Rab11-exosome biogenesis regulators mediate Aβ-induced intercellular propagation of endolysosomal trafficking defects and neurodegeneration

Alzheimer's disease (AD) is marked by two observable features: intracellular tau-containing structures known as neurofibrillary tangles and extracellular clumps of amyloid beta (Aβ), a specific fragment of the Amyloid Precursor Protein (APP). Researchers believe that Aβ-related neuronal damage may begin with internal processes that impact endolysosomal transport, which can spread between cells.

In non-neuronal Drosophila secondary cells (SCs), recent research has demonstrated that Aβ disrupts APP-regulated protein aggregation, resulting in insoluble dense-core granules (DCGs) during typical regulated secretion. This leads to endolysosomal abnormalities that are passed on to other cells. Through SCs, scientists have found that suppressing the gene encoding the ESCRT-III protein Chmp5—responsible for regulating the formation of intraluminal vesicles (ILVs) inside SC DCG compartments that are later expelled as Rab11-exosomes—prevents the transmission of Aβ-induced endolysosomal transport disruptions.

Additionally, disabling Chmp5 or other ESCRT-III genes also mitigates Aβ-induced, neurodegeneration-associated structural issues in the Drosophila eye. These findings suggest that genes involved in the Rab11-exosome biogenesis pathway play a crucial role in both Aβ-induced endolysosomal transport issues linked to irregular regulated secretion and cellular factors contributing to neurodegeneration.

The results indicate that these processes are interconnected and could imply potential new therapeutic targets for future AD treatments.