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.

Differential molecular chaperone response associated with various mouse adapted scrapie strains

“…Recent evidence indicate that PrP misfolding in cellular models relevant to both infectious and hereditary prionoses affect ER Ca 2+ homeostasis and sensitize cells to endoplasmic reticulum stress [27]. Impaired intraneuronal Ca 2+ homeostasis, including increased ER Ca 2+ store levels is also a hallmark of AD pathogenesis and akin to our findings in APPPS1-21 mice upregulation of Grp78 was also described in two months old 3×Tg-AD tg mice in association with intraneuronal presence of Aβ aggregates [22]. Grp58 is a disulfide isomerase, which was shown to bind PrP Sc and prevent apoptosis through inhibiting caspase-12 activation [13].…”

Conformation-specific antibodies to target amyloid β oligomers and their application to immunotherapy for Alzheimer’s disease

“…Ohyagi and colleagues showed that intraneuronal staining by 11A1 was more closely related to the onset of memory impairment in 3xTg-AD mice than that by 4G8. 120 is thus a unique antibody that preferably recognizes intracellular amyloid in the human brain along with senile plaques. These findings highlight that the toxic conformer of Aβ42 could accumulate within neurons at the early stage during AD progression.…”

Mitochondrial Movement and Number Deficits in Embryonic Cortical Neurons from 3xTg-AD Mice

“…The potential mechanisms of action of (+)SKF-10,047 on increasing mitochondrial movement should be evaluated, including effects on mitochondrial ATP production and interaction with mitochondrial motor proteins. The relationship of reduced mitochondrial number and movement to ER stress should also be examined, as ER stress markers are increased in 3xTg-AD mice as early as 2 months of age [40]. σ 1 R attenuate ER stress [41] and could potentially exert their mitochondrial effects through this pathway.…”