzheimer's disease neuropathology, enhanced neuroinflammation, deregulated lipid metabolism, mitochondrial dysfunction, and impaired synaptic plasticity.
“On the molecular level, ApoE4 has been associated with aggravated AD neuropathology, enhanced neuroinflammation, deregulated lipid metabolism, mitochondrial dysfunction, and impaired synaptic plasticity (Nagy et al., 1995;Chang et al., 2005;Rapp et al., 2006;Klein et al., 2010;Rodriguez et al., 2014).”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Chang et al., 2005
The Abstract links ApoE4 to AD risk and describes plaque formation and synaptic deficits among proposed mechanisms; the Results and Discussion report that ApoE4 fragments impair mitochondrial function. The paper does not establish enhanced neuroinflammation, deregulated lipid metabolism, or impaired synaptic plasticity specifically. The indexed passages do not provide page numbers. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Expression of apoE4 fragments containing the lipid-binding domain in N2a cells results in neurotoxicity.
“expression of fragments containing this domain in N2a cells results in neurotoxicity [17]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
The Results report that expressing apoE4(1–272), which contains the lipid-binding region, caused greater cell death in Neuro-2a cells. But the Results also state that the lipid-binding region alone caused no neurotoxicity: the receptor-binding region was required too. The claim omits that qualification. (LLM, conf=0.88)
Experimental — accuracy not yet measured
The largest apoE4 fragment, apoE4(1-272), causes mitochondrial fragmentation.
“and cause mitochondrial fragmentation [10, 17, 20]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
The Results report that apoE4(1-272) interacted with mitochondria in Neuro-2a cells and reduced MitoTracker fluorescence, which the authors interpret as impaired mitochondrial function and integrity. They do not report mitochondrial fragmentation; the filamentous inclusions described in the Results concern the apoE4 fragment, not mitochondrial shape. (LLM, conf=0.85)
Experimental — accuracy not yet measured

