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

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.

SUBMITTER: Kuszczyk MA 

PROVIDER: S-EPMC3644726 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature