P3-134: Intraneuronal amyloid-beta oligomers cause cell death via endoplasmic reticulum stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo
Abstract
Intraneuronal accumulation of Abeta is an early event in Alzheimer's disease (AD). We previously identified the E693Delta mutation (“Osaka” mutation) in amyloid precursor protein (APP) from familial AD (Tomiyama et al. 2008). This mutation increased Abeta oligomerization, but never showed Abeta fibrillization. In transgenic (Tg) mice expressing APPE693Delta (APPOSK) (Tomiyama et al. 2010), Abeta oligomers accumulated in neurons, then synapse loss and neuronal loss occured; however, they showed no extracellular amyloid deposition. These suggest that intracellular Abeta oligomers play a crucial role, not only in synaptic pathology, but also in neuronal death in AD. We investigated this mechanism. To study the sub cellular localization of Abeta oligomers, brain sections of APPOSK-Tg mice were double stained with Abeta oligomer selective antibody NU-1 (Lambert et al. 2007) and antibodies to organelle markers including calnexin for ER, LAMP1 for endosomes/lysosomes, and Tom20 for mitochondria. The toxicity of intracellular Abeta oligomers was evaluated in both transfected COS-7 cells and APPOSK-Tg mouse brains. By immunohistochemistry and western blotting, we examined the up regulation of the molecular chaperon Grp78 and the E3 ubiquitin ligase HRD1 to detect ER stress, the leakage of cathepsin D into cytoplasm to measure endosomal/lysosomal damage, the release of cytochrome c from mitochondria to prove mitochondrial injury, and the activation of capase-3 to determine the occurrence of apoptosis. These damage were also examined by Lucifer yellow, JC-1, and Annexin V staining, respectively, in transfected COS-7 cells. We found Abeta oligomer accumulation in the ER, endosomes/lysosomes, and mitochondria in hippocampal neurons of APPOSK-Tg mice. We also detected up regulation of Grp78 and HRD1, leakage of cathepsin D from endosomes/lysosomes into cytoplasm, cytochrome c release from mitochondria, and activation of caspase-3 by the immunohistchemistry of the hippocampi of APPOSK-Tg mice. These findings were consistent in the results of in vitro experiments. Intraneuronal Abeta oligomers localized into the ER, endosomes/lysosomes, and mitochondria in the brain of APPOSK-Tg mice. Then, this intraorganelle accumulation of Abeta oligomers leads to apoptotic pathway via damage of these organelles, in vitro and in vivo. Our findings suggest the possible mechanisms by which intraneuronal Abeta oligomers cause cell death in AD brains.
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In 22-month-old APPE693Δ mice, Aβ oligomers localize to ER, endosomes/lysosomes, and mitochondria, suggesting intraneuronal Aβ peptides cause cell death via ER stress, endosomal/lysosomal leakage, and mitochondrial dysfunction.
“More thorough analyses in 22-month-old mice located the Aβ oligomers to endoplasmic reticulum (ER), endosomes/lysosomes, and mitochondria, suggesting that intraneuronal Aβ peptides cause cell death via an induction of ER stress, endosomal/lysosomal leakage, and mitochondrial dysfunction [90].”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [90]
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- Authors
- Umeda, T., Tomiyama, T., Sakama, N., Tanaka, S., Lambert, M., Klein, W., & Mori, H.
- Affiliations
- Osaka City University (JP)
- Yamaguchi University (JP)
- Northwestern University (US)
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2011-07
- Volume
- 7
- Issue
- 4S_Part_16
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- OpenAlex
- W1975897546
- Cited by
- 41
- References
- 0
- Citations by year
- 2020: 1 · 2017: 2 · 2016: 3 · 2015: 8 · 2014: 9 · 2013: 9 · 2012: 7
- FWCI
- 5.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Alzheimer s & Dementia (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
- Keywords
- amyloid-beta oligomers
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