Intracellular accumulation of toxic turn amyloid-ß is associated with endoplasmic reticulum stress in Alzheimer's disease.

Soejima, Naoko; Ohyagi, Yasumasa; Nakamura, Norimichi; Himeno, Eri; Iinuma, Kyoko M; Sakae, Nobutaka; Yamasaki, Ryo; Tabira, Takeshi; Murakami, Kazuma; Irie, Kazuhiro; Kinoshita, Noriaki; LaFerla, Frank M; Kiyohara, Yutaka; Iwaki, Toru; Kira, Jun-ichi

Soejima, Naoko; Ohyagi, Yasumasa; Nakamura, Norimichi; Himeno, Eri; Iinuma, Kyoko M; Sakae, Nobutaka; Yamasaki, Ryo; Tabira, Takeshi; Murakami, Kazuma; Irie, Kazuhiro; Kinoshita, Noriaki; LaFerla, Frank M; Kiyohara, Yutaka; Iwaki, Toru; Kira, Jun-ichi.

Afiliación

Soejima N; Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.

Curr Alzheimer Res ; 10(1): 11-20, 2013 Jan.

Article en En | MEDLINE | ID: mdl-22950910

RESUMEN

Amyloid-ß protein (Aß) accumulates in the neurons of Alzheimer's disease (AD) patients at an early stage of the disease. Recently, we found that Aß with a toxic turn at positions 22 and 23 accumulates in neurons in AD brain. Here, we studied the accumulation of Aß, toxic turn Aß and high-molecular-weight Aß oligomers in presenilin 1 (PS1) gene-transfected SH-SY5Y cells as well as in the brains of 3xTg-AD mice and AD patients. Immunostaining revealed that accumulation of toxic turn Aß was promoted in G384A- and I143T-mutant PS1-transfected cells and further enhanced by co-transfection of cells with the Aß-precursor protein (AßPP) gene. In contrast, accumulation of high-molecular-weight Aß oligomers was promoted in mutant PS1 cells but attenuated by co-transfection of cells with the AßPP gene. Toxic turn Aß was detected in the neurons of 3xTg-AD mice aged 2 months, when the mice were cognitively unimpaired. In contrast, high-molecular-weight Aß oligomers were detected in the neurons of 7-month-old mice, when memory dysfunction is apparent. Furthermore, immunostaining and western blotting for Rab4, Rab6 and GRP78 revealed increased levels of these proteins in mutant PS1 cells and their accumulation in the neurons of 3xTg-AD mice. Remarkably, GRP78 immunoreactivity was increased at 2 months of age. Double-label immunostaining of AD brain revealed an apparent association between toxic turn Aß and GRP78, an endoplasmic reticulum (ER) stress marker. Intraneuronal accumulation of toxic turn Aß may be associated with ER stress in the brains of AD model mice and AD patients at an early stage.

Asunto(s)

Enfermedad de Alzheimer; Péptidos beta-Amiloides/metabolismo; Encéfalo/metabolismo; Estrés del Retículo Endoplásmico/fisiología; Líquido Intracelular/metabolismo; Enfermedad de Alzheimer/metabolismo; Enfermedad de Alzheimer/patología; Enfermedad de Alzheimer/fisiopatología; Precursor de Proteína beta-Amiloide/genética; Animales; Células Cultivadas; Chaperón BiP del Retículo Endoplásmico; Proteínas de Unión al GTP/genética; Proteínas de Unión al GTP/metabolismo; Humanos; Ratones; Ratones Transgénicos; Presenilina-1/genética; Transfección; Proteínas tau/genética

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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Encéfalo / Péptidos beta-Amiloides / Enfermedad de Alzheimer / Estrés del Retículo Endoplásmico / Líquido Intracelular Tipo de estudio: Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Curr Alzheimer Res Asunto de la revista: NEUROLOGIA Año: 2013 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Emiratos Árabes Unidos

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