Novel immunotherapies for Alzheimer's disease have in recent years finally succeeded in clearing toxic extracellular amyloid-β aggregates from the brain in human clinical trials. Nonetheless, this advance has failed to meaningfully improve patient outcomes. This outcome has led to renewed theorizing on the mechanisms of Alzheimer's disease, in search of an explanation as to how amyloid-β can be so clearly associated with the condition, but fail as a target for therapy.
Some researchers focus on chronic inflammation as the primary mechanism of disease progression, seeing amyloid-β aggregation as a side-effect at best, while others suggest that amyloid-β is critically important, but inside cells rather than outside cells. Here, researchers discuss a possible role for age-related dysfunctions in the cellular maintenance process of autophagy, specifically focusing on the capability of lysosomes to break down the molecular waste that accumulates within them. Impaired autophagy and accumulation of waste in the lysosome harms cells, and is suggested to produce amyloid-β aggregation outside cells as a side-effect of those harms.
The amyloid precursor protein (APP) is infamous for its putatively critical role in the pathogenesis of Alzheimer's disease (AD). However a recent study found that autolysosome acidification declines in neurons with advancing age more than 4 months before amyloid β-protein (Aβ) is deposited extracellularly. Endolysosome de-acidification increases intraneuronal and secreted levels of Aβ. On the other hand, autolysosome acidification increases the degradation of accumulated Aβ in autophagic vacuoles and promotes glial clearance of oligomeric amyloid-β. Therefore, autolysosome acidification declines directly result in Aβ aggregation.
APP accumulates selectively within enlarged and de-acidified lysosomes. In more compromised yet still intact neurons, profuse Aβ-positive autophagic vacuoles pack into large membrane tubules. Then lysosomal membrane permeabilization, cathepsin release, and lysosomal-mediated cell death occur, accompanied by microglial invasion. Thus, Aβ accumulation may be the "result" rather than the "cause". The finding prompts rethinking of the conventionally accepted sequence of AD plaque formation and may help explain the inefficiency of Aβ/amyloid vaccines and Aβ/amyloid-targeted therapies.