Xenografted human iPSC-derived neurons with the familial Alzheimer's disease APPV717I mutation reveal dysregulated transcriptome signatures linked to synaptic function and implicate LINGO2 as a disease signaling mediator.

Alzheimer's disease (AD) is the most common cause of dementia, and disease mechanisms are still not fully understood. Here, we explored pathological changes in human induced pluripotent stem cell (iPSC)-derived neurons carrying the familial AD APPV717I mutation after cell injection into the mouse forebrain. APPV717I mutant iPSCs and isogenic controls were differentiated into neurons revealing enhanced Aß42 production, elevated phospho-tau, and impaired neurite outgrowth in APPV717I neurons. Two months after transplantation, APPV717I and control neural cells showed robust engraftment but at 12 months post-injection, APPV717I grafts were smaller and demonstrated impaired neurite outgrowth compared to controls, while plaque and tangle pathology were not seen. Single-nucleus RNA-sequencing of micro-dissected grafts, performed 2 months after cell injection, identified significantly altered transcriptome signatures in APPV717I iPSC-derived neurons pointing towards dysregulated synaptic function and axon guidance. Interestingly, APPV717I neurons showed an increased expression of genes, many of which are also upregulated in postmortem neurons of AD patients including the transmembrane protein LINGO2. Downregulation of LINGO2 in cultured APPV717I neurons rescued neurite outgrowth deficits and reversed key AD-associated transcriptional changes related but not limited to synaptic function, apoptosis and cellular senescence. These results provide important insights into transcriptional dysregulation in xenografted APPV717I neurons linked to synaptic function, and they indicate that LINGO2 may represent a potential therapeutic target in AD.

Brain and serum lipidomic profiles implicate Lands cycle acyl chain remodeling association with APOEε4 and mild cognitive impairment.

Introduction: At least one-third of the identified risk alleles from Genome-Wide Association Studies (GWAS) of Alzheimer's disease (AD) are involved in lipid metabolism, lipid transport, or direct lipid binding. In fact, a common genetic variant (ε4) in a cholesterol and phospholipid transporter, Apolipoprotein E (APOEε4), is the primary genetic risk factor for late-onset AD. In addition to genetic variants, lipidomic studies have reported severe metabolic dysregulation in human autopsy brain tissue, cerebrospinal fluid, blood, and multiple mouse models of AD. Methods: We aimed to identify an overarching metabolic pathway in lipid metabolism by integrating analyses of lipidomics and transcriptomics from the Religious Order Study and Rush Memory Aging Project (ROSMAP) using differential analysis and network correlation analysis. Results: Coordinated differences in lipids were found to be dysregulated in association with both mild cognitive impairment (MCI) and APOEε4 carriers. Interestingly, these correlations were weakened when adjusting for education. Indeed, the cognitively non-impaired APOEε4 carriers have higher education levels in the ROSMAP cohort, suggesting that this lipid signature may be associated with a resilience phenotype. Network correlation analysis identified multiple differential lipids within a single module that are substrates and products in the Lands Cycle for acyl chain remodeling. In addition, our analyses identified multiple genes in the Lands Cycle acyl chain remodeling pathway, which were associated with cognitive decline independent of amyloid-ß (Aß) load and tau tangle pathologies. Discussion: Our studies highlight the critical differences in acyl chain remodeling in brain tissue from APOEε4 carriers and individual non-carriers with MCI. A coordinated lipid profile shift in dorsolateral prefrontal cortex from both APOEε4 carriers and MCI suggests differences in lipid metabolism occur early in disease stage and highlights lipid homeostasis as a tractable target for early disease modifying intervention.

Cell type-specific changes identified by single-cell transcriptomics in Alzheimer's disease.

The rapid advancement of single-cell transcriptomics in neurology has allowed for profiling of post-mortem human brain tissue across multiple diseases. Over the past 3 years, several studies have examined tissue from donors with and without diagnoses of Alzheimer's disease, highlighting key changes in cell type composition and molecular signatures associated with pathology and, in some cases, cognitive decline. Although all of these studies have generated single-cell/nucleus RNA-seq or ATAC-seq data from the full array of major cell classes in the brain, they have each focused on changes in specific cell types. Here, we synthesize the main findings from these studies and contextualize them in the overall space of large-scale omics studies of Alzheimer's disease. Finally, we touch upon new horizons in the field, in particular advancements in high-resolution spatial interrogation of tissue and multi-modal efforts-and how they are likely to further advance mechanistic and target-selection studies on Alzheimer's disease.

Closing the Gap: Training Experiences and Career Outcomes for Underrepresented Minorities in Plastic Surgery.

Background: The present study assesses training characteristics, scholastic achievements, and traditional career accomplishments of ethnically underrepresented in medicine (UIM) plastic and reconstructive surgery (PRS) faculty relative to non-UIM PRS faculty. Method: A cross-sectional analysis of core PRS faculty appointed to accredited United States residency training programs (n = 99) was performed. Results: Of the 949 US PRS faculty, a total of 51 (5.4%) were identified as UIM. Compared with non-UIM faculty, there were few differences when evaluating medical education, residency training, pursuit of advanced degrees, and attainment of subspecialty fellowship training. UIM faculty were more likely than non-UIM faculty to have graduated from a medical school outside the United States (25% versus 13%, P = 0.014). In addition, UIM faculty did not differ from non-UIM counterparts in traditional career accomplishments, including promotion to full professor, obtaining NIH funding, serving as program director, receiving an endowed professorship, appointment to a peer-reviewed editorial board, scholarly contributions (H-index and number of publications), and appointment to chief/chair of their division/department. Conclusions: The historical lack of ethnic diversity that comprise US academic PRS faculty persists. This study reveals that those UIM faculty who are able to obtain faculty appointments are equally successful in achieving scholastic success and traditional career accomplishments as their non-UIM counterparts. As we strive toward increasing representation of UIM physicians in academic plastic surgery, the field will benefit from efforts that promote a pipeline for underrepresented groups who traditionally face barriers to entry.