Alzheimer’s disease (AD) is the most prevalent cause of dementia and can be conceptualized as a tauopathy initiated by the accumulation of amyloid-β (Aβ) in the brain. The clinical introduction of anti-Aβ antibody therapies has marked the beginning of a new era in disease-modifying treatment for dementia. While the deleterious effects of Aβ on postsynaptic spines and axonal microtubules have been increasingly clarified, recent studies have shifted attention beyond extracellular Aβ deposition as senile plaques to the pathogenic significance of intracellular Aβ. In particular, accumulating evidence highlights lysosomes as critical sites of intracellular Aβ toxicity. Interactions between Aβ and gangliosides, v-ATPase-dependent lysosomal acidification, and lysosomal membrane integrity are the key determinants of disease progression. In parallel, additional molecular players, including components of the complement cascade and asparaginyl endopeptidase, have been implicated in linking Aβ pathology to tau dysregulation and neurodegeneration. As therapeutic strategies targeting Aβ enter clinical practice, these emerging pathways represent promising targets for the next generation of AD treatment. Here, we summarize current insights and ongoing therapeutic developments centered on these mechanisms.
Takahashi et al. (Thu,) studied this question.