Dataset Information

A lifespan observation of a novel mouse model: in vivo evidence supports a? oligomer hypothesis.

ABSTRACT: Transgenic mouse models are powerful tools in exploring the mechanisms of AD. Most current transgenic models of AD mimic the memory impairment and the main pathologic features, among which the formation of beta-amyloid (A?) plaques is considered a dominant pathologic event. Recently, A? oligomers have been identified as more neurotoxic than A? plaques. However, no ideal transgenic mouse model directly support A? oligomers as a neurotoxic species due to the puzzling effects of amyloid plaques in the more widely-used models. Here, we constructed a single-mutant transgenic (Tg) model harboring the PS1V97L mutation and used Non-Tg littermates as a control group. Employing the Morris water maze, electrophysiology, immunohistochemistry, biochemistry, and electron microscopy, we investigated behavioral changes and pathology progression in our single-mutant transgenic model. We discovered the pathological alteration of intraneuronal accumulation of A? oligomers without A? plaques in the PS1V97L-Tg mouse model, which might be the result of PS1 gene mutation. Following A? oligomers, we detected synaptic alteration, tau hyperphosphorylation and glial activation. This model supports an initial role for A? oligomers in the onset of AD and suggests that A? plaques may not be the only prerequisite. This model provides a useful tool for studying the role of A? oligomers in AD pathogenesis.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC3897547 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A lifespan observation of a novel mouse model: in vivo evidence supports aβ oligomer hypothesis.

Zhang Yichi Y Lu Lu L Jia Jianping J Jia Longfei L Geula Changiz C Pei Jinjing J Xu Zhiqing Z Qin Wei W Liu Ruiqin R Li Dan D Pan Na N

PloS one 20140121 1

Transgenic mouse models are powerful tools in exploring the mechanisms of AD. Most current transgenic models of AD mimic the memory impairment and the main pathologic features, among which the formation of beta-amyloid (Aβ) plaques is considered a dominant pathologic event. Recently, Aβ oligomers have been identified as more neurotoxic than Aβ plaques. However, no ideal transgenic mouse model directly support Aβ oligomers as a neurotoxic species due to the puzzling effects of amyloid plaques in ...[more]

PMID: 24465766

Similar Datasets

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

A lifespan observation of a novel mouse model: in vivo evidence supports a? oligomer hypothesis.

Publications

A lifespan observation of a novel mouse model: in vivo evidence supports aβ oligomer hypothesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets