A Mouse Model of Amyloid β Oligomers: Their Contribution to Synaptic Alteration, Abnormal Tau Phosphorylation, Glial Activation, and Neuronal Loss<i>In Vivo</i>

Tomiyama, Takami; Matsuyama, Shogo; Iso, Hiroyuki; Umeda, Tomohiro; Takuma, Hiroshi; Ohnishi, Kiyouhisa; Ishibashi, Keiichiro; Teraoka, Rie; Sakama, Naomi; Yamashita, Takenari; Nishitsuji, Kazuchika; Ito, Kenyu; Shimada, Hiroyuki; Lambert, Mary P.; Klein, William L.; Mori, Hiroshi

doi:10.1523/jneurosci.5825-09.2010

Cited by 353 publications

(392 citation statements)

References 51 publications

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“…6B). Importantly, these same pathways involving phospho-tau and caspase-3 previously were shown to be involved in oligomeric Aβ-induced abnormal excitability and synaptic spine loss (10,11,14,(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56). For example, the relatively specific inhibitor of caspase-3 activity, z-DEVD-fmk, blocks a pathway leading to dendritic spine shrinkage via activation of calcineurin, which results in dephosphorylation and internalization of synaptic AMPARs (56).…”

Section: Extrasynaptic Nmdars Mediate Aβ-induced Molecular Cascadesmentioning

confidence: 85%

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Talantova

Sanz-Blasco

Zhang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

502

524

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Significance Communication between nerve cells occurs at specialized cellular structures known as synapses. Loss of synaptic function is associated with cognitive decline in Alzheimer’s disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here we describe a pathway for synaptic damage whereby amyloid-β 1–42 peptide (Aβ 1–42 ) releases, via stimulation of α7 nicotinic receptors, excessive amounts of glutamate from astrocytes, in turn activating extrasynaptic NMDA-type glutamate receptors (eNMDARs) to mediate synaptic damage. The Food and Drug Administration-approved drug memantine offers some beneficial effect, but the improved eNMDAR antagonist NitroMemantine completely ameliorates Aβ-induced synaptic loss, providing hope for disease-modifying intervention in AD.

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Section: Extrasynaptic Nmdars Mediate Aβ-induced Molecular Cascadesmentioning

confidence: 85%

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Talantova

Sanz-Blasco

Zhang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

502

524

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“…Neuronal loss and atrophy are one of the hallmarks of and cause of memory deficits in AD in humans. 23,24 Recent studies showed that Ab-binding heat-shock proteins, which prevent Ab aggregation and oligomerization, inhibit Ab-induced neuronal death. 19,25 To elucidate the effect of DBP on the cytotoxicity of Ab, we examined whether DBP influences Ab-mediated neuronal death using the MTT assay, MTS assay, and DAPI staining.…”

Section: Resultsmentioning

confidence: 99%

Vitamin D-binding protein interacts with Aβ and suppresses Aβ-mediated pathology

et al. 2012

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The level of vitamin D-binding protein (DBP) is increased in the cerebrospinal fluid of patients with Alzheimer's disease (AD), suggesting a relationship with its pathogenesis. In this study, we investigated whether and how DBP is related to AD using several different approaches. A pull-down assay and a surface plasmon resonance binding assay indicated direct interactions between purified DBP and amyloid beta (Ab), which was confirmed in the brain of AD patients and transgenic AD model mice by immunoprecipitation assay and immunohistochemical double-staining method. Moreover, atomic force microscopic examination revealed that DBP reduced Ab aggregation in vitro. DBP also prevented Ab-mediated death in cultured mouse hippocampal HT22 cell line. Finally, DBP decreased Ab-induced synaptic loss in the hippocampus and rescued memory deficits in mice after injection of Ab into the lateral ventricle. These results provide converging evidence that DBP attenuates the harmful effects of Ab by a direct interaction, and suggest that DBP is a promising therapeutic agent for the treatment of AD.

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“…With regard to short-term effects, oligomers have been shown to impair synaptic plasticity by blocking longterm potentiation and reinforcing long-term depression (72). Tomiyama et al (73) generated APP transgenic mice expressing the E693⌬ mutation, which causes neuronal cell death and cognitive impairment by enhanced intracellular A␤ oligomerization without plaque formation.…”

Section: Soluble Oligomeric Pyroglutamate A␤: the Missing Link In A␤mentioning

confidence: 99%

Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease

Jawhar

Wirths

Bayer

2011

Journal of Biological Chemistry

194

225

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Pyroglutamate-modified amyloid-␤ (A␤ pE3 ) peptides are gaining considerable attention as potential key participants in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Transgenic mice that produce high levels of A␤ pE3-42 show severe neuron loss. Recent in vitro and in vivo experiments have proven that the enzyme glutaminyl cyclase catalyzes the formation of A␤ pE3 . In this minireview, we summarize the current knowledge on A␤ pE3 , discussing its discovery, biochemical properties, molecular events determining formation, prevalence in the brains of AD patients, Alzheimer mouse models, and potential as a target for therapy and as a diagnostic marker.When Alois Alzheimer presented the case of his patient Auguste Deter at the Tübingen meeting of the Southwest German Psychiatrists in 1906, he did not attract much attention or stimulate any discussion in the audience. The young doctor likely would not have believed that, 100 years later, the disease that now holds his name would be the most common cause of dementia and a source of a critical medical and economical problem. At this meeting, Alzheimer presented Auguste Deter's symptoms and reported the histopathological features that are now associated with Alzheimer disease (AD) 2 : neuron loss, extracellular amyloid plaques, and intracellular neurofibrillary tangles. For more than 2 decades, the amyloid hypothesis has been the cardinal hypothesis in describing the sequence of AD etiology. The amyloid hypothesis considers amyloid-␤ (A␤) deposition to be the causative event of AD pathology and that neurofibrillary tangles, cell loss, vascular damage, and dementia occur as a consequence of it (1). However, it has been recently suggested that the extracellular formation of A␤ plaques and other AD pathological events are preceded by intraneuronal A␤ accumulation, giving rise to a modified amyloid hypothesis (2).The story of successful discoveries in modern AD research using novel molecular biological tools started with the biochemical analysis of ␤-amyloid-containing blood vessels (congophilic amyloid angiopathy) (3) and amyloid plaques consisting of A␤ (4), which led to the isolation and sequencing of the gene encoding the larger amyloid precursor protein (APP) (5, 6).In vitro and in vivo analyses of amyloid deposits in AD revealed various N-and C-terminal variants (4, 7, 8). Increased C-terminal length of A␤ (from A␤ x-40 to A␤ x-42 ) in AD enhanced aggregation and early deposition and promoted the toxicity of A␤ (9 -11). Recently, A␤ 1-43 has been discussed as a novel toxic peptide in AD (12).Beside A␤ peptides, starting with aspartate as the first amino acid (A␤ 1-x ), several N-terminally truncated and modified A␤ species have been described (4, 13-15). Among A␤ species present in AD plaques, Lewis et al. (16) reported that A␤ 4 -42 is a relatively abundant species in AD, aged control, and vascular dementia patients. Using immunoprecipitation in combination with mass spectrome...

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A Mouse Model of Amyloid β Oligomers: Their Contribution to Synaptic Alteration, Abnormal Tau Phosphorylation, Glial Activation, and Neuronal LossIn Vivo

Cited by 353 publications

References 51 publications

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss

Vitamin D-binding protein interacts with Aβ and suppresses Aβ-mediated pathology

Pyroglutamate Amyloid-β (Aβ): A Hatchet Man in Alzheimer Disease

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