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Lysosomal dysfunction in the brain of a mouse model with intraneuronal accumulation of carboxyl terminal fragments of the amyloid precursor protein
Recent data suggest that intraneuronal accumulation of metabolites of the amyloid β precursor protein (APP) is neurotoxic. We observed that transgenic mice overexpressing in neurons a human APP gene harboring the APP(E693Q) (Dutch) mutation have intraneuronal lysosomal accumulation of APP carboxyl-t...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405008/ https://www.ncbi.nlm.nih.gov/pubmed/27777419 http://dx.doi.org/10.1038/mp.2016.189 |
Sumario: | Recent data suggest that intraneuronal accumulation of metabolites of the amyloid β precursor protein (APP) is neurotoxic. We observed that transgenic mice overexpressing in neurons a human APP gene harboring the APP(E693Q) (Dutch) mutation have intraneuronal lysosomal accumulation of APP carboxyl-terminal fragments (APP-CTFs) and oligomeric amyloid β (oAβ) but no histological evidence of amyloid deposition. Morphometric quantification using the lysosomal marker protein 2 (LAMP-2) immunolabeling showed higher neuronal lysosomal counts in brain neurons of 12 months old APP(E693Q) as compared to age-matched non-transgenic littermates, and Western blots showed increased lysosomal proteins including LAMP-2, cathepsin D and LC3. At 24 months of age, these mice also exhibited an accumulation of α-synuclein in the brain, along with increased conversion of LC3-I to LC3-II, an autophagosomal/autolysosomal marker. In addition to lysosomal changes at 12 months of age, these mice developed cholinergic neuronal loss in the basal forebrain, GABAergic neuronal loss in the cortex, hippocampus and basal forebrain, and gliosis and microgliosis in the hippocampus. These findings suggest a role for the intraneuronal accumulation of oAβ and APP-CTFs and resultant lysosomal pathology at early stages of Alzheimer’s disease-related pathology. |
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