The largest apoE4 fragment, apoE4(1-272), interacts directly with mitochondria to reduce mitochondrial membrane potential.
“The largest apoE4 fragment, apoE4(1–272), interacts directly with mitochondria to reduce mitochondrial membrane potential”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
The Results report that apoE4(1–272) was found in mitochondria and that cells expressing it had 25% lower MitoTracker fluorescence than cells expressing full-length apoE4. The paper explains that MitoTracker uptake depends on normal membrane potential, but describes the result as suggesting impaired mitochondrial function and integrity; it does not directly establish a reduction in membrane potential. (LLM, conf=0.84)
Experimental — accuracy not yet measured
In neurons, apoE4 is associated with impaired mitochondrial respiration.
“In neurons, apoE4 is associated with impaired mitochondrial respiration”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
The Results report impaired mitochondrial function in Neuro-2a cells expressing truncated apoE4 fragments, measured by MitoTracker fluorescence. They do not report a direct measure of mitochondrial respiration, and the effect was observed with fragments rather than full-length apoE4. (LLM, conf=0.87)
Experimental — accuracy not yet measured
The cleaved C-terminus of APOE can exist in the cytoplasm and associate with mitochondria in neurons.
“Studies on the trafficking of APOE have also suggested that the cleaved C-terminus of APOE can exist in the cytoplasm and associate with mitochondria in neurons (Chang et al., 2005).”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Chang et al., 2005
The Results report that apoE4(1–272) fragments escaped the secretory pathway and were observed at mitochondria in Neuro-2a cells; the Discussion describes their entry into the cytosol. The paper studies C-terminally truncated apoE4, however, not an isolated cleaved C-terminus. That distinction limits support for the claim as worded. (LLM, conf=0.82)
Experimental — accuracy not yet measured
ApoE4 fragments are found in higher levels in Alzheimer's disease patients carrying APOE ε4 than in age- and sex-matched controls.
“and in higher levels than in age- and sex-matched controls [29].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [29]
The Abstract reports higher levels of apoE fragments in the brains of AD patients than in age- and sex-matched controls. It also says apoE4 is more susceptible to cleavage than apoE3, but does not specify that the patients in that comparison carried APOE ε4 or that the measured fragments were exclusively apoE4. (LLM, conf=0.84)
Experimental — accuracy not yet measured
ApoE4 largest fragment (1-272 aa) directly interacts with mitochondria, leading to decrease in Δψm and mitochondrial fragmentation.
“ApoE4 largest fragment (1–272 aa) was shown to directly interact with mitochondria, which leads to a decrease in Δψm and mitochondrial fragmentation [26,29,73].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [29]
The Results report that apoE4(1–272) localized to mitochondria in transfected Neuro-2a cells and reduced MitoTracker fluorescence, which the authors interpret as evidence of impaired mitochondrial function and integrity associated with membrane potential. They do not report a direct measurement of Δψm or show mitochondrial fragmentation; the reported filamentous inclusions are not described as fragmented mitochondria. (LLM, conf=0.88)
Experimental — accuracy not yet measured
A particular fragment of apoE (1-272 amino acids) can translocate to cytosol and interact with cytoskeletal proteins.
“Limited data suggest that a particular fragment of apoE (1–272 amino acids) can translocate to cytosol and interacts with cytoskeletal proteins (Chang et al., 2005).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Chang et al., 2005
Not all apoE4 forms found in the brains of AD patients are equally bioactive, and specific apoE4 forms may be involved in processes associated with AD pathogenesis.
“These and other findings suggest that not all apoE4 forms found in the brains of AD patients are equally bioactive and that specific apoE4 forms may be involved in processes associated with AD pathogenesis (10, 14 -17).”
From Molecular Basis for Increased Risk for Late-onset Alzheimer Disease Due to the Naturally Occurring L28P Mutation in Apolipoprotein E4 (2014) · cites this paper as [16]
Fragments of APOE, which are more abundant with APOE4 than with APOE3, can cause neuronal mitochondrial dysfunction in vitro.
“In vitro studies have shown that fragments of APOE, which are more abundant with APOE4 than with APOE3, can cause neuronal mitochondrial dysfunction165,166.”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [165]
The apoE4 (1-272) fragment interacts directly with mitochondria, resulting in mitochondrial dysfunction and neurotoxicity.
“apoE4 (1-272) fragment appears to interact directly with mitochondria, resulting in mitochondrial dysfunction and neurotoxicity [13]”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [13]
ApoE4 (1-272) fragments can directly interact with mitochondria, causing mitochondrial dysfunction and neurotoxicity.
“Available literature also shows that apoE4 (1-272) fragments can directly interact with mitochondria, causing mitochondrial dysfunction and neurotoxicity [13].”
From APOE4 genotype exacerbates the depression-like behavior of mice during aging through ATP decline (2021) · cites this paper as [13]
ApoE fragments escape the secretory pathway into the cytosol.
“The resulting apoE fragments escape the secretory pathway into the cytosol”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
In neurons, apoE4 is associated with neurotoxicity.
“and neurotoxicity [10, 17–19, 34, 35]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
ApoE fragments interact directly with mitochondria and disrupt their function.
“Although apoE fragments interact directly with mitochondria and disrupt their function [17, 20]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
The interaction of apoE4 fragments with mitochondria is dependent on the apoE lipid-binding domain.
“The interaction of apoE4 fragments with mitochondria is dependent on the apoE lipid-binding domain”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
ApoE fragments engage in abnormal interactions in the cytosol that lead to neurodegeneration.
“where they engage in abnormal interactions that lead to neurodegeneration [17–19]”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
ApoE4 N-terminal fragments (1-272 aa) interact with mitochondria and may impact mitochondrial function and cell viability.
“some studies in N2a cells demonstrated that ApoE4 N-terminal fragments (1–272 aa) interact with mitochondria and may possibly impact on mitochondrial function and cell viability [29]”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [29]
Both the receptor-binding and lipid-binding regions are critical for ApoE4 fragment-related neurotoxicity and mitochondrial impairment, rather than full-length protein.
“Both regions are thought to be critical for ApoE4 fragment-related neurotoxicity and mitochondrial impairment, rather than full-length protein [29,31].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [29]
In vitro studies in N2a cells showed that ApoE4 fragments (aa 1-272) interact with mitochondria and cause mitochondrial dysfunction and neurotoxicity.
“In vitro studies in N2a cells showed that ApoE4 fragments (aa 1–272) interact with mitochondria and cause mitochondrial dysfunction and neurotoxicity [29].”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [29]
More recent data suggests the possibility that a fragment of apoE4 (1-272 amino acids), but not full-length apoE4, escapes the secretory pathway, translocates to the cytosolic compartment, and interacts with cytoskeletal components, including tau and neurofilament.
“Of note, more recent data suggests the possibility that a fragment of apoE4 (1–272 amino acids), but not full-length apoE4, escapes the secretory pathway, translocates to the cytosolic compartment, and interacts with cytoskeletal components, including tau and neurofilament (Chang et al., 2005).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Chang et al., 2005
In neurons, apoE4 is associated with decreased neurite outgrowth.
“decreased neurite outgrowth”
From Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function (2019) · cites this paper as [17]
The Results report greater cell death from an apoE4 fragment in Neuro-2a cells, but do not report decreased neurite outgrowth. Searches for “neurite outgrowth” and “neurite extension” found no passage in our copy addressing that outcome. (LLM, conf=0.76)
Experimental — accuracy not yet measured
The APOE gene product appears to influence mitochondrial function.
“The APOE gene product, interestingly, also appears to influence mitochondrial function [164-167].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [164]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Gene Dose of Apolipoprotein E Type 4 Allele and the Risk of Alzheimer's Disease in Late Onset Families
Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L., & Pericak-Vance, M. A. (1993) · Science · doi:10.1126/science.8346443 · Cited by 9,429 · see citing works
Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease.
Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.5.1977 · Cited by 4,268 · see citing works
Apolipoprotein E: Cholesterol Transport Protein with Expanding Role in Cell Biology
Mahley, R. W. (1988) · Science · doi:10.1126/science.3283935 · Cited by 4,028 · see citing works
Self-citation
Cellular uptake of the tat protein from human immunodeficiency virus
Frankel, A. D., & Pabo, C. O. (1988) · Cell · doi:10.1016/0092-8674(88)90263-2 · Cited by 2,782 · see citing works
In Vivo Protein Transduction: Delivery of a Biologically Active Protein into the Mouse
Schwarze, S. R., Ho, A. L., Vocero-Akbani, A. M., & Dowdy, S. F. (1999) · Science · doi:10.1126/science.285.5433.1569 · Cited by 2,418 · see citing works
Apolipoprotein E: Far More Than a Lipid Transport Protein
Mahley, R. W., & Rall, S. C. (2000) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.1.1.507 · Cited by 1,836 · see citing works
Self-citation
Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein
Green, M., & Loewenstein, P. M. (1988) · Cell · doi:10.1016/0092-8674(88)90262-0 · Cited by 1,551 · see citing works
Characterization of the Cellular Reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT): Subcellular Localization, Substrate Dependence, and Involvement of Mitochondrial Electron Transport in MTT Reduction
Berridge, M. V., & Tan, A. S. (1993) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1993.1311 · Cited by 1,443 · see citing works
Mitochondrial abnormalities in Alzheimer's disease
Hirai, K., Aliev, G., Nunomura, A., Fujioka, H., Russell, R. L., Atwood, C. S., Johnson, A. B., Kress, Y., Vinters, H. V., Tabaton, M., et al. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-09-03017.2001 · Cited by 1,367 · see citing works
Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease.
Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D., & Roses, A. D. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.17.8098 · Cited by 1,363 · see citing works
Tat-mediated delivery of heterologous proteins into cells.
Fawell, S. E., Seery, J., Daikh, Y., Moore, C., Chen, L. L., Pepinsky, B., & Barsoum, J. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.2.664 · Cited by 1,225 · see citing works
Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia
Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., Saunders, A. M., & Hardy, J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2635903100 · Cited by 977 · see citing works
Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease
Holtzman, D. M., Bales, K. R., Tenkova, T., Fagan, A. M., Parsadanian, M., Sartorius, L. J., Mackey, B., Olney, J., McKeel, D., Wozniak, D., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.050004797 · Cited by 937 · see citing works
Apolipoprotein E allele–specific antioxidant activity and effects on cytotoxicity by oxidative insults and β–amyloid peptides
Miyata, M., & Smith, J. D. (1996) · Nature Genetics · doi:10.1038/ng0996-55 · Cited by 889 · see citing works
Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments
Ma, J., Yee, A., Brewer, H. B., Das, S., & Potter, H. (1994) · Nature · doi:10.1038/372092a0 · Cited by 871 · see citing works
Endocytic Pathway Abnormalities Precede Amyloid β Deposition in Sporadic Alzheimer’s Disease and Down Syndrome
Cataldo, A. M., Peterhoff, C. M., Troncoso, J. C., Gómez‐Isla, T., Hyman, B. T., & Nixon, R. A. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64538-5 · Cited by 832 · see citing works
Apolipoprotein E: Structure-Function Relationships
Weisgraber, K. H. (1994) · Advances in Protein Chemistry · doi:10.1016/s0065-3233(08)60642-7 · Cited by 830 · see citing works
Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer’s disease
Small, G. W., Ercoli, L. M., Silverman, D. H. S., Huang, S.-C., Komo, S., Bookheimer, S. Y., Lavretsky, H., Miller, K., Siddarth, P., Rasgon, N. L., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.090106797 · Cited by 790 · see citing works
Apolipoprotein E Type 4 Allele and Cerebral Glucose Metabolism in Relatives at Risk for Familial Alzheimer Disease
Small, G. W. (1995) · JAMA: The Journal of the American Medical Association · doi:10.1001/jama.1995.03520360056039 · Cited by 604 · see citing works
Isoform-specific binding of apolipoprotein E to beta-amyloid.
LaDu, M. J., Falduto, M. T., Manelli, A. M., Reardon, C. A., Getz, G. S., & Frail, D. E. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31529-6 · Cited by 540 · see citing works
Apolipoprotein E is essential for amyloid deposition in the APP V717F transgenic mouse model of Alzheimer's disease
Bales, K. R., Verina, T., Cummins, D. J., Du, Y., Dodel, R. C., Saura, J., Fishman, C. E., DeLong, C. A., Piccardo, P., Petegnief, V., et al. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.26.15233 · Cited by 486 · see citing works
Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease.
Strittmatter, W. J., Saunders, A. M., Goedert, M., Weisgraber, K. H., Dong, L. M., Jakes, R., Huang, D. Y., Pericak-Vance, M., Schmechel, D., & Roses, A. D. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.23.11183 · Cited by 474 · see citing works
Declining brain activity in cognitively normal apolipoprotein E ɛ4 heterozygotes: A foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease
Reiman, E. M., Caselli, R. J., Chen, K., Alexander, G. E., Bandy, D., & Frost, J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.061509598 · Cited by 467 · see citing works
Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro.
(1994) · PubMed Central · Cited by 441 · see citing works
In VivoDelivery of a Bcl-xL Fusion Protein Containing the TAT Protein Transduction Domain Protects against Ischemic Brain Injury and Neuronal Apoptosis
Cao, G., Pei, W., Ge, H., Liang, Q., Luo, Y., Sharp, F. R., Lu, A., Ran, R., Graham, S. H., & Chen, J. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-13-05423.2002 · Cited by 420 · see citing works
Neuron-Specific Apolipoprotein E4 Proteolysis Is Associated with Increased Tau Phosphorylation in Brains of Transgenic Mice
Brecht, W. J., Harris, F. M., Chang, S., Tesseur, I., Yu, G.-Q., Xu, Q., Dee Fish, J., Wyss-Coray, T., Buttini, M., Mucke, L., et al. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.4315-03.2004 · Cited by 403 · see citing works
Self-citation
Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer’s disease: Neuropathologic evidence for a mechanism of increased β-amyloidogenesis
Cataldo, A. M., Barnett, J. L., Pieroni, C., & Nixon, R. A. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-16-06142.1997 · Cited by 393 · see citing works
Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons
Huang, Y., Liu, X. Q., Wyss-Coray, T., Brecht, W. J., Sanan, D. A., & Mahley, R. W. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151254698 · Cited by 392 · see citing works
Self-citation
Apolipoprotein E
Mahley, R. W., & Huang, Y. (1999) · Current Opinion in Lipidology · doi:10.1097/00041433-199906000-00003 · Cited by 388 · see citing works
Self-citation
Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: Increased susceptibility of females
Raber, J., Wong, D., Buttini, M., Orth, M., Bellosta, S., Pitas, R. E., Mahley, R. W., & Mucke, L. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.18.10914 · Cited by 364 · see citing works
Self-citation
Expression of Human Apolipoprotein E3 or E4 in the Brains ofApoe−/−Mice: Isoform-Specific Effects on Neurodegeneration
Buttini, M., Orth, M., Bellosta, S., Akeefe, H., Pitas, R. E., Wyss‐Coray, T., Mucke, L., & Mahley, R. W. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-12-04867.1999 · Cited by 361 · see citing works
Self-citation
Monoclonal antibodies to the low density lipoprotein receptor as probes for study of receptor-mediated endocytosis and the genetics of familial hypercholesterolemia
Beisiegel, U., Schneider, W. J., Goldstein, J. L., Anderson, R. G., & Brown, M. S. (1981) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)68494-2 · Cited by 357 · see citing works
Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice
Harris, F. M., Brecht, W. J., Xu, Q., Tesseur, I., Kekonius, L., Wyss-Coray, T., Fish, J. D., Masliah, E., Hopkins, P. C., Scearce-Levie, K., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1434398100 · Cited by 342 · see citing works
Self-citation
Apolipoprotein E Affects the Rate of Alzheimer Disease Expression: β-Amyloid Burden Is a Secondary Consequence Dependent on APOE Genotype and Duration of Disease
Roses, A. D. (1994) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199409000-00002 · Cited by 329 · see citing works
Abnormal Mitochondrial Morphology in Sporadic Parkinson's and Alzheimer's Disease Cybrid Cell Lines
Trimmer, P. A., Swerdlow, R. H., Parks, J. K., Keeney, P. M., Bennett, J. P., Miller, S. W., Davis, R. E., & Parker, W. D. (2000) · Experimental Neurology · doi:10.1006/exnr.2000.7333 · Cited by 296 · see citing works
Neuropathological changes in scrapie and Alzheimer's disease are associated with increased expression of apolipoprotein E and cathepsin D in astrocytes
Diedrich, J. F., Minnigan, H. J., Carp, R. I., Whitaker, J. N., Race, R., Frey, W. H., & Haase, A. T. (1991) · Journal of Virology · doi:10.1128/jvi.65.9.4759-4768.1991 · Cited by 295 · see citing works
Apolipoprotein E: Diversity of Cellular Origins, Structural and Biophysical Properties, and Effects in Alzheimer's Disease
Huang, Y., Weisgraber, K. H., Mucke, L., & Mahley, R. W. (2004) · Journal of Molecular Neuroscience · doi:10.1385/jmn:23:3:189 · Cited by 242 · see citing works
Self-citation
Expression of Human Apolipoprotein E4 in Neurons Causes Hyperphosphorylation of Protein Tau in the Brains of Transgenic Mice
Tesseur, I. C., Dorpe, J. V., Spittaels, K., den Haute, C. V., Moechars, D., & LEUVEN, F. V. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64963-2 · Cited by 241 · see citing works
