Blocking the interaction between apolipoprotein e and Aβ reduces intraneuronal accumulation of Aβ and inhibits synaptic degeneration

Magdalena A. Kuszczyk, Sandrine Sanchez, Joanna Pankiewicz, Jungsu Kim, Malgorzata Duszczyk, Maitea Guridi, Ayodeji A. Asuni, Patrick M. Sullivan, David M. Holtzman, Martin J. Sadowski

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Abstract

Accumulation of β-amyloid (Aβ) 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 Aβ and has been implicated in the receptor-mediated Aβ uptake by neurons. To characterize ApoE involvement in the intraneuronal Aβ accumulation and to investigate whether blocking the ApoE/Aβ interaction could reduce intraneuronal Aβ buildup, we used a noncontact neuronal-astrocytic co-culture system, where synthetic Aβ peptides were added into the media without or with cotreatment with Aβ12-28P, which is a nontoxic peptide antagonist of ApoE/Aβ binding. Compared with neurons cultured alone, intraneuronal Aβ 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 Aβ, increased level of intraneuronal Aβ oligomers, and marked down-regulation of several synaptic proteins. Aβ12-28P treatment significantly reduced intraneuronal Aβ accumulation, including Aβ oligomer level, and inhibited loss of synaptic proteins. Furthermore, we showed significantly reduced intraneuronal Aβ accumulation in APPSW/PS1 dE9/ApoE KO mice compared with APPSW/PS1 dE9/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 Aβ accumulation and provide evidence that ApoE/Aβ binding antagonists can effectively prevent this process.

Original languageEnglish (US)
Pages (from-to)1750-1768
Number of pages19
JournalAmerican Journal of Pathology
Volume182
Issue number5
DOIs
StatePublished - May 1 2013

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Kuszczyk, M. A., Sanchez, S., Pankiewicz, J., Kim, J., Duszczyk, M., Guridi, M., Asuni, A. A., Sullivan, P. M., Holtzman, D. M., & Sadowski, M. J. (2013). Blocking the interaction between apolipoprotein e and Aβ reduces intraneuronal accumulation of Aβ and inhibits synaptic degeneration. American Journal of Pathology, 182(5), 1750-1768. https://doi.org/10.1016/j.ajpath.2013.01.034