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 - 2012/10/24
Y1 - 2012/10/24
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 ε4 (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/ ε4AD 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 monitoringAβ 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.
AB - 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 ε4 (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/ ε4AD 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 monitoringAβ 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.
UR - http://www.scopus.com/inward/record.url?scp=84867797446&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1542-12.2012
DO - 10.1523/JNEUROSCI.1542-12.2012
M3 - Article
C2 - 23100439
AN - SCOPUS:84867797446
SN - 0270-6474
VL - 32
SP - 15181
EP - 15192
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 43
ER -