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The secreted APP ectodomain sAPP?, but not sAPP?, protects neurons against A? oligomer-induced dendritic spine loss and increased tau phosphorylation.

ABSTRACT: AIM:The amyloid precursor protein (APP) is endoproteolytically processed to generate either the neurotoxic beta-amyloid peptide (A?) or the secreted ectodomain APP alpha (sAPP?). While neurotrophic properties of sAPP? were suggested in several studies, it is still unclear if and how sAPP? counteracts pathogenic effects of A?. Direct comparisons with sAPP?, produced in the A?-generating pathway, are missing in order to determine the role of sAPP?'s carbonyl-terminal end in its possible neuroprotective activity. METHODS:Mouse neuronal primary cultures and hippocampal slices were treated with oligomeric A?42. The effects on tau phosphorylation and dendritic spine densities were assessed by western blot and confocal imaging, respectively. Co-administration of either sAPP? or sAPP? was used to determine activity on A?-induced toxicity. RESULTS/DISCUSSION:We found that oligomeric A? strongly increased AT8 and AT180 phosphorylation of tau and caused a loss of dendritic spines. SAPP? completely abolished A? effects whereas sAPP? had no such rescue activity. Interestingly, sAPP? or sAPP? alone neither affected tau phosphorylation nor dendritic spine numbers. Together, our data suggest that sAPP? specifically protects neurons against A?-dependent toxicity supporting the strategy of activating ?-secretase-dependent endoproteolytic APP processing to increase sAPP? shedding from the neuronal plasma membrane as a therapeutic intervention for the protection of dendritic spines and phospho-tau-dependent toxicity in Alzheimer's disease.

SUBMITTER: Tackenberg C

PROVIDER: S-EPMC6440141 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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The secreted APP ectodomain sAPPα, but not sAPPβ, protects neurons against Aβ oligomer-induced dendritic spine loss and increased tau phosphorylation.

Tackenberg Christian C Nitsch Roger M RM

Molecular brain 20190329 1

<h4>Aim</h4>The amyloid precursor protein (APP) is endoproteolytically processed to generate either the neurotoxic beta-amyloid peptide (Aβ) or the secreted ectodomain APP alpha (sAPPα). While neurotrophic properties of sAPPα were suggested in several studies, it is still unclear if and how sAPPα counteracts pathogenic effects of Aβ. Direct comparisons with sAPPβ, produced in the Aβ-generating pathway, are missing in order to determine the role of sAPPα's carbonyl-terminal end in its possible ne ...[more]

PMID: 30922360

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Project description:BackgroundAlzheimer's disease (AD) is characterized by progressive cognitive decline due to accumulating synaptic insults by toxic oligomers of amyloid beta (AβO) and tau (TauO). There is growing consensus that preventing these oligomers from interacting with synapses might be an effective approach to treat AD. However, recent clinical trial failures suggest low effectiveness of targeting Aβ in late-stage AD. Researchers have redirected their attention toward TauO as the levels of this species increase later in disease pathogenesis. Here we show that AβO and TauO differentially target synapses and affect each other's binding dynamics.MethodsBinding of labeled, pre-formed Aβ and tau oligomers onto synaptosomes isolated from the hippocampus and frontal cortex of mouse and postmortem cognitively intact elderly human brains was evaluated using flow-cytometry and western blot analyses. Binding of labeled, pre-formed Aβ and tau oligomers onto mouse primary neurons was assessed using immunofluorescence assay. The synaptic dysfunction was measured by fluorescence analysis of single-synapse long-term potentiation (FASS-LTP) assay.ResultsWe demonstrated that higher TauO concentrations effectively outcompete AβO and become the prevailing synaptic-associated species. Conversely, high concentrations of AβO facilitate synaptic TauO recruitment. Immunofluorescence analyses of mouse primary cortical neurons confirmed differential synaptic binding dynamics of AβO and TauO. Moreover, in vivo experiments using old 3xTgAD mice ICV injected with either AβO or TauO fully supported these findings. Consistent with these observations, FASS-LTP analyses demonstrated that TauO-induced suppression of chemical LTP was exacerbated by AβO. Finally, predigestion with proteinase K abolished the ability of TauO to compete off AβO without affecting the ability of high AβO levels to increase synaptic TauO recruitment. Thus, unlike AβO, TauO effects on synaptosomes are hampered by the absence of protein substrate in the membrane.ConclusionsThese results introduce the concept that TauO become the main synaptotoxic species at late AD, thus supporting the hypothesis that TauO may be the most effective therapeutic target for clinically manifest AD.

Dataset Information

The secreted APP ectodomain sAPP?, but not sAPP?, protects neurons against A? oligomer-induced dendritic spine loss and increased tau phosphorylation.

Publications

The secreted APP ectodomain sAPPα, but not sAPPβ, protects neurons against Aβ oligomer-induced dendritic spine loss and increased tau phosphorylation.

Similar Datasets

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