Rab5-stimulated Up-regulation of the Endocytic Pathway Increases Intracellular β-Cleaved Amyloid Precursor Protein Carboxyl-terminal Fragment Levels and Aβ Production
Grbovic, O. M., Mathews, P. M., Jiang, Y., Schmidt, S. D., Dinakar, R., Terio, N. B., Ceresa, B. P., Nixon, R. A., & Cataldo, A. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304122200 · Cited by 236 · see citing works
Apolipoprotein E receptors: linking brain development and alzheimer's disease
Herz, J., & Beffert, U. (2000) · Nature reviews. Neuroscience · doi:10.1038/35036221 · Cited by 218 · see citing works
Apolipoprotein E is localized to the cytoplasm of human cortical neurons: a light and electron microscopic study
Han, S.-H., Einstein, G., Weisgraber, K. H., Strittmatter, W. J., Saunders, A. M., Pericak-Vance, M., Roses, A. D., & Schmechel, D. E. (1994) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199409000-00013 · Cited by 195 · see citing works
Androgens Protect against Apolipoprotein E4-Induced Cognitive Deficits
Raber, J., Bongers, G., LeFevour, A., Buttini, M., & Mucke, L. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-12-05204.2002 · Cited by 187 · see citing works
Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype
Gibson, G. E., Haroutunian, V. H., Zhang, H., Park, L. C. H., Shi, Q., LESSER, M. L., Mohs, R. C., Sheu, R., & Blass, J. P. (2000) · Annals of Neurology · doi:10.1002/1531-8249(200009)48:3 · Cited by 184 · see citing works
Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid β peptides but not on plaque formation
Buttini, M., Yu, G.-Q., Shockley, K., Huang, Y., Jones, B., Masliah, E., Mallory, M., Yeo, T., Longo, F. M., & Mucke, L. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-24-10539.2002 · Cited by 183 · see citing works
Self-citation
Human Apolipoprotein E2, E3, and E4 Isoform-Specific Transgenic Mice: Human-like Pattern of GlialandNeuronal Immunoreactivity in Central Nervous System Not Observed in Wild-Type Mice
Xu, P.-T., Schmechel, D., Rothrock-Christian, T., Burkhart, D. S., Qiu, H.-L., Popko, B., Sullivan, P., Maeda, N., Saunders, A. M., Roses, A. D., et al. (1996) · Neurobiology of Disease · doi:10.1006/nbdi.1996.0023 · Cited by 178 · see citing works
Specific Regional Transcription of Apolipoprotein E in Human Brain Neurons
Xu, P., Gilbert, J. R., Qiu, H.-L., Ervin, J. F., Rothrock‐Christian, T., Hulette, C., & Schmechel, D. E. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65305-9 · Cited by 177 · see citing works
Apolipoprotein E4 Potentiates Amyloid β Peptide-induced Lysosomal Leakage and Apoptosis in Neuronal Cells
Ji, Z.-S., Miranda, R. D., Newhouse, Y. M., Weisgraber, K. H., Huang, Y., & Mahley, R. W. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m112109200 · Cited by 177 · see citing works
Self-citation
Deficiency in Mitochondrial Aldehyde Dehydrogenase Increases the Risk for Late-Onset Alzheimer's Disease in the Japanese Population
Kamino, K., Nagasaka, K., Imagawa, M., Yamamoto, H., Yoneda, H., Ueki, A., Kitamura, S., Namekata, K., Miki, T., & Ohta, S. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2923 · Cited by 173 · see citing works
Molecular basis of exchangeable apolipoprotein function
Narayanaswami, V., & Ryan, R. O. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/s1388-1981(99)00176-6 · Cited by 152 · see citing works
Truncated apolipoprotein E (ApoE) causes increased intracellular calcium and may mediate ApoE neurotoxicity
Tolar, M., Keller, J. N., Chan, S., Mattson, M. P., Marques, M. A., & Crutcher, K. A. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-16-07100.1999 · Cited by 148 · see citing works
Astroglial Regulation of Apolipoprotein E Expression in Neuronal Cells
Harris, F. M., Tesseur, I., Brecht, W. J., Xu, Q., Mullendorff, K., Chang, S., Wyss-Coray, T., Mahley, R. W., & Huang, Y. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m309475200 · Cited by 135 · see citing works
Self-citation
Effects of Age, Sex, and Ethnicity on the Association Between Apolipoprotein E Genotype and Alzheimer Disease: A Meta-analysis
Farrer, L. A. (1997) · JAMA · doi:10.1001/jama.1997.03550160069041 · Cited by 124 · see citing works
Neurotoxicity of the 22 kDa Thrombin-Cleavage Fragment of Apolipoprotein E and Related Synthetic Peptides Is Receptor-Mediated
Tolar, M., Marques, M. A., Harmony, J. A. K., & Crutcher, K. A. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-15-05678.1997 · Cited by 115 · see citing works
Increased Expression of Neuronal Apolipoprotein E in Human Brain With Cerebral Infarction
Aoki, K., Uchihara, T., Sanjo, N., Nakamura, A., Ikeda, K., Tsuchiya, K., & Wakayama, Y. (2003) · Stroke · doi:10.1161/01.str.0000064320.73388.c6 · Cited by 108 · see citing works
Mitochondrial ALDH2 Deficiency as an Oxidative Stress
Ohta, S., Ohsawa, I., Kamino, K., Ando, F., & Shimokata, H. (2004) · Springer eBooks · doi:10.1007/978-3-662-41088-2_4 · Cited by 103 · see citing works
Quantitation of apoE Domains in Alzheimer Disease Brain Suggests a Role for apoE in Aß Aggregation
Cho, H. S., Hyman, B. T., Greenberg, S. M., & Rebeck, G. W. (2001) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/60.4.342 · Cited by 102 · see citing works
Neurons of the Human Frontal Cortex Display Apolipoprotein E Immunoreactivity
Metzger, R. E., LaDu, M. J., Pan, J. B., Getz, G. S., Frail, D. E., & Falduto, M. T. (1996) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199603000-00013 · Cited by 94 · see citing works
Apolipoprotein E affects the amount, form, and anatomical distribution of amyloid β-peptide deposition in homozygous APP V717F transgenic mice
Irizarry, M. C., Cheung, B. S., Rebeck, G. W., Paul, S. M., Bales, K. R., & Hyman, B. T. (2000) · Acta Neuropathologica · doi:10.1007/s004010000263 · Cited by 93 · see citing works
Apolipoprotein E, Plaques, Tangles and Cholinergic Dysfunction in Alzheimer's Diseasea
Beffert, U., & Poirier, J. (1996) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1996.tb34415.x · Cited by 93 · see citing works
Use of Cytoplasmic Hybrid Cell Lines for Elucidating the Role of Mitochondrial Dysfunction in Alzheimer's Disease and Parkinson's Disease
Ghosh, S. S., Swerdlow, R. H., Miller, S. W., Sheeman, B., Parker, W. D., & DAVIS, R. E. (1999) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1999.tb07825.x · Cited by 91 · see citing works
Mitochondrial ALDH2 Deficiency as an Oxidative Stress
Ohta, S., Ohsawa, I., Kamino, K., Ando, F., & Shimokata, H. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1293.004 · Cited by 91 · see citing works
Comparison of the effect of mitochondrial inhibitors on mitochondrial membrane potential in two different cell lines using flow cytometry and spectrofluorometry
Kalbáčová, M. H., Vrbacký, M., Drahota, Z., & Mělková, Z. (2003) · Cytometry Part A · doi:10.1002/cyto.a.10031 · Cited by 74 · see citing works
Regionally specific neuronal expression of human APOE gene in transgenic mice
Xu, P., Gilbert, J. R., Qiu, H.-L., Rothrock‐Christian, T., Settles, D. L., Roses, A. D., & Schmechel, D. E. (1998) · Neuroscience Letters · doi:10.1016/s0304-3940(98)00247-x · Cited by 50 · see citing works
Sialylated Human Apolipoprotein E (apoEs) Is Preferentially Associated with Neuron-Enriched Cultures from APOE Transgenic Mice
Xu, P., Schmechel, D. E., Qiu, H.-L., Herbstreith, M. H., Rothrock‐Christian, T., Eyster, M. V., Roses, A. D., & Gilbert, J. R. (1999) · Neurobiology of Disease · doi:10.1006/nbdi.1998.0213 · Cited by 46 · see citing works
ApoE Synthesis in Human Neuroblastoma Cells
Dupont-Wallois, L., Soulié, C., Sergeant, N., Wrieze, N. W.-D., Chartier‐Harlin, M., Delacourte, A., & Caillet‐Boudin, M. (1997) · Neurobiology of Disease · doi:10.1006/nbdi.1997.0155 · Cited by 45 · see citing works
Expression of apolipoprotein E in normal and diverse neurodegenerative disease brain
Bao, F., Arai, H., Matsushita, S., Higuchi, S., & Sasaki, H. (1996) · Neuroreport · doi:10.1097/00001756-199607290-00008 · Cited by 44 · see citing works
Truncated apoE forms tangle-like structures in a neuronal cell line
Ljungberg, M. C., Dayanandan, R., Asuni, A. A., Rupniak, T., Anderton, B. H., & Lovestone, S. (2002) · Neuroreport · doi:10.1097/00001756-200205070-00026 · Cited by 28 · see citing works
Identification of Two Regions in Apolipoprotein B100 that are Exposed on the Cytosolic Side of the Endoplasmic Reticulum Membrane
Du, X., Stoops, J. D., Mertz, J. R., Stanley, C. M., & Dixon, J. L. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.141.3.585 · Cited by 26 · see citing works
Plasma Lipids and Their Role in Disease
(2003) · CRC Press eBooks · doi:10.1201/9781482298253 · Cited by 25 · see citing works
Synthesis and Regulation of Apolipoprotein E during the Differentiation of Human Neuronal Precursor NT2/D1 Cells into Postmitotic Neurons
Ferreira, S., Dupire, M.-J., Delacourte, A., Najïb, J., & Caillet‐Boudin, M. (2000) · Experimental Neurology · doi:10.1006/exnr.2000.7510 · Cited by 25 · see citing works
Efficient Nuclear Delivery of Antisense Oligodeoxynucleotides and Selective Inhibition of CETP Expression by Apo E Peptide in a Human CETP–Stably Transfected CHO Cell Line
Liu, K., Ou, J., Saku, K., Jimi, S., Via, D. P., Sparrow, J. T., Zhang, B., Pownall, H. J., Smith, L. C., & Arakawa, K. (1999) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.19.9.2207 · Cited by 7 · see citing works
Transfer of Antisense Oligodeoxynucleotides Against Endothelin Receptors A and B Into Human Coronary Smooth Muscle Cells and Endothelial Cells by Apolipoprotein E Peptide. An in Vitro Study.
Miura, S.-I., Okamoto, T., Via, D. P., & Saku, K. (2002) · Circulation Journal · doi:10.1253/circj.66.1054 · Cited by 3 · see citing works

