Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques

Interrogation of neuronal autophagy in vivo in Alzheimer & apos;s disease mouse models identified deficient autolysosome acidification as the basis for extreme autophagic stress, yielding beta-amyloid accumulation within intact neurons, which are the main source of senile plaques. 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 A beta/APP-beta CTF selectively within enlarged de-acidified autolysosomes. In more compromised yet still intact neurons, profuse A beta-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.

Automated summary

This study reveals unique autophagy dysregulation within neurons in Alzheimer's disease mouse models, particularly deficient autolysosome acidification, leading to the accumulation of autophagic vacuoles and the formation of flower-like structures called "PANTHOS," which may contribute to the development of senile plaques in Alzheimer's disease.