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Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide.
J Neurosci. 2012 Oct 24; 32(43):15181-92.JN

Abstract

Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid β peptide (Aβ) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component. The apolipoprotein E ε 4 (apoE ε4) allele is known to be a genetic risk factor for developing AD. However, it is still unknown how apoE impacts the process of Aβ oligomerization. Here, we found that the level of Aβ oligomers in APOE ε4/ε4 AD patient brains is 2.7 times higher than those in APOE ε3/ε3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of Aβ oligomers. To test this hypothesis, we examined the effect of apoE on Aβ oligomer formation. Using both synthetic Aβ and a split-luciferase method for monitoring Aβ oligomers, we observed that apoE increased the level of Aβ oligomers in an isoform-dependent manner (E2 < E3 < E4). This effect appears to be dependent on the ApoE C-terminal domain. Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of Aβ oligomers. Together, these data show that lipidated apoE, especially apoE4, increases Aβ oligomers in the brain. Higher levels of Aβ oligomers in the brains of APOE ε4/ε4 carriers compared with APOE ε3/ε3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD.

Authors+Show Affiliations

Department of Neurology, Alzheimer's Disease Research Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23100439

Citation

Hashimoto, Tadafumi, et al. "Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid Β Peptide." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 32, no. 43, 2012, pp. 15181-92.
Hashimoto T, Serrano-Pozo A, Hori Y, et al. Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. J Neurosci. 2012;32(43):15181-92.
Hashimoto, T., Serrano-Pozo, A., Hori, Y., Adams, K. W., Takeda, S., Banerji, A. O., Mitani, A., Joyner, D., Thyssen, D. H., Bacskai, B. J., Frosch, M. P., Spires-Jones, T. L., Finn, M. B., Holtzman, D. M., & Hyman, B. T. (2012). Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 32(43), 15181-92. https://doi.org/10.1523/JNEUROSCI.1542-12.2012
Hashimoto T, et al. Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid Β Peptide. J Neurosci. 2012 Oct 24;32(43):15181-92. PubMed PMID: 23100439.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid β peptide. AU - Hashimoto,Tadafumi, AU - Serrano-Pozo,Alberto, AU - Hori,Yukiko, AU - Adams,Kenneth W, AU - Takeda,Shuko, AU - Banerji,Adrian Olaf, AU - Mitani,Akinori, AU - Joyner,Daniel, AU - Thyssen,Diana H, AU - Bacskai,Brian J, AU - Frosch,Matthew P, AU - Spires-Jones,Tara L, AU - Finn,Mary Beth, AU - Holtzman,David M, AU - Hyman,Bradley T, PY - 2012/10/27/entrez PY - 2012/10/27/pubmed PY - 2013/1/8/medline SP - 15181 EP - 92 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J. Neurosci. VL - 32 IS - 43 N2 - Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid β peptide (Aβ) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component. The apolipoprotein E ε 4 (apoE ε4) allele is known to be a genetic risk factor for developing AD. However, it is still unknown how apoE impacts the process of Aβ oligomerization. Here, we found that the level of Aβ oligomers in APOE ε4/ε4 AD patient brains is 2.7 times higher than those in APOE ε3/ε3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of Aβ oligomers. To test this hypothesis, we examined the effect of apoE on Aβ oligomer formation. Using both synthetic Aβ and a split-luciferase method for monitoring Aβ oligomers, we observed that apoE increased the level of Aβ oligomers in an isoform-dependent manner (E2 < E3 < E4). This effect appears to be dependent on the ApoE C-terminal domain. Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of Aβ oligomers. Together, these data show that lipidated apoE, especially apoE4, increases Aβ oligomers in the brain. Higher levels of Aβ oligomers in the brains of APOE ε4/ε4 carriers compared with APOE ε3/ε3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/23100439/Apolipoprotein_E_especially_apolipoprotein_E4_increases_the_oligomerization_of_amyloid_β_peptide_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&amp;pmid=23100439 DB - PRIME DP - Unbound Medicine ER -