Flagged first, then by citations

1 of the 73 references couldn’t be matched to a known paper.

Research works printed but not linked: 70

[1]Mahley, R. W. (1988) Science 240, 622-630. [DOI] [PubMed] [Google Scholar]
[2]Mahley, R. W. & Huang, Y. (1999) Curr. Opin. Lipidol. 10, 207-217. [DOI] [PubMed] [Google Scholar]
[4]Mahley, R. W. & Rall, S. C., Jr., (2000) Annu. Rev. Genomics Hum. Genet. 1, 507-537. [DOI] [PubMed] [Google Scholar]
[5]Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S. & Roses, A. D. (1993) Proc. Natl. Acad. Sci. USA 90, 1977-1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
[6]Roses, A. D. (1994) J. Neuropathol. Exp. Neurol. 53, 429-437. [DOI] [PubMed] [Google Scholar]
[7]Corder, E. H., Saunders, A. M., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Small, G. W., Roses, A. D., Haines, J. L. & Pericak-Vance, M. A. (1993) Science 261, 921-923. [DOI] [PubMed] [Google Scholar]
[8]Farrer, L. A., Cupples, L. A., Haines, J. L., Hyman, B., Kukull, W. A., Mayeux, R., Myers, R. H., Pericak-Vance, M. A., Risch, N. & Van Duijn, C. M. (1997) J. Am. Med. Assoc. 278, 1349-1356. [PubMed] [Google Scholar]
[9]Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L.-M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D. & Roses, A. D. (1993) Proc. Natl. Acad. Sci. USA 90, 8098-8102. [DOI] [PMC free article] [PubMed] [Google Scholar]
[10]Ma, J., Yee, A., Brewer, H. B., Jr., Das, S. & Potter, H. (1994) Nature 372, 92-94. [DOI] [PubMed] [Google Scholar]
[11]Wisniewski, T., Castaño, E. M., Golabek, A., Vogel, T. & Frangione, B. (1994) Am. J. Pathol. 145, 1030-1035. [PMC free article] [PubMed] [Google Scholar]
[12]LaDu, M. J., Falduto, M. T., Manelli, A. M., Reardon, C. A., Getz, G. S. & Frail, D. E. (1994) J. Biol. Chem. 269, 23403-23406. [PubMed] [Google Scholar]
[13]Holtzman, D. M., Bales, K. R., Tenkova, T., Fagan, A. M., Parsadanian, M., Sartorius, L. J., Mackey, B., Olney, J., McKeel, D., Wozniak, D. & Paul, S. M. (2000) Proc. Natl. Acad. Sci. USA 97, 2892-2897. [DOI] [PMC free article] [PubMed] [Google Scholar]
[14]Bales, K. R., Verina, T., Cummins, D. J., Du, Y., Dodel, R. C., Saura, J., Fishman, C. E., DeLong, C. A., Piccardo, P., Petegnief, V., et al. (1999) Proc. Natl. Acad. Sci. USA 96, 15233-15238. [DOI] [PMC free article] [PubMed] [Google Scholar]
[15]Irizarry, M. C., Cheung, B. S., Rebeck, G. W., Paul, S. M., Bales, K. R. & Hyman, B. T. (2000) Acta. Neuropathol. 100, 451-458. [DOI] [PubMed] [Google Scholar]
[16]Buttini, M., Yu, G.-Q., Shockley, K., Huang, Y., Jones, B., Masliah, E., Mallory, M., Yeo, T., Longo, F. M. & Mucke, L. (2002) J. Neurosci. 22, 10539-10548. [DOI] [PMC free article] [PubMed] [Google Scholar]
[17]Buttini, M., Orth, M., Bellosta, S., Akeefe, H., Pitas, R. E., Wyss-Coray, T., Mucke, L. & Mahley, R. W. (1999) J. Neurosci. 19, 4867-4880. [DOI] [PMC free article] [PubMed] [Google Scholar]
[18]Miyata, M. & Smith, J. D. (1996) Nat. Genet. 14, 55-61. [DOI] [PubMed] [Google Scholar]
[19]Gibson, G. E., Haroutunian, V., Zhang, H., Park, L. C. H., Shi, Q., Lesser, M., Mohs, R. C., Sheu, R. K.-F. & Blass, J. P. (2000) Ann. Neurol. 48, 297-303. [PubMed] [Google Scholar]
[20]Ohta, S., Ohsawa, I., Kamino, K., Ando, F. & Shimokata, H. (2004) Ann. N.Y. Acad. Sci. 1011, 36-44. [DOI] [PubMed] [Google Scholar]
[21]Kamino, K., Nagasaka, K., Imagawa, M., Yamamoto, H., Yoneda, H., Ueki, A., Kitamura, S., Namekata, K., Miki, T. & Ohta, S. (2000) Biochem. Biophys. Res. Commun. 273, 192-196. [DOI] [PubMed] [Google Scholar]
[22]Herz, J. & Beffert, U. (2000) Nat. Rev. Neurosci. 1, 51-58. [DOI] [PubMed] [Google Scholar]
[23]Strittmatter, W. J., Saunders, A. M., Goedert, M., Weisgraber, K. H., Dong, L.-M., Jakes, R., Huang, D. Y., Pericak-Vance, M., Schmechel, D. & Roses, A. D. (1994) Proc. Natl. Acad. Sci. USA 91, 11183-11186. [DOI] [PMC free article] [PubMed] [Google Scholar]
[24]Tesseur, I., Van Dorpe, J., Spittaels, K., Van den Haute, C., Moechars, D. & Van Leuven, F. (2000) Am. J. Pathol. 156, 951-964. [DOI] [PMC free article] [PubMed] [Google Scholar]
[25]Huang, Y., Liu, X. Q., Wyss-Coray, T., Brecht, W. J., Sanan, D. A. & Mahley, R. W. (2001) Proc. Natl. Acad. Sci. USA 98, 8838-8843. [DOI] [PMC free article] [PubMed] [Google Scholar]
[26]Ljungberg, M. C., Dayanandan, R., Asuni, A., Rupniak, T. H., Anderton, B. H. & Lovestone, S. (2002) NeuroReport 13, 867-870. [DOI] [PubMed] [Google Scholar]
[27]Harris, F. M., Brecht, W. J., Xu, Q., Tesseur, I., Kekonius, L., Wyss-Coray, T., Fish, J. D., Masliah, E., Hopkins, P. C., Scearce-Levie, K., et al. (2003) Proc. Natl. Acad. Sci. USA 100, 10966-10971. [DOI] [PMC free article] [PubMed] [Google Scholar]
[28]Brecht, W. J., Harris, F. M., Chang, S., Tesseur, I., Yu, G.-Q., Xu, Q., Fish, J. D., Wyss-Coray, T., Buttini, M., Mucke, L., Mahley, R. W. & Huang, Y. (2004) J. Neurosci. 24, 2527-2534. [DOI] [PMC free article] [PubMed] [Google Scholar]
[29]Raber, J., Wong, D., Buttini, M., Orth, M., Bellosta, S., Pitas, R. E., Mahley, R. W. & Mucke, L. (1998) Proc. Natl. Acad. Sci. USA 95, 10914-10919. [DOI] [PMC free article] [PubMed] [Google Scholar]
[30]Raber, J., Bongers, G., LeFevour, A., Buttini, M. & Mucke, L. (2002) J. Neurosci. 22, 5204-5209. [DOI] [PMC free article] [PubMed] [Google Scholar]
[31]Ji, Z.-S., Miranda, R. D., Newhouse, Y. M., Weisgraber, K. H., Huang, Y. & Mahley, R. W. (2002) J. Biol. Chem. 277, 21821-21828. [DOI] [PubMed] [Google Scholar]
[32]Cataldo, A. M., Barnett, J. L., Pieroni, C. & Nixon, R. A. (1997) J. Neurosci. 17, 6142-6151. [DOI] [PMC free article] [PubMed] [Google Scholar]
[33]Cataldo, A. M., Peterhoff, C. M., Troncoso, J. C., Gomez-Isla, T., Hyman, B. T. & Nixon, R. A. (2000) Am. J. Pathol. 157, 277-286. [DOI] [PMC free article] [PubMed] [Google Scholar]
[34]Grbovic, O. M., Mathews, P. M., Jiang, Y., Schmidt, S. D., Dinakar, R., Summers-Terio, N. B., Ceresa, B. P., Nixon, R. A. & Cataldo, A. M. (2003) J. Biol. Chem. 278, 31261-31268. [DOI] [PubMed] [Google Scholar]
[35]Beffert, U. & Poirier, J. (1996) Ann. N.Y. Acad. Sci. 777, 166-174. [DOI] [PubMed] [Google Scholar]
[36]Beisiegel, U., Schneider, W. J., Goldstein, J. L., Anderson, R. G. W. & Brown, M. S. (1981) J. Biol. Chem. 256, 11923-11931. [PubMed] [Google Scholar]
[37]Diedrich, J. F., Minnigan, H., Carp, R. I., Whitaker, J. N., Race, R., Frey, W., II & Haase, A. T. (1991) J. Virol. 65, 4759-4768. [DOI] [PMC free article] [PubMed] [Google Scholar]
[38]Han, S.-H., Einstein, G., Weisgraber, K. H., Strittmatter, W. J., Saunders, A. M., Pericak-Vance, M., Roses, A. D. & Schmechel, D. E. (1994) J. Neuropathol. Exp. Neurol. 53, 535-544. [DOI] [PubMed] [Google Scholar]
[39]Bao, F., Arai, H., Matsushita, S., Higuchi, S. & Sasaki, H. (1996) NeuroReport 7, 1733-1739. [DOI] [PubMed] [Google Scholar]
[40]Metzger, R. E., LaDu, M. J., Pan, J. B., Getz, G. S., Frail, D. E. & Falduto, M. T. (1996) J. Neuropathol. Exp. Neurol. 55, 372-380. [DOI] [PubMed] [Google Scholar]
[41]Xu, P.-T., Schmechel, D., Qiu, H.-L., Herbstreith, M., Rothrock-Christian, T., Eyster, M., Roses, A. D. & Gilbert, J. R. (1999) Neurobiol. Dis. 6, 63-75. [DOI] [PubMed] [Google Scholar]
[42]Xu, P.-T., Gilbert, J. R., Qiu, H.-L., Ervin, J., Rothrock-Christian, T. R., Hulette, C. & Schmechel, D. E. (1999) Am. J. Pathol. 154, 601-611. [DOI] [PMC free article] [PubMed] [Google Scholar]
[43]Xu, P.-T., Gilbert, J. R., Qiu, H.-L., Rothrock-Christian, T., Settles, D. L., Roses, A. D. & Schmechel, D. E. (1998) Neurosci. Lett. 246, 65-68. [DOI] [PubMed] [Google Scholar]
[44]Xu, P.-T., Schmechel, D., Rothrock-Christian, T., Burkhart, D. S., Qiu, H.-L., Popko, B., Sullivan, P., Maeda, N., Saunders, A. M., Roses, A. D. & Gilbert, J. R. (1996) Neurobiol. Dis. 3, 229-245. [DOI] [PubMed] [Google Scholar]
[45]Aoki, K., Uchihara, T., Sanjo, N., Nakamura, A., Ikeda, K., Tsuchiya, K. & Wakayama, Y. (2003) Stroke (Dallas) 34, 875-880. [DOI] [PubMed] [Google Scholar]
[46]Dupont-Wallois, L., Soulié, C., Sergeant, N., Wavrant-de Wrieze, N., Chartier-Harlin, M.-C., Delacourte, A. & Caillet-Boudin, M.-L. (1997) Neurobiol. Dis. 4, 356-364. [DOI] [PubMed] [Google Scholar]
[47]Ferreira, S., Dupire, M.-J., Delacourte, A., Najib, J. & Caillet-Boudin, M.-L. (2000) Exp. Neurol. 166, 415-421. [DOI] [PubMed] [Google Scholar]
[48]Harris, F. M., Tesseur, I., Brecht, W. J., Xu, Q., Mullendorff, K., Chang, S., Wyss-Coray, T., Mahley, R. W. & Huang, Y. (2004) J. Biol. Chem. 279, 3862-3868. [DOI] [PubMed] [Google Scholar]
[49]Huang, Y., Weisgraber, K. H., Mucke, L. & Mahley, R. W. (2004) J. Mol. Neurosci. 23, 189-204. [DOI] [PubMed] [Google Scholar]
[50]Narayanaswami, V. & Ryan, R. O. (2000) Biochim. Biophys. Acta 1483, 15-36. [DOI] [PubMed] [Google Scholar]
[51]Du, X., Stoops, J. D., Mertz, J. R., Stanley, C. M. & Dixon, J. L. (1998) J. Cell Biol. 141, 585-599. [DOI] [PMC free article] [PubMed] [Google Scholar]
[52]Berridge, M. V. & Tan, A. S. (1993) Arch. Biochem. Biophys. 303, 474-482. [DOI] [PubMed] [Google Scholar]
[53]Kalbácová, M., Vrbacky, M., Drahota, Z. & Melková, Z. (2003) Cytometry 52A, 110-116. [DOI] [PubMed] [Google Scholar]
[54]Weisgraber, K. H. (1994) Adv. Protein Chem. 45, 249-302. [DOI] [PubMed] [Google Scholar]
[55]Tolar, M., Marques, M. A., Harmony, J. A. K. & Crutcher, K. A. (1997) J. Neurosci. 17, 5678-5686. [DOI] [PMC free article] [PubMed] [Google Scholar]
[56]Tolar, M., Keller, J. N., Chan, S., Mattson, M. P., Marques, M. A. & Crutcher, K. A. (1999) J. Neurosci. 19, 7100-7110. [DOI] [PMC free article] [PubMed] [Google Scholar]
[57]Frankel, A. D. & Pabo, C. O. (1988) Cell 55, 1189-1193. [DOI] [PubMed] [Google Scholar]
[58]Green, M. & Loewenstein, P. M. (1988) Cell 55, 1179-1188. [DOI] [PubMed] [Google Scholar]
[59]Schwarze, S. R., Ho, A., Vocero-Akbani, A. & Dowdy, S. F. (1999) Science 285, 1569-1572. [DOI] [PubMed] [Google Scholar]
[60]Cao, G., Pei, W., Ge, H., Liang, Q., Luo, Y., Sharp, F. R., Lu, A., Ran, R., Graham, S. H. & Chen, J. (2002) J. Neurosci. 22, 5423-5431. [DOI] [PMC free article] [PubMed] [Google Scholar]
[61]Fawell, S., Seery, J., Daikh, Y., Moore, C., Chen, L. L., Pepinsky, B. & Barsoum, J. (1994) Proc. Natl. Acad. Sci. USA 91, 664-668. [DOI] [PMC free article] [PubMed] [Google Scholar]
[62]Miura, S.-I., Okamoto, T., Via, D. P. & Saku, K. (2002) Circ. J. 66, 1054-1056. [DOI] [PubMed] [Google Scholar]
[63]Liu, K., Ou, J., Saku, K., Jimi, S., Via, D. P., Sparrow, J. T., Zhang, B., Pownall, H. J., Smith, L. C. & Arakawa, K. (1999) Arterioscler. Thromb. Vasc. Biol. 19, 2207-2213. [DOI] [PubMed] [Google Scholar]
[64]Cho, H. S., Hyman, B. T., Greenberg, S. M. & Rebeck, G. W. (2001) J. Neuropathol. Exp. Neurol. 60, 342-349. [DOI] [PubMed] [Google Scholar]
[65]Ghosh, S. S., Swerdlow, R. H., Miller, S. W., Sheeman, B., Parker, W. D., Jr. & Davis, R. E. (1999) Ann. N.Y. Acad. Sci. 893, 176-191. [DOI] [PubMed] [Google Scholar]
[66]Trimmer, P. A., Swerdlow, R. H., Parks, J. K., Keeney, P., Bennett, J. P., Jr., Miller, S. W., Davis, R. E. & Parker, W. D., Jr. (2000) Exp. Neurol. 162, 37-50. [DOI] [PubMed] [Google Scholar]
[67]Hirai, K., Aliev, G., Nunomura, A., Fujioka, H., Russell, R. L., Atwood, C. S., Johnson, A. B., Kress, Y., Vinters, H. V., Tabaton, M., et al. (2001) J. Neurosci. 21, 3017-3023. [DOI] [PMC free article] [PubMed] [Google Scholar]
[68]Small, G. W., Mazziotta, J. C., Collins, M. T., Baxter, L. R., Phelps, M. E., Mandelkern, M. A., Kaplan, A., La Rue, A., Adamson, C. F. & Chang, L. (1995) J. Am. Med. Assoc. 273, 942-947. [PubMed] [Google Scholar]
[69]Small, G. W., Ercoli, L. M., Silverman, D. H. S., Huang, S.-C., Komo, S., Bookheimer, S. Y., Lavretsky, H., Miller, K., Siddarth, P., Rasgon, N. L., et al. (2000) Proc. Natl. Acad. Sci. USA 97, 6037-6042. [DOI] [PMC free article] [PubMed] [Google Scholar]
[70]Reiman, E. M., Caselli, R. J., Chen, K., Alexander, G. E., Bandy, D. & Frost, J. (2001) Proc. Natl. Acad. Sci. USA 98, 3334-3339. [DOI] [PMC free article] [PubMed] [Google Scholar]
[71]Reiman, E. M., Chen, K., Alexander, G. E., Caselli, R. J., Bandy, D., Osborne, D., Saunders, A. M. & Hardy, J. (2004) Proc. Natl. Acad. Sci. USA 101, 284-289. [DOI] [PMC free article] [PubMed] [Google Scholar]

