Rational Development of a Small-Molecule Activator of CK1γ2 That Decreases C99 and Beta-Amyloid Levels.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the accumulation of ß-amyloid (Aß), C99, and Tau in vulnerable areas of the brain. Despite extensive research, current strategies to lower Aß levels have shown limited efficacy in slowing the cognitive decline associated with AD. Recent findings suggest that C99 may also play a crucial role in the pathogenesis of AD. Our laboratory has discovered that CK1γ2 phosphorylates Presenilin 1 at the γ-secretase complex, leading to decreased C99 and Aß levels. Thus, CK1γ2 activation appears as a promising therapeutic target to lower both C99 and Aß levels. In this study, we demonstrate that CK1γ2 is inhibited by intramolecular autophosphorylation and describe a high-throughput screen designed to identify inhibitors of CK1γ2 autophosphorylation. We hypothesize that these inhibitors could lead to CK1γ2 activation and increased PS1-Ser367 phosphorylation, ultimately reducing C99 and Aß levels. Using cultured cells, we investigated the impact of these compounds on C99 and Aß concentrations and confirmed that CK1γ2 activation effectively reduced their levels. Our results provide proof of concept that CK1γ2 is an attractive therapeutic target for AD. Future studies should focus on the identification of specific compounds that can inhibit CK1γ2 autophosphorylation and evaluate their efficacy in preclinical models of AD. These studies will pave the way for the development of novel therapeutics for the treatment of AD.

Dismantling Racial Inequities in Early Psychosis Family Psychoeducation.

Families and caregivers play a critical role in the recovery of their loved ones with schizophrenia. Early intervention services, including family psychoeducation, can improve clinical outcomes and reduce stress for caregivers. Despite the benefits of family psychoeducation, Black caregivers engage in treatment at lower rates than do White caregivers. To eliminate disparities in early intervention care, mental health clinicians must understand the system of racism that shapes the Black caregiver experience. This column examines racial disparities in family psychoeducation engagement by contextualizing the Black caregiver experience and encourages culturally appropriate early intervention services to improve psychosis care.