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

Abstract

Amyloid-β protein (Aβ) accumulates in the neurons of Alzheimer's disease (AD) patients at an early stage of the disease. Recently, we found that Aβ with a toxic turn at positions 22 and 23 accumulates in neurons in AD brain. Here, we studied the accumulation of Aβ, toxic turn Aβ and high-molecular-weight Aβ 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 Aβ was promoted in G384A- and I143T-mutant PS1-transfected cells and further enhanced by co-transfection of cells with the Aβ-precursor protein (AβPP) gene. In contrast, accumulation of high-molecular-weight Aβ oligomers was promoted in mutant PS1 cells but attenuated by co-transfection of cells with the AβPP gene. Toxic turn Aβ was detected in the neurons of 3xTg-AD mice aged 2 months, when the mice were cognitively unimpaired. In contrast, high-molecular-weight Aβ 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 Aβ and GRP78, an endoplasmic reticulum (ER) stress marker. Intraneuronal accumulation of toxic turn Aβ may be associated with ER stress in the brains of AD model mice and AD patients at an early stage.

• Authors: Naoko Soejima, Yasumasa Ohyagi, Norimichi Nakamura, Eri Himeno, Kyoko M Iinuma, Nobutaka Sakae, Ryo Yamasaki, Takeshi Tabira, Kazuma Murakami, Kazuhiro Irie, Noriaki Kinoshita, Frank M LaFerla, Yutaka Kiyohara, Toru Iwaki, Jun-ichi Kira
• Journal: Current Alzheimer research (Curr Alzheimer Res) Vol. 10 Issue 1 Pg. 11-20 (Jan 2013) ISSN: 1875-5828 [Electronic] United Arab Emirates
• PMID: 22950910 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Endoplasmic Reticulum Chaperone BiP
• HSPA5 protein, human
• Hspa5 protein, mouse
• PSEN1 protein, human
• Presenilin-1
• tau Proteins
• GTP-Binding Proteins

Topics

• Alzheimer Disease (metabolism, pathology, physiopathology)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics)
• Animals
• Brain (metabolism)
• Cells, Cultured
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (physiology)
• GTP-Binding Proteins (genetics, metabolism)
• Humans
• Intracellular Fluid (metabolism)
• Mice
• Mice, Transgenic
• Presenilin-1 (genetics)
• Transfection
• tau Proteins (genetics)