Sorted by citations

Alzheimer Mechanisms and Therapeutic Strategies
Huang, Y., & Mucke, L. (2012) · Cell · doi:10.1016/j.cell.2012.02.040 · Cited by 1,758 · see citing works
Self-citation
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661 · see citing works
Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
Bu, G. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2620 · Cited by 1,168 · see citing works
Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation
Johnson, E. C. B., Dammer, E. B., Duong, D. M., Ping, L., Zhou, M., Yin, L., Higginbotham, L. A., Guajardo, A., White, B., Troncoso, J. C., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0815-6 · Cited by 1,001 · see citing works
Amyloid beta, mitochondrial dysfunction and synaptic damage: Implications for cognitive decline in aging and Alzheimer’s disease
Reddy, P. H., & Beal, M. F. (2008) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2007.12.002 · Cited by 975 · see citing works
Identification of miRNA changes in Alzheimer's disease brain and CSF yields putative biomarkers and insights into disease pathways
Cogswell, J. P., Ward, J., Taylor, I. A., Waters, M., Shi, Y., Cannon, B., Kelnar, K., Kemppainen, J., Brown, D., Chen, C., et al. (2008) · Journal of Alzheimer s Disease · doi:10.3233/jad-2008-14103 · Cited by 943 · see citing works
Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease
Mahley, R. W., Weisgraber, K. H., & Huang, Y. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0600549103 · Cited by 912 · see citing works
Self-citation
Mitochondria and Mitochondrial Cascades in Alzheimer’s disease
Swerdlow, R. H. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170585 · Cited by 850 · see citing works
Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders
Mahley, R. W. (2016) · Journal of Molecular Medicine · doi:10.1007/s00109-016-1427-y · Cited by 837 · see citing works
Self-citation
Apolipoprotein E: Structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases
Huang, Y., & Mahley, R. W. (2014) · Neurobiology of Disease · doi:10.1016/j.nbd.2014.08.025 · Cited by 829 · see citing works
Self-citation
The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.09.010 · Cited by 786 · see citing works
Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer’s disease
Risner, M. E., Saunders, A. M., Altman, J. F. B., Ormandy, G. C., Craft, S., Foley, I. M., Zvartau-Hind, M. E., Hosford, D. A., Roses, A. D., & for the Rosiglitazone in Alzheimer's Disease Study Group (2006) · The Pharmacogenomics Journal · doi:10.1038/sj.tpj.6500369 · Cited by 686 · see citing works
Age, APOE and sex: triad of risk of Alzheimer’s disease.
Riedel, B. C., Thompson, P. M., & Brinton, R. D. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.03.012 · Cited by 627 · see citing works
Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS
Mahley, R. W., Weisgraber, K. H., & Huang, Y. (2009) · Journal of Lipid Research · doi:10.1194/jlr.r800069-jlr200 · Cited by 580 · see citing works
Self-citation
The Alzheimer’s Disease Mitochondrial Cascade Hypothesis
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100339 · Cited by 562 · see citing works
“tein E or its degradation products also appear to influence mitochondrial function [102].”
Background
Reelin, lipoprotein receptors and synaptic plasticity
Herz, J., & Chen, Y. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn2009 · Cited by 524 · see citing works
Profile and Regulation of Apolipoprotein E (ApoE) Expression in the CNS in Mice with Targeting of Green Fluorescent Protein Gene to the ApoE Locus
Xu, Q., Bernardo, A., Walker, D., Kanegawa, T., Mahley, R. W., & Huang, Y. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.5476-05.2006 · Cited by 524 · see citing works
Self-citation
Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism
Mahley, R. W. (2016) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.116.307023 · Cited by 516 · see citing works
Self-citation
Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease
Li, H., Wetten, S., Li, L., St. Jean, P. L., Upmanyu, R., Surh, L., Hosford, D., Barnes, M. R., Briley, J. D., Borrie, M., et al. (2008) · Archives of Neurology · doi:10.1001/archneurol.2007.3 · Cited by 499 · see citing works
ApoE4: an emerging therapeutic target for Alzheimer’s disease
Safieh, M., Korczyn, A. D., & Michaelson, D. M. (2019) · BMC Medicine · doi:10.1186/s12916-019-1299-4 · Cited by 449 · see citing works
Mitochondrial dysfunction in Alzheimer's disease: role in pathogenesis and novel therapeutic opportunities
Perez Ortiz, J. M., & Swerdlow, R. H. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14585 · Cited by 426 · see citing works
Apolipoprotein e sets the stage: response to injury triggers neuropathology
Mahley, R. W., & Huang, Y. (2012) · Neuron · doi:10.1016/j.neuron.2012.11.020 · Cited by 412 · see citing works
Self-citation
A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease
Roses, A. D., Lutz, M. W., Amrine‐Madsen, H., Saunders, A. M., Crenshaw, D. G., Sundseth, S. S., Huentelman, M. J., Welsh-Bohmer, K. A., & Reiman, E. M. (2009) · The Pharmacogenomics Journal · doi:10.1038/tpj.2009.69 · Cited by 391 · see citing works
Antioxidant Therapies for Alzheimer's Disease
Feng, Y., & Wang, X. (2012) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2012/472932 · Cited by 382 · see citing works
Oxidative Stress Signaling in Alzheimers Disease
Su, B., Wang, X., Nunomura, A., Moreira, P., Lee, H.-G., Perry, G., Smith, M., & Zhu, X. (2008) · Current Alzheimer Research · doi:10.2174/156720508786898451 · Cited by 344 · see citing works
Apolipoprotein E: From lipid transport to neurobiology
Hauser, P. S., Narayanaswami, V., & Ryan, R. O. (2011) · Progress in Lipid Research · doi:10.1016/j.plipres.2010.09.001 · Cited by 320 · see citing works
A mitochondrial etiology of Alzheimer and Parkinson disease
Coskun, P. E., Wyrembak, J., Schriner, S. E., Chen, H.-W., Marciniack, C., LaFerla, F. M., & Wallace, D. C. (2011) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2011.08.008 · Cited by 297 · see citing works
GABAergic Interneuron Dysfunction Impairs Hippocampal Neurogenesis in Adult Apolipoprotein E4 Knockin Mice
Li, G., Bien-Ly, N., Andrews-Zwilling, Y., Xu, Q., Bernardo, A., Ring, K., Halabisky, B., Deng, C., Mahley, R. W., & Huang, Y. (2009) · Cell Stem Cell · doi:10.1016/j.stem.2009.10.015 · Cited by 288 · see citing works
Self-citation
Oxidative stress and β-amyloid protein in Alzheimer’s disease
Cai, Z., Zhao, B., & Ratka, A. (2011) · NeuroMolecular Medicine · doi:10.1007/s12017-011-8155-9 · Cited by 279 · see citing works
Mechanisms of mitochondrial dysfunction and energy deficiency in Alzheimer’s disease
Atamna, H., & Frey, W. H. (2007) · Mitochondrion · doi:10.1016/j.mito.2007.06.001 · Cited by 278 · see citing works
Pathogenesis of Alzheimer's disease.
Swerdlow, R. H. (2007) · PubMed Central · Cited by 236 · see citing works
Chronic Stress and Oxidative Stress as Common Factors of the Pathogenesis of Depression and Alzheimer’s Disease: The Role of Antioxidants in Prevention and Treatment
Juszczyk, G., Mikulska, J., Kasperek, K., Pietrzak, D., Mrozek, W., & Herbet, M. (2021) · Antioxidants · doi:10.3390/antiox10091439 · Cited by 235 · see citing works
Apolipoprotein E and Alzheimer’s disease: Findings, hypotheses, and potential mechanisms
Koutsodendris, N., Nelson, M. R., Rao, A., & Huang, Y. (2022) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathmechdis-030421-112756 · Cited by 231 · see citing works
Self-citation
Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer's disease
Bossers, K., Wirz, K. T. S., Meerhoff, G. F., Essing, A. H. W., van Dongen, J. W., Houba, P., Kruse, C. G., Verhaagen, J., & Swaab, D. F. (2010) · Brain · doi:10.1093/brain/awq258 · Cited by 230 · see citing works
Mitochondrial Medicine for Aging and Neurodegenerative Diseases
Reddy, P. H. (2008) · NeuroMolecular Medicine · doi:10.1007/s12017-008-8044-z · Cited by 230 · see citing works
The Genetic Variability of APOE in Different Human Populations and Its Implications for Longevity
Abondio, P., Sazzini, M., Garagnani, P., Boattini, A., Monti, D., Franceschi, C., Luiselli, D., & Giuliani, C. (2019) · Genes · doi:10.3390/genes10030222 · Cited by 226 · see citing works
APOE and Alzheimer’s Disease: Evidence Mounts that Targeting APOE4 may Combat Alzheimer’s Pathogenesis
Uddin, M. S., Kabir, M. T., Al Mamun, A., Abdel-Daim, M. M., Barreto, G. E., & Ashraf, G. M. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1237-z · Cited by 212 · see citing works
Apolipoprotein E4 domain interaction mediates detrimental effects on mitochondria and is a potential therapeutic target for Alzheimer disease
Chen, H.-K., Ji, Z.-S., Dodson, S. E., Miranda, R. D., Rosenblum, C. I., Reynolds, I. J., Freedman, S. B., Weisgraber, K. H., Huang, Y., & Mahley, R. W. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.151084 · Cited by 209 · see citing works
Self-citation
The Alzheimer's disease mitochondrial cascade hypothesis: an update
Swerdlow, R. H., & Khan, S. M. (2009) · Experimental Neurology · doi:10.1016/j.expneurol.2009.01.011 · Cited by 206 · see citing works
Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease
Cioffi, F., Adam, R. H. I., & Broersen, K. (2019) · Journal of Alzheimer s Disease · doi:10.3233/jad-190863 · Cited by 204 · see citing works
“ance of A [240, 241], mitochondrial dysfunction, 972 and impairment of calcium [242, 243] or cellular 973 iron homeostasis [244], and ApoE4 affects synaptic 974 architecture and functioning [245, 246].”
Background
Mitochondria in Neurodegeneration
Lezi, E., & Swerdlow, R. H. (2011) · Advances in experimental medicine and biology · doi:10.1007/978-94-007-2869-1_12 · Cited by 204 · see citing works
Mitochondria and Cell Bioenergetics: Increasingly Recognized Components and a Possible Etiologic Cause of Alzheimer's Disease
Swerdlow, R. H. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2011.4149 · Cited by 203 · see citing works
Oxidized cholesterol as the driving force behind the development of Alzheimer’s disease
Gamba, P., Testa, G., Gargiulo, S., Staurenghi, E., Poli, G., & Leonarduzzi, G. (2015) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2015.00119 · Cited by 202 · see citing works
Molecular links between Alzheimer’s disease and diabetes mellitus
Yang, Y., & Song, W. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.07.009 · Cited by 201 · see citing works
Multifaceted roles of APOE in Alzheimer disease
Jackson, R. J., Hyman, B. T., & Serrano-Pozo, A. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-024-00988-2 · Cited by 193 · see citing works
Mitochondrial Amyloid-β Levels are Associated with the Extent of Mitochondrial Dysfunction in Different Brain Regions and the Degree of Cognitive Impairment in Alzheimer's Transgenic Mice
Dragicevic, N., Mamcarz, M. B., Zhu, Y., Buzzeo, R. W., Tan, J., Arendash, G. W., & Bradshaw, P. C. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100342 · Cited by 193 · see citing works
Green Tea Epigallocatechin-3-Gallate (EGCG) and Other Flavonoids Reduce Alzheimer's Amyloid-Induced Mitochondrial Dysfunction
Dragicevic, N., Smith, A., Lin, X., Yuan, F., Copes, N., Delic, V., Tan, J., Cao, C., Shytle, R. D., & Bradshaw, P. C. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101629 · Cited by 189 · see citing works
Apolipoprotein E and oxidative stress in brain with relevance to Alzheimer's disease
Butterfield, D. A., & Mattson, M. P. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104795 · Cited by 187 · see citing works
Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention
Wu, L., Zhang, X., & Zhao, L. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.2262-17.2018 · Cited by 185 · see citing works
Pathways to neurodegeneration: mechanistic insights from GWAS in Alzheimer's disease, Parkinson's disease, and related disorders.
Ramanan, V. K., & Saykin, A. J. (2013) · Europe PMC (PubMed Central) · Cited by 185 · see citing works
Melatonin treatment restores mitochondrial function in Alzheimer’s mice: a mitochondrial protective role of melatonin membrane receptor signaling
Dragicevic, N., Copes, N., O’Neal-Moffitt, G., Jin, J., Buzzeo, R. W., Mamcarz, M., Tan, J., Cao, C., Olcese, J., Arendash, G. W., et al. (2011) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2011.00864.x · Cited by 185 · see citing works
Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease
