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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

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Abstract

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 APPE693Q (Dutch) mutation have intraneuronal lysosomal accumulation of APP carboxylterminal 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 of 12-months-old APPE693Q as compared with 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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Acknowledgements

National Institutes of Health, Alzheimer’s association.

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Authors and Affiliations

  1. Center of Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA

    G Kaur, M Pawlik, J F Smiley & E Levy

  2. Departments of Neurology and Psychiatry, and Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    S E Gandy

  3. James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA

    S E Gandy

  4. Departments of Neurology and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    M E Ehrlich

  5. Department of Psychiatry, NYU Langone Medical Center, New York, NY, USA

    J F Smiley & E Levy

  6. Department of Biochemistry and Molecular Pharmacology, NYU Langone Medical Center, New York, NY, USA

    E Levy

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  1. G Kaur
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Kaur, G., Pawlik, M., Gandy, S. et al. Lysosomal dysfunction in the brain of a mouse model with intraneuronal accumulation of carboxyl terminal fragments of the amyloid precursor protein. Mol Psychiatry 22, 981–989 (2017). https://doi.org/10.1038/mp.2016.189

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