| First Author | Lee JH | Year | 2022 |
| Journal | Nat Neurosci | Volume | 25 |
| Issue | 6 | Pages | 688-701 |
| PubMed ID | 35654956 | Mgi Jnum | J:335649 |
| Mgi Id | MGI:7482084 | Doi | 10.1038/s41593-022-01084-8 |
| Citation | Lee JH, et al. (2022) Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Abeta in neurons, yielding senile plaques. Nat Neurosci 25(6):688-701 |
| abstractText | 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 Abeta/APP-betaCTF selectively within enlarged de-acidified autolysosomes. In more compromised yet still intact neurons, profuse Abeta-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 beta-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. |