Najm, R., Jones, E. A., & Huang, Y. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0324-6 · Cited by 183 · see citing works
Self-citation
Synaptic Depression and Aberrant Excitatory Network Activity in Alzheimer’s Disease: Two Faces of the Same Coin?
Palop, J. J., & Mucke, L. (2009) · NeuroMolecular Medicine · doi:10.1007/s12017-009-8097-7 · Cited by 177 · see citing works
Pharmacogenetics in drug discovery and development: a translational perspective
Roses, A. D. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2593 · Cited by 174 · see citing works
Aβ-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer's disease
Huang, Y. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.04.004 · Cited by 170 · see citing works
Self-citation
Apolipoprotein E as a Therapeutic Target in Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence
Yamazaki, Y., Painter, M. M., Bu, G., & Kanekiyo, T. (2016) · CNS Drugs · doi:10.1007/s40263-016-0361-4 · Cited by 166 · see citing works
Small Molecule Structure Correctors Abolish Detrimental Effects of Apolipoprotein E4 in Cultured Neurons
Chen, H.-K., Liu, Z., Meyer-Franke, A., Brodbeck, J., Miranda, R. D., McGuire, J. G., Pleiss, M. A., Ji, Z.-S., Balestra, M. E., Walker, D. W., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.276162 · Cited by 163 · see citing works
Self-citation
Systemic Mitochondrial Dysfunction and the Etiology of Alzheimer's Disease and Down Syndrome Dementia
Coskun, P. E., Wyrembak, J., Derbereva, O., Melkonian, G., Doran, E. W., Lott, I. T., Head, E., Cotman, C. W., & Wallace, D. C. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100351 · Cited by 158 · see citing works
Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies
Pires, M., & Rego, A. C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24010778 · Cited by 157 · see citing works
Natural Antioxidant Anthocyanins—A Hidden Therapeutic Candidate in Metabolic Disorders with Major Focus in Neurodegeneration
Ullah, R., Khan, M., Shah, S. A., Saeed, K. M., & Kim, M. O. (2019) · Nutrients · doi:10.3390/nu11061195 · Cited by 154 · see citing works
Reduced Posterior Cingulate Mitochondrial Activity in Expired Young Adult Carriers of the APOE ε4 Allele, the Major Late-Onset Alzheimer's Susceptibility Gene
Valla, J., Yaari, R., Wolf, A. B., Kusne, Y., Beach, T. G., Roher, A. E., Corneveaux, J. J., Huentelman, M. J., Caselli, R. J., & Reiman, E. M. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100129 · Cited by 150 · see citing works
Invited Review: APOE at the interface of inflammation, neurodegeneration and pathological protein spread in Alzheimer's disease
Tzioras, M., Davies, C., Newman, A., Jackson, R., & Spires‐Jones, T. (2019) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12529 · Cited by 147 · see citing works
Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms
Kim, J., Yoon, H., Basak, J., & Kim, J. (2014) · Molecules and Cells · doi:10.14348/molcells.2014.0248 · Cited by 141 · see citing works
“Limited data suggest that a particular fragment of apoE (1-272 amino acids) can translocate to cytosol and interacts with cytoskeletal proteins (Chang et al., 2005).”
Background
APOE genotype and stress response - a mini review
Dose, J., Huebbe, P., Nebel, A., & Rimbach, G. (2016) · Lipids in Health and Disease · doi:10.1186/s12944-016-0288-2 · Cited by 137 · see citing works
Atherosclerosis and Alzheimer - diseases with a common cause? Inflammation, oxysterols, vasculature
Lathe, R., Tsitrina, A. A., & Kotelevtsev, Y. V. (2014) · BMC Geriatrics · doi:10.1186/1471-2318-14-36 · Cited by 136 · see citing works
Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene
Boehm-Cagan, A., & Michaelson, D. M. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.5198-13.2014 · Cited by 134 · see citing works
Small-Molecule Structure Correctors Target Abnormal Protein Structure and Function: Structure Corrector Rescue of Apolipoprotein E4–Associated Neuropathology: Miniperspective
Mahley, R. W., & Huang, Y. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm3008618 · Cited by 132 · see citing works
Self-citation
3-Hydroxybutyrate methyl ester as a potential drug against Alzheimer's disease via mitochondria protection mechanism
Zhang, J., Cao, Q., Li, S., Lu, X., Zhao, Y., Guan, J., Chen, J., Wu, Q., & Chen, G. (2013) · Biomaterials · doi:10.1016/j.biomaterials.2013.06.043 · Cited by 130 · see citing works
Genetic architecture of Alzheimer's disease
Neuner, S. M., TCW, J., & Goate, A. M. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104976 · Cited by 126 · see citing works
“nervous system, APOEε4 has been linked to impaired Aβ clearance [71, 72], disruption of lysosomes and neuronal apoptosis [73, 74], as well as mitochondrial dysfunction [75].”
Background
Apolipoprotein E4 (1–272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells
Nakamura, T., Watanabe, A., Fujino, T., Hosono, T., & Michikawa, M. (2009) · Molecular Neurodegeneration · doi:10.1186/1750-1326-4-35 · Cited by 124 · see citing works
Epigenomics of Alzheimer's disease
Bennett, D. A., Yu, L., Yang, J., Srivastava, G. P., Aubin, C., & Jager, P. L. D. (2014) · Translational research · doi:10.1016/j.trsl.2014.05.006 · Cited by 124 · see citing works
Mitochondrial dysfunction and Alzheimer's disease
Maruszak, A., & Żekanowski, C. (2010) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2010.07.004 · Cited by 123 · see citing works
Intron-3 Retention/Splicing Controls Neuronal Expression of Apolipoprotein E in the CNS
Xu, Q., Walker, D., Bernardo, A., Brodbeck, J., Balestra, M. E., & Huang, Y. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.3253-07.2008 · Cited by 122 · see citing works
Self-citation
An inherited variable poly-T repeat genotype in TOMM40 in Alzheimer disease
Roses, A. D. (2010) · Archives of Neurology · doi:10.1001/archneurol.2010.88 · Cited by 118 · see citing works
New Insights in the Amyloid-Beta Interaction with Mitochondria
Spuch, C., Ortolano, S., & Fernández-Balbuena, C. N. (2012) · Journal of Aging Research · doi:10.1155/2012/324968 · Cited by 117 · see citing works
The Thiazolidinedione Pioglitazone Alters Mitochondrial Function in Human Neuron-Like Cells
Ghosh, S., Patel, N., Rahn, D. A., McAllister, J., Sadeghi, S., Horwitz, G., Berry, D., Wang, K. X., & Swerdlow, R. H. (2007) · Molecular Pharmacology · doi:10.1124/mol.106.033845 · Cited by 116 · see citing works
Structure-dependent Impairment of Intracellular Apolipoprotein E4 Trafficking and Its Detrimental Effects Are Rescued by Small-molecule Structure Correctors
Brodbeck, J., McGuire, J., Liu, Z., Meyer-Franke, A., Balestra, M. E., Jeong, D.-E., Pleiss, M., McComas, C., Hess, F., Witter, D., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.217380 · Cited by 113 · see citing works
Self-citation
ApoE and Neurodegenerative Diseases in Aging
Yin, Y., & Wang, Z. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-1117-8_5 · Cited by 111 · see citing works
Central and Peripheral Metabolic Defects Contribute to the Pathogenesis of Alzheimer's Disease: Targeting Mitochondria for Diagnosis and Prevention
Peng, Y., Gao, P., Shi, L., Chen, L., Liu, J., & Long, J. (2020) · Antioxidants & Redox Signaling · doi:10.1089/ars.2019.7763 · Cited by 110 · see citing works
Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets
Fišar, Z. (2022) · Biomolecules · doi:10.3390/biom12111676 · Cited by 110 · see citing works
Characterizing the Preclinical Stages of Alzheimer's Disease and the Prospect of Presymptomatic Intervention
Caselli, R. J., & Reiman, E. M. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-129026 · Cited by 109 · see citing works
Complex disease-associated pharmacogenetics: drug efficacy, drug safety, and confirmation of a pathogenetic hypothesis (Alzheimer's disease)
Roses, A. D., Saunders, A. M., Huang, Y., Strum, J. C., Weisgraber, K. H., & Mahley, R. W. (2006) · The Pharmacogenomics Journal · doi:10.1038/sj.tpj.6500397 · Cited by 109 · see citing works
Self-citation
APOE alters glucose flux through central carbon pathways in astrocytes
Williams, H. C., Farmer, B. C., Piron, M. A., Walsh, A. E., Bruntz, R. C., Gentry, M. S., Sun, R. C., & Johnson, L. A. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104742 · Cited by 105 · see citing works
Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function
Orr, A. L., Kim, C., Jimenez-Morales, D., Newton, B. W., Johnson, J. R., Krogan, N. J., Swaney, D. L., & Mahley, R. W. (2019) · Journal of Alzheimer's Disease · doi:10.3233/jad-181184 · Cited by 103 · see citing works
Self-citation
The cell biology of APOE in the brain
Windham, I. A., & Cohen, S. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.09.004 · Cited by 103 · see citing works
Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype
Hesse, R., Hurtado, M. L., Jackson, R. J., Eaton, S. L., Herrmann, A. G., Colom‐Cadena, M., Tzioras, M., King, D., Rose, J. L., Tulloch, J., et al. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0847-7 · Cited by 103 · see citing works
Slow Excitotoxicity in Alzheimer's Disease
Ong, W.-Y., Tanaka, K., Dawe, G. S., Ittner, L. M., & Farooqui, A. A. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-121990 · Cited by 101 · see citing works
Insight into the genetic etiology of Alzheimer's disease: A comprehensive review of the role of rare variants
Hoogmartens, J., Cacace, R., & Broeckhoven, C. V. (2021) · Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring · doi:10.1002/dad2.12155 · Cited by 101 · see citing works
Genetic variation at a single locus and age of onset for Alzheimer's disease
Lutz, M. W., Crenshaw, D. G., Saunders, A. M., & Roses, A. D. (2010) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2010.01.011 · Cited by 101 · see citing works
Reevaluating Metabolism in Alzheimer's Disease from the Perspective of the Astrocyte-Neuron Lactate Shuttle Model
Newington, J. T., Harris, R. A., & Cumming, R. C. (2013) · Journal of Neurodegenerative Diseases · doi:10.1155/2013/234572 · Cited by 101 · see citing works
Mitochondria in Alzheimer's disease and their potential role in Alzheimer's proteostasis
Weidling, I. W., & Swerdlow, R. H. (2020) · Experimental Neurology · doi:10.1016/j.expneurol.2020.113321 · Cited by 100 · see citing works
Gout and the risk of dementia: a nationwide population-based cohort study
Hong, J.-Y., Lan, T.-Y., Tang, G., Tang, C., Chen, T., & Lin, H.-Y. (2015) · Arthritis Research & Therapy · doi:10.1186/s13075-015-0642-1 · Cited by 100 · see citing works
Hydrogen/deuterium exchange and electron-transfer dissociation mass spectrometry determine the interface and dynamics of apolipoprotein E oligomerization
Huang, R. Y.-C., Garai, K., Frieden, C., & Gross, M. L. (2011) · Biochemistry · doi:10.1021/bi2010027 · Cited by 97 · see citing works
Apolipoprotein E4 produced in GABAergic interneurons causes learning and memory deficits in mice
Knoferle, J., Yoon, S. Y., Walker, D., Leung, L., Gillespie, A. K., Tong, L. M., Bien-Ly, N., & Huang, Y. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.2281-14.2014 · Cited by 97 · see citing works
Self-citation
APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size
Windham, I. A., Powers, A. E., Ragusa, J. V., Wallace, E. D., Zanellati, M. C., Williams, V. H., Wagner, C. H., White, K. K., & Cohen, S. (2024) · Journal of Cell Biology · doi:10.1083/jcb.202305003 · Cited by 96 · see citing works
Disentangling Mitochondria in Alzheimer’s Disease
Johri, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111520 · Cited by 96 · see citing works
Amyloid precursor protein and mitochondrial dysfunction in Alzheimer's disease
Anandatheerthavarada, H. K., & Devi, L. (2007) · The Neuroscientist · doi:10.1177/1073858407303536 · Cited by 95 · see citing works
Roles of ApoE4 on the Pathogenesis in Alzheimer’s Disease and the Potential Therapeutic Approaches
Sun, Y.-Y., Wang, Z., & Huang, H. (2023) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-023-01365-1 · Cited by 95 · see citing works
Pathophysiological Mechanisms Linking Type 2 Diabetes and Dementia: Review of Evidence from Clinical, Translational and Epidemiological Research
Bello‐Chavolla, O. Y., Antonio‐Villa, N. E., Vargas‐Vázquez, A., Ávila‐Funes, J. A., & Aguilar-Salinas, C. A. (2019) · Current Diabetes Reviews · doi:10.2174/1573399815666190129155654 · Cited by 93 · see citing works
Alzheimer’s Disease and Cholesterol: The Fat Connection
Canevari, L., & Clark, J. B. (2006) · Neurochemical Research · doi:10.1007/s11064-006-9200-1 · Cited by 93 · see citing works

