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 Inducib Show more
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. 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. 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. Neuronal IDOL, but not microglial IDOL, plays a key role in Alzheimer's disease pathogenesis by regulating the levels of brain APOE receptors. 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. Show less
Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of fu Show more
Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Two subjects (aged 18 and 23 years) were non-ambulatory at baseline. Upper limb, pulmonary, and cardiac function appeared stable in the 2 subjects in whom they could be evaluated. Dystrophin expression increased from 0.94 % ±0.59% (mean±SD) of normal to 5.1% ±2.9% by western blot. Percent dystrophin positive fibers also rose from 14% ±17% at baseline to 50% ±42% . Our results provide initial evidence that the use of exon-skipping drugs may increase dystrophin levels in patients with single-exon duplications. Show less