Work

Deletion of neuronal Idol ameliorates Alzheimer's disease–related pathologies via APOE receptors

Year: 2025

Type: article

Abstract: INTRODUCTION: Overexpression of the low-density lipoprotein receptor (LDLR) is known to decrease apolipoprotein E (APOE) levels and alleviate amyloid beta (Aβ) pathology. We hypothesized that inhibiting the Inducible Degrader of LDLR (IDOL), an enzyme that ubiquitinates LDLR for degradation, would increase endogenous LDLR levels and attenuate amyloid pathology. METHODS: To investigate the cell-type-specific role of IDOL, we generated Idol conditional knockout mice on an Aβ-amyloidosis mouse model and performed biochemical, histological, and multi-omics analyses. RESULTS: We demonstrated that neuronal, but not microglial, Idol deletion reduced amyloid accumulation and altered brain LDLR and APOE levels, indicating the critical role of neuronal IDOL-LDLR in amyloid pathology. In addition, neuronal Idol deletion increased the levels of Reelin receptors important for synaptic function, and single-nuclei RNA sequencing revealed significant changes associated with synaptic organization. DISCUSSION: Neuronal IDOL, but not microglial IDOL, plays a key role in Alzheimer's disease pathogenesis by regulating the levels of brain APOE receptors. HIGHLIGHTS: Neuronal, but not microglial, Idol deletion reduces amyloid burden and modulates brain APOE and LDLR levels. Deletion of neuronal Idol increases the levels of APOER2 and VLDLR, the Reelin receptors, in the brain. Single-nuclei RNA sequencing highlights the neuronal IDOL's impact on inhibitory neurons and synaptic organization. Targeting neuronal IDOL may provide multiple therapeutic benefits in Alzheimer's disease by modulating APOE receptors.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz.70949