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PANTHOS - a 'toxic flower' as a cause of amyloid plaques in Alzheimer's disease ?

A cell has various mechanisms to get rid of defective proteins and organelles. Often these have exceeded their life span or are no longer in a functional state. Misfolded proteins, for example, are degraded via the UPR (unfolded protein response) or directly via the UPS (ubiquitin-proteasome system). In addition, autophagy, the cellular 'eating of oneself', plays a role in disturbances of protein homeostasis and the degradation of cellular components that are no longer needed (see also chap. 2.1.1 in my book on neurodegeneration).

In autophagy, protein aggregates or cellular organelles are enclosed by membranes and removed by intracellular degradation in the lysosome or by ejection (exocytosis). In neurons, the requirements for autophagy are particularly high because of the often long cellular projections and the resulting very high number of proteins. Autophagy can be additionally stimulated by cell stress. In Alzheimer's disease, autophagosomes containing incompletely digested substrates accumulate in the earliest stages of the disease.

In a recent study published in Nature Neuroscience, Lee and colleagues have now investigated the molecular and cellular basis for defective autophagy in Alzheimer's disease models by specifically fluorescently tagging the autophagy adaptor protein LC3 in mice and only in neurons. These animals were then mated with mice that develop Alzheimer's-like pathology during their lifetime.

As we know, Alzheimer's disease is associated with significant synaptic dysfunction and cognitive decline. The affected brain structures are histologically characterized by neurofibrillary tangles (protein tangles called NFTs) and amyloid plaques composed of deposited β-amyloid peptides (Aβ). The latter are formed by proteolytic processing of the extracellular domain of the amyloid precursor protein, APP. It is now generally accepted that plaques form temporally before tangles but are not specific for the disease, whereas NFTs indicate an advanced stage.

A key finding of the study now presented is that early deficits in lysosomal ATPase activity are seen in all five mouse models of AD examined. This enzyme is necessary for the acidification of autophagy vesicles so that their contents can be degraded at all. However, if the hydrolases, which are only active in the acidic pH range, cannot cleave the contents, an accumulation of APP and Aβ-peptides occurs and this long before extracellular β-amyloid deposits are observed.

The authors also demonstrated an autophagic stress response in damaged neurons associated with an increase in lysosomal vesicles and large membrane-enclosed bubbles. These structures filled with Aβ/APP and with APP cleavage products produce flower-like profiles in the microscope, which the authors term PANTHOS ('toxic flower'). They are also clearly detectable in postmortem human brain samples from Alzheimer's patients and are schematically reflected in the following figure.

This diagram shows how poorly acidified autolysosomes (AL, purple) accumulate in the soma of neurons (left) and bulge the cell membrane to form petal-like structures called PANTHOS in this way. Lysosomes, the protein-degrading organelles of a cell, begin to secrete enzymes. Aβ-fibrils (shown as blue filaments) accumulate in lysosomal tubular structures around the nucleus. At some point, neurons rupture and Aβ-aggregates are deposited extracellularly with the participation of glial cells (pa-AL = weakly acidic autolysosomes; pa-LY = weakly acidic lysosomes; Ly = lysosomes; AP = autophagosome; β-CTF = beta-carboxy terminal fragment formed by cleavage of the amyloid precursor protein, APP, by β-secretase). Source: Korte and Köster, 2022, Signal Transduct Target Ther 7:344.

Based on a variety of imaging and histochemical techniques, it has also been shown by the research group led by Ralph Nixon of New York University, USA, that PANTHOS neurons may be the origin of senile plaques, which would turn the previously proposed temporal sequence for the pathogenesis of the deposits on its head. Thus, the prerequisite of plaque formation seems to be a disturbance in the process of autophagy. According to the new hypothesis, the plaques, which were assumed to originate from the plasma membrane and then to be formed extracellularly, arise due to an intracellular process and enter the immediate environment by neuronal cell death.

On the basis of the new results, the much-discussed inflammatory processes of Alzheimer's disease also come into a new light. Glia presumably react only when amyloid plaques have already formed and matured in PANTHOS-containing neurons. Microglia then presumably induces cell death of affected neurons and causes the release of plaques into the extracellular space, which will further promote the spread of the deposits.

However, one important question remains unanswered in this work, namely, what mechanism mediates the reduction in ATPase activity in lysosomes and why, despite this, there are still autophagosomes that have a normal pH. Also, it would still need to be explained why forebrain cholinergic neurons appear to be affected first by the changes, even though autophagy is present in all neurons. Are the changes perhaps reversible, i.e. could the restoration of acidic conditions prevent PANTHOS formation in Alzheimer's tissue ? Exciting results often lead to even more exciting questions!


Korte M, Köster RW (2022) Opening the box of PANTHORA in Alzheimer's disease. Signal Transduct Target Ther 7:344

Lee JH, Yang DS, Goulbourne CN, ..., Staufenbiel M, Nixon RA. 2022. Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat Neurosci 25:688

Image credit: iStock/Ibrahim Akcengiz


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