한빛사 논문
Nathan Kline Institute for Psychiatric Research/NYU Langone Medical Center
Ju-Hyun Lee 1,2,*, Dun-Sheng Yang 1,2, Chris N. Goulbourne1, Eunju Im 1,2, Philip Stavrides1, Anna Pensalfini1, Han Chan3, Cedric Bouchet-Marquis3, Cynthia Bleiwas1, Martin J. Berg1, Chunfeng Huo1, James Peddy1, Monika Pawlik 1, Efrat Levy 1,2,4,5, Mala Rao1,2, Mathias Staufenbiel6 and Ralph A. Nixon 1,2,5,7,*
1Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, NY, USA. 2Department of Psychiatry, New York University Langone Health, New York, NY, USA. 3Thermo Fisher Scientific, Hillsboro, OR, USA. 4Departments of Biochemistry & Molecular Pharmacology, New York University Langone Health, New York, NY, USA. 5NYU Neuroscience Institute, New York University Langone Health, New York, NY, USA. 6Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. 7Department of Cell Biology, New York University Langone Health, New York, NY, USA.
*Corresponding author.
Abstract
Autophagy is markedly impaired in Alzheimer’s disease (AD). Here we reveal unique autophagy dysregulation within neurons in five AD mouse models in vivo and identify its basis using a neuron-specific transgenic mRFP-eGFP-LC3 probe of autophagy and pH, multiplex confocal imaging and correlative light electron microscopy. Autolysosome acidification declines in neurons well before extracellular amyloid deposition, associated with markedly lowered vATPase activity and build-up of Aβ/APP-βCTF selectively within enlarged de-acidified autolysosomes. In more compromised yet still intact neurons, profuse Aβ-positive autophagic vacuoles (AVs) pack into large membrane blebs forming flower-like perikaryal rosettes. This unique pattern, termed PANTHOS (poisonous anthos (flower)), is also present in AD brains. Additional AVs coalesce into peri-nuclear networks of membrane tubules where fibrillar β-amyloid accumulates intraluminally. Lysosomal membrane permeabilization, cathepsin release and lysosomal cell death ensue, accompanied by microglial invasion. Quantitative analyses confirm that individual neurons exhibiting PANTHOS are the principal source of senile plaques in amyloid precursor protein AD models.
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