Autophagosomes are microscopic bodies that help balance the inner environment within the cell. They do this by engulfing defective cellular components, which are then degraded when the autophagosomes fuse with cell structures called lysosomes. Alterations in this degradation pathway have been implicated in the development of Alzheimer’s disease (AD). However, the link between these alterations and the formation of amyloid plaques in the brain is not yet understood. In a new published study in Nature Neuroscience journal, a team of researchers led by Ralph A. Nixon and Ju-Hyun Lee of the New York University Langone Health (New York, US) identified the relationship between the extracellular accumulation of amyloid and the neuronal lysosomal dysfunction in five different mouse models for AD. In order to study the autophagy-lysosomal pathway in the brain, the researchers used different mouse models where they tracked and measured the acidity, also known as pH, inside the lysosomes of brain cells during the development of AD. By tracking pH using confocal microscopy, the researchers were able to show that lysosomes were less acidic in animal models of AD.
This change of pH was linked to the accumulation of cellular debris and proteins, such as the amyloid precursor protein (APP) metabolites, long before the AD mouse models develop amyloid plaques in the brain. The researchers also demonstrated that the enlarged and faulty lysosomes containing the APP metabolites (amyloid (Aβ) and APP-βCTF) accumulate around nuclei of neurons, distort their plasma membrane and end up shaping them in a structure with a unique pattern called PANTHOS (poisonous flower) which was also identified within the neurons of human AD brain tissue. The accumulation of Aβ within the faulty lysosomes causes them to break down. The researchers suggested that this could lead to the accumulation of Aβ in brain cells, which then become extracellular amyloid deposits when the cells die. This study points towards lysosome dysfunction as an early cause of extracellular amyloid deposition. Furthermore, strategies targeting lysosome pH deficits may be a beneficial pharmacological target to help prevent the downstream AD-related pathologies. https://www.nature.com/articles/s41593-022-01084-8
