| First Author | Kuszczyk MA | Year | 2013 |
| Journal | Am J Pathol | Volume | 182 |
| Issue | 5 | Pages | 1750-68 |
| PubMed ID | 23499462 | Mgi Jnum | J:195341 |
| Mgi Id | MGI:5478649 | Doi | 10.1016/j.ajpath.2013.01.034 |
| Citation | Kuszczyk MA, et al. (2013) Blocking the Interaction between Apolipoprotein E and Abeta Reduces Intraneuronal Accumulation of Abeta and Inhibits Synaptic Degeneration. Am J Pathol 182(5):1750-68 |
| abstractText | Accumulation of beta-amyloid (Abeta) in the brain is a key event in Alzheimer disease pathogenesis. Apolipoprotein (Apo) E is a lipid carrier protein secreted by astrocytes, which shows inherent affinity for Abeta and has been implicated in the receptor-mediated Abeta uptake by neurons. To characterize ApoE involvement in the intraneuronal Abeta accumulation and to investigate whether blocking the ApoE/Abeta interaction could reduce intraneuronal Abeta buildup, we used a noncontact neuronal-astrocytic co-culture system, where synthetic Abeta peptides were added into the media without or with cotreatment with Abeta12-28P, which is a nontoxic peptide antagonist of ApoE/Abeta binding. Compared with neurons cultured alone, intraneuronal Abeta content was significantly increased in neurons co-cultured with wild-type but not with ApoE knockout (KO) astrocytes. Neurons co-cultured with astrocytes also showed impaired intraneuronal degradation of Abeta, increased level of intraneuronal Abeta oligomers, and marked down-regulation of several synaptic proteins. Abeta12-28P treatment significantly reduced intraneuronal Abeta accumulation, including Abeta oligomer level, and inhibited loss of synaptic proteins. Furthermore, we showed significantly reduced intraneuronal Abeta accumulation in APPSW/PS1dE9/ApoE KO mice compared with APPSW/PS1dE9/ApoE targeted replacement mice that expressed various human ApoE isoforms. Data from our co-culture and in vivo experiments indicate an essential role of ApoE in the mechanism of intraneuronal Abeta accumulation and provide evidence that ApoE/Abeta binding antagonists can effectively prevent this process. |
