Cell type-specific functions of Alzheimer's disease endocytic risk genes.

Endocytosis is a key cellular pathway required for the internalization of cellular nutrients, lipids and receptor-bound cargoes. It is also critical for the recycling of cellular components, cellular trafficking and membrane dynamics. The endocytic pathway has been consistently implicated in Alzheimer's disease (AD) through repeated genome-wide association studies and the existence of rare coding mutations in endocytic genes. BIN1 and PICALM are two of the most significant late-onset AD risk genes after APOE and are both key to clathrin-mediated endocytic biology. Pathological studies also demonstrate that endocytic dysfunction is an early characteristic of late-onset AD, being seen in the prodromal phase of the disease. Different cell types of the brain have specific requirements of the endocytic pathway. Neurons require efficient recycling of synaptic vesicles and microglia use the specialized form of endocytosis-phagocytosis-for their normal function. Therefore, disease-associated changes in endocytic genes will have varied impacts across different cell types, which remains to be fully explored. Given the genetic and pathological evidence for endocytic dysfunction in AD, understanding how such changes and the related cell type-specific vulnerabilities impact normal cellular function and contribute to disease is vital and could present novel therapeutic opportunities. This article is part of a discussion meeting issue 'Understanding the endo-lysosomal network in neurodegeneration'.

Impact of Hormone Treatment on Psychosocial Functioning in Gender-Diverse Young People.

Purpose: Few studies have assessed the effects of hormonal treatments such as gonadotropin-releasing hormone agonists (GnRHa) and gender-affirming hormones (GAH) on mental health outcomes in clinically referred gender-diverse young people from a younger age. Where this research has been conducted, findings have been mixed. This study investigated a cohort of young people before treatment, 1 year into GnRHa, and 1 year into GAH treatment to understand psychological and behavioral impacts over time. Methods: Thirty-eight young people (28 assigned female and 10 assigned male) referred to endocrinology, younger than 15 years at/beyond Tanner stage two, who received GnRHa followed by GAH treatment, were assessed in a retrospective analysis study. Young people completed the Youth Self Report (YSR), the Body Image Scale, and the Utrecht Gender Dysphoria Scale, while caregivers completed the Child Behavior Checklist (CBCL) and the Social Responsiveness Scale-2 at all time points. Results: Dissatisfaction with primary sexual characteristics (p = 0.02), gender dysphoria (p = 0.01), and social motivation (p = 0.04) improved significantly over time. Self-harm and suicidality also showed a general decrease. Caregivers reported a significant reduction in internalizing (p = 0.03) behaviors on the CBCL after GnRHa. Other subcategories of the YSR and CBCL were within normal ranges with no significant difference (p > 0.05). Conclusion: These findings demonstrate some improvements in psychological and behavioral outcomes in young people concurrently receiving psychosocial support and hormone treatment. Future research with larger and more diverse samples is warranted to further understand generalizability.