Neuronal SORT1 coordinates endosomal homeostasis and neuroinflammation crosstalk to protect against Alzheimer’s disease

In Alzheimer’s disease (AD), early endosomal dysfunction and chronic neuroinflammation critically shape disease progression, yet the neuronal mechanisms underlying the coordinating intracellular trafficking and microglial immune responses remain poorly defined. Sortilin-1 (SORT1), a neuronal VPS10P-domain receptor implicated in endosomal trafficking, proteostasis, and AD genetic risk, acts as a potential integrator of neuronal homeostasis and neuroimmune signaling. Here, we investigated the role of neuronal SORT1 in regulating endosomal integrity and neuron-microglia communication in AD models. Using a co-culture system of human iPSC-derived neurons and microglia-like cells, we found that neuronal SORT1 deficiency disrupted endosomal trafficking and proteostatic balance, leading to the accumulation of β-C-terminal fragments (β-CTFs) of amyloid precursor protein (APP) and pathological tau species. These neuronal defects were accompanied by heightened microglial pro-inflammatory activation and increased neuronal vulnerability. Single-cell RNA-sequencing (scRNA-seq) analyses revealed that SORT1 was dynamically expressed in inflammatory microglial populations, supporting early adaptive activation but declining in late-stage AD, which coincided with chronic neuroinflammation. In contrast, preservation of neuronal SORT1 stabilized endosomal organization, attenuated maladaptive microglial responses, and promoted neuronal survival. Moreover, in the 5xFAD mouse model of AD, AAV-mediated neuronal SORT1 expression reduced DNA damage, decreased microglia-associated neuroinflammation, reduced Aβ plaque burden and improved cognitive performance. Together, these findings establish neuronal SORT1 as a critical regulator that preserves endosomal homeostasis, coordinates neuron-microglia crosstalk, and mitigates neurodegeneration and cognitive decline in AD models, highlighting its potential as a target for early therapeutic intervention. Neuronal SORT1 preserves endosomal homeostasis and restrains neuroinflammation in Alzheimer’s disease