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

Overexpression of the low-density lipoprotein receptor (LDLR) is known to decrease apolipoprotein E (APOE) levels and alleviate amyloid beta (Aß) 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. To investigate the cell-type–specific role of IDOL, we generated Idol conditional knockout mice on an Aß-amyloidosis mouse model and performed biochemical, histological, and multi-omics analyses. 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. Overall design: Posterior cortices of 2 female 5XFAD mice and 2 female 5XFAD mice with a neuron-specific loss of IDOL were processed for single nucleus RNA sequencing