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Enlarged vesicles in axons cause network deficits


Morbus Alzheimer (AD) is characterized by an accumulation of vesicles (endolysosomes) in neurons. These are thought to result from impaired fusion between endosomes and lysosomes, leading to an accumulation of organic material. Aggregated proteins may contribute to the pathogenesis of AD by disrupting normal protein turnover and maintenance of cellular homeostasis (see Chapter 2.3.3 in my book on Neurodegeneration).


AD is characterized by the formation of protein plaques containing highly aggregated Aβ-peptides surrounded by neuronal processes (axons) that exhibit abnormal swelling and are filled with a large number of large vesicles. As Yuan and colleagues at Yale University in New Haven, USA, from Jaime Grutzendler's research group have recently shown, these dystrophic neurites impair the function of diverse neuronal circuits.

Their work used high-resolution video microscopy to examine individual neurites with or without plaque-associated dystrophic changes in living mice. The authors found that the size of axonal swellings changed dynamically over long periods of time (sometimes for months). A few pathologically altered axons returned to normal, suggesting that the swellings do not necessarily indicate degenerating axons.


To investigate the effects of dystrophic neurites on neuronal functions, the authors measured the influx of calcium ions into the neurons. They were able to show that an increased volume of axonal swelling reduces electrical activity, decreases conduction velocity and blocks the propagation of action potentials. Because the brains of people with advanced disease contain more than 20 plaques per square millimeter, axonal conduction abnormalities therefore likely play a significant role in the development of Alzheimer's symptoms.


Furthermore, dystrophic neurites can be considered hotspots for intracellular accumulation of tau and amyloid precursor proteins. These block the bidirectional transport of biomolecules between the cell body (perikaryon) and the synaptic terminals of a neuron. However, it appears that the abnormally enlarged vesicles and multivesicular bodies (MVBs) found by Yuan et al. are also involved.


In this context, the authors identified the enzyme phospholipase D3 (PLD3) as a possible triggering factor. PLD3 is a transmembrane protein that is predominantly localized in the endolysosomal system and has been shown to play an important role in regulating fusion between endosomes and lysosomes. Previous studies had shown that PLD3 expression is increased in the brains of Alzheimer's disease patients and, conversely, that a reduction in PLD3 can reduce the accumulation of amyloid peptides (Aβ) in the brains of transgenic mouse models of Alzheimer's disease.


Thus, PLD3 may represent a promising target for therapeutic intervention. However, further studies would need to investigate the cellular mechanisms underlying the beneficial effects of silencing PLD3. In addition, it remains unclear how PLD3 variants, which are also detectable in humans, increase Alzheimer's risk and promote the accumulation of organelles in dystrophic neurites.


It has been known for more than 30 years that synaptic abnormalities and loss of synapses can be used as predictors of cognitive decline in Alzheimer's disease. In this context, synaptic dysfunction is triggered by soluble amyloid-β and occurs independently of insoluble amyloid plaques. Therefore, Alzheimer's disease is essentially a disorder of synapses and a dysfunction of neuronal networks. This hypothesis is strengthened by the finding that therapies directed against Aβ can effectively clear plaques but have little beneficial effect on cognitive function.


Reference:


Yuan P, Zhang M, Tong L, Morse TM, McDougal RA, Ding H, Chan D, Cai Y, Grutzendler J (2022) PLD3 affects axonal spheroids and network defects in Alzheimer's disease. Nature 612:328


Image credit: iStock/Rost-9D

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