Apolipoprotein E4 (1–272) fragment is associated with mitochondrial proteins and affects mitochondrial function in neuronal cells
Nakamura, T., Watanabe, A., Fujino, T., Hosono, T., & Michikawa, M. (2009) · Molecular Neurodegeneration · doi:10.1186/1750-1326-4-35 · Cited by 124 · see citing works
O3‐03–03: Apolipoprotein E4 and its fragment impair mitochondrial dynamics in neuronal cultures
Brodbeck, J., Balestra, M. E., Freedman, S. B., Weisgraber, K. H., Mahley, R. W., & Huang, Y. (2008) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2008.05.425 · Cited by 4 · see citing works
Self-citation
Apolipoprotein E4 expression inhibits neurite outgrowth from neuroblastoma cells
Bellosta, S., Nathan, B. P., Mahley, R. W., & Pitas, R. E. (1995) · Pharmacological Research · doi:10.1016/1043-6618(95)86746-5
Self-citation
Investigating the effect of C-terminal truncated apolipoprotein E4 on amyloid-beta-induced neuronal and behavioral deficits in mice
Bien‐Ly, N. (2011) · eScholarship (California Digital Library)
ApoE4 (Δ272–299) induces mitochondrial‐associated membrane formation and mitochondrial impairment by enhancing GRP75-modulated mitochondrial calcium overload in neuron
Liang, T., Hang, W., Chen, J., Wu, Y., Wen, B., Xu, K., Ding, B., & Chen, J. (2021) · Cell & Bioscience · doi:10.1186/s13578-021-00563-y · Cited by 54 · see citing works

Authors: Chang, S., Ma, T. R., Miranda, R. D., Balestra, M. E., Mahley, R. W., & Huang, Y.
Affiliations: University of California, San Francisco (US)
Gladstone Institutes (US)
ORCID: Mahley, Robert W.
Huang, Yadong
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2005-12-12
Volume: 102
Issue: 51
Pages: 18694-18699
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0508254102
PMC: PMC1311737
OpenAlex: W2022943683
Cited by: 319
References: 73
Citations by year: 2026: 16 · 2025: 8 · 2024: 15 · 2023: 16 · 2022: 14 · 2021: 14 · 2020: 16 · 2019: 21 · 2018: 13 · 2017: 14 · 2016: 18 · 2015: 10 · 2014: 15 · 2013: 19 · 2012: 18
FWCI: 7.62
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: GlaxoSmithKline
National Institutes of Health (AG‐022074)
National Institute on Aging (P01AG022074)
National Heart, Lung, and Blood Institute (R01 HL37063, R01HL037063)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: APOE ε4, neurotoxicity, mitochondrial dysfunction, receptor-binding region, Alzheimer's disease, tau phosphorylation, N2a cells, transgenic mice
MeSH terms: Alzheimer Disease, Animals, Apolipoproteins E, Cytoskeleton, Lipids, Mitochondria, Mutation, Neurons, Peptide Fragments, Receptors, Lipoprotein, Cell Line, Tumor, Mice, Apolipoprotein E4

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Self-check

Cites

Cited by

Related

Record

About these checks