Rethinking of Alzheimer's disease: Lysosomal overloading and dietary therapy

The amyloid precursor protein (APP) is infamous for its putatively critical role in the pathogenesis of Alzheimer's disease (AD) (Kim et al., 2022; Lee et al., 2022; Öhman et al., 2022; Thorwald et al., 2022). However a recent study found that autolysosome acidification declines in neurons age more than 4 months before amyloid β-protein (Aβ) deposited extracellularly (Lee et al., 2022). Endolysosome de-acidification increases intraneuronal and secreted levels of Aβ (Hui et al., 2019). On the other hand, autolysosome acidification increases the degradation of accumulated Aβ in autophagic vacuoles (AVs; Nie et al., 2018) and promotes glial clearance of oligomeric amyloid-β (oAβ; Huang et al., 2022). 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 AVs pack into large membrane tubules. Then lysosomal membrane permeabilization, cathepsin release and lysosomal-mediated cell death occur, accompanied by microglial invasion (Lee et al., 2022). 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 (Lee and Nixon, 2022).