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

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.

Modeling the Competition between Misfolded Aβ Conformers That Produce Distinct Types of Amyloid Pathology in Alzheimer’s Disease

“…A recent study suggests that cored deposits may originate from Aβ aggregates that initially form within endosomal/lysosomal compartments [ 42 ]. It is not known whether diffuse deposits could also originate in intracellular compartments.…”

In-Depth Characterization of Endo-Lysosomal Aβ in Intact Neurons

“…Aβ peptides are generated from the sequential cleavage of APP by β- and γ-secretases within vesicles inside cells and on the plasma membrane, and are normally secreted under physiological conditions [ 42 ]. On the other hand, there is evidence showing the presence of intracellular Aβ, particularly in mouse models of amyloidosis [ 24 , 25 , 26 , 27 , 28 , 29 ], suggesting that some Aβ is retained inside the neurons. However, the detailed properties of intracellular Aβ are not fully established.…”

“…In transgenic rodents designed to develop amyloidosis, large amounts of early intraneuronal Aβ were observed prior to the formation of plaques, which could be linked to deficits in synaptic plasticity, learning, and memory [ 27 , 28 ]. A recent study has added a new significant insight that the deficit in the autolysosome acidification, accompanied by the accumulation of C99 and Aβ peptides, is an early event in neurons, and such neurons could be the principal sources of neuritic plaques in amyloidosis models [ 29 ].…”

Tea Polyphenols as Prospective Natural Attenuators of Brain Aging

“…Previous studies have attributed the neuronal damage observed in AD to what happens following the accumulation of β-amyloid (Aβ) outside the cell, rather than before it and inside the neuron. Recent studies have found that the neuronal damage observed in AD may be attributed to the lower activity of lysosomal acidic enzymes in brain cells; before plaques are formed outside the cells, the nerve cells are paralyzed [ 21 ].…”