Ultrastructural Abnormalities in APP/PSEN1 Transgenic Mouse Brain as the Alzheimer’s Disease Model
2
조회
0
다운로드
3
인용
0
참고문헌
키워드
초록
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Neuropathological hallmarks of AD are amyloid plaques, dystrophic neurite, and alteration of subcellular organelles. However, the morpho-functional study of this degenerative process and ultimate neuronal death remains poorly elucidated. In this study, immunohistochemical and ultrastructural analyses were performed to clarify the abnormal morphological alterations caused by the progression of AD in APP/PSEN1 transgenic mice, express human amyloid precursor protein, as a model for AD. In transgenic AD mice brain, the accumulation of Amyloid β plaques and well-developed dystrophic neurites containing anti-LC3 antibody-positive autophagosomes were detected in the hippocampus and cortex regions. We also found severe disruption of mitochondrial cristae using high-voltage electron microscopy and three-dimensional electron tomography (3D tomography). These results provide morpho-functional evidence on the alteration of subcellular organelles in AD and may help in the investigation of the pathogenesis of AD.
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Neuropathological hallmarks of AD are amyloid plaques, dystrophic neurite, and alteration of subcellular organelles. However, the morpho-functional study of this degenerative process and ultimate neuronal death remains poorly elucidated. In this study, immunohistochemical and ultrastructural analyses were performed to clarify the abnormal morphological alterations caused by the progression of AD in APP/PSEN1 transgenic mice, express human amyloid precursor protein, as a model for AD. In transgenic AD mice brain, the accumulation of Amyloid β plaques and well-developed dystrophic neurites containing anti-LC3 antibody-positive autophagosomes were detected in the hippocampus and cortex regions. We also found severe disruption of mitochondrial cristae using high-voltage electron microscopy and three-dimensional electron tomography (3D tomography). These results provide morpho-functional evidence on the alteration of subcellular organelles in AD and may help in the investigation of the pathogenesis of AD.
참고문헌 (22)
- Almeida C G, "Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses", Neurobiol. Dis, 20, pp.187~198 (2005)
- Baloyannis S J, "Mitochondrial alterations in Alzheimer’s disease", J. Alzheimers. Dis, 9, pp.119~126 (2006)
- Bertoni-Freddari C, "Synaptic structural dynamics and aging", Gerontology, 42, pp.170~180 (1996)
- Chi V, "Immunohistochemistry: paraffi n sections using the Vectastain ABC kit from vector labs", J. Vis. Exp, 8, pp.308~ (2007)
- Geng J, "The Golgi as a potential membrane source for autophagy", Autophagy, 6, pp.950~951 (2010)
- Gylys K H, "Synaptic changes in Alzheimer’s disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD- 95 fl uorescence", Am. J. Pathol, 165, pp.1809~1817 (2004)
- Kabeya Y, "LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing", EMBO. J, 19, pp.5720~5728 (2000)
- Keil U, "Amyloid beta-induced changes in nitric oxide production and mitochondrial activity lead to apoptosis", J. Biol. Chem, 279, pp.50310~50320 (2004)
- Kocherhans S, "Reduced Reelin expression accelerates amyloid-beta plaque formation and tau pathology in transgenic Alzheimer’s disease mice", J. Neurosci, 30, pp.9228~9240 (2010)
- Kremer J R, "Computer visualization of three-dimensional image data using IMOD", J. Struct. Biol, 116, pp.71~76 (1996)
- Manczak M, "Mitochondria are a direct site of A beta accumulation in Alzheimer’s disease neurons: implications for free radical generation and oxidative damage in disease progression", Hum. Mol. Genet, 15, pp.1437~1449 (2006)
- Manczak M, "Mitochondria-targeted antioxidants protect against Abeta toxicity in Alzheimer’s disease neurons", J. Alzheimers. Dis, 20, pp.S609~S631 (2010)
- Nixon R A, "Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study", J. Neuropathol. Exp. Neurol, 64, pp.113~122 (2005)
- Pickford F, "The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice", J. Clin. Invest, 118, pp.2190~2199 (2008)
- Reddy P H, "Amyloid beta, mitochondrial structural and functional dynamics in Alzheimer’s disease", Exp. Neurol, 218, pp.286~292 (2009)
- Reddy P H, "Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease", Trends. Mol. Med, 14, pp.45~53 (2008)
- Kaye J, "Differential loss of synaptic proteins in Alzheimer’s disease: implications for synaptic dysfunction", J. Alzheimers. Dis, 7, pp.103~117 (2005)
- Scheff S W, "Quantitation of synaptic density in the septal nuclei of young and aged Fischer 344 rats", Neurobiol. Aging, 12, pp.3~12 (1991)
- Stieber A, "In Alzheimer’s disease the Golgi apparatus of a population of neurons without neurofi brillary tangles is fragmented and atrophic", Am. J. Pathol, 148, pp.415~426 (1996)
- Takahashi R H, "Oligomerization of Alzheimer’s β-amyloid within processes and synapses of cultured neurons and brain", J. Neurosci, 24, pp.3592~3599 (2004)
- Umeda T, "Intraneuronal amyloid β oligomers cause cell death via endoplasmic reticulum stress, endosomal", lysosomal leakage, and mitochondrial dysfunction in vivo, 2011, pp.89, 1031~1042
- Yu W H, "Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer’s disease", Int. J. Biochem. Cell. Biol, 36, pp.2531~2540 (2004)