Blocking the interaction between apolipoprotein E and A? reduces intraneuronal accumulation of A? and inhibits synaptic degeneration

Kuszczyk, Magdalena A., Sanchez, Sandrine, Pankiewicz, Joanna, Kim, Jungsu, Duszczyk, Malgorzata, Guridi, Maitea, Asuni, Ayodeji A., Sullivan, Patrick M., Holtzman, David M. and Sadowski, Martin J. (2013) Blocking the interaction between apolipoprotein E and A? reduces intraneuronal accumulation of A? and inhibits synaptic degeneration. The American Journal of Pathology. (doi:10.1016/j.ajpath.2013.01.034). (PMID:23499462)

Abstract

Accumulation of ?-amyloid (A?) 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 A? and has been implicated in the receptor-mediated A? uptake by neurons. To characterize apoE involvement in the intraneuronal A? accumulation and to investigate whether blocking the apoE/A? interaction could reduce intraneuronal A? buildup, we used a noncontact neuronal-astrocytic co-culture system, where synthetic A? peptides were added into the media without or with cotreatment with A?12-28P, which is a nontoxic peptide antagonist of apoE/A? binding. Compared with neurons cultured alone, intraneuronal A? 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 A?, increased level of intraneuronal A? oligomers, and marked down-regulation of several synaptic proteins. A?12-28P treatment significantly reduced intraneuronal A? accumulation, including A? oligomer level, and inhibited loss of synaptic proteins. Furthermore, we showed significantly reduced intraneuronal A? 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 A? accumulation and provide evidence that apoE/A? binding antagonists can effectively prevent this process.

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