The ability of neurons to identify correct synaptic partners is fundamental to the proper assembly and function of neural circuits. Relative to other steps in circuit formation such as axon guidance, our knowledge of how synaptic partner selection is regulated is severely limited. Drosophila Dpr and DIP immunoglobulin superfamily (IgSF) cell-surface proteins bind heterophilically and are expressed in a complementary manner between synaptic partners in the visual system. Here, we show that in the lamina, DIP misexpression is sufficient to promote synapse formation with Dpr-expressing neurons and that disrupting DIP function results in ectopic synapse formation. These findings indicate that DIP proteins promote synapses to form between specific cell types and that in their absence, neurons synapse with alternative partners. We propose that neurons have the capacity to synapse with a broad range of cell types and that synaptic specificity is achieved by establishing a preference for specific partners.
BackgroundDespite progress, disparities in Alzheimer’s Disease (AD) research participation continue to be a problem. Underrepresentation of certain racial and ethnic groups can result from several factors, including narrow recruitment strategies and strict exclusion criteria, and hinders our understanding of AD. We examined racial/ethnic differences in recruitment and screen failure in the Harvard Aging Brain Study (HABS), a longitudinal observational study, to elucidate these discrepancies.MethodWe analyzed HABS screening data from September 2010 to December 2021. Eligible participants were 50‐90 years old, cognitively intact (based on CDR, Logical Memory, and MMSE scores), in stable physical health, and had a study partner who could answer questions about their daily functioning. Participants were categorized into four mutually exclusive racial/ethnic groups based on self‐report data: Hispanic/Latino, White, Black, and other (Asian, American Indian/Alaskan Native, >1 Race, or did not disclose). Screen fail reasons were divided into clinical/cognitive, MRI/PET contraindications, medical and psychiatric history, and other. Statistical analyses included chi‐square, odds ratio, and t‐tests.ResultThe racial/ethnic breakdown of the 514 screened participants was 72.0% White, 14.0% Black, 10.9% Hispanic/Latino, and 3.1% other. Black participants had lower mean years of education than White participants (p < .05; Black, Mean [SD] = 14.28 [2.76]; White, 16.00 [2.96]). A total of 18.7% of participants screen failed with 17.8% of White, 19.4% of Black, and 28.6% of Hispanic/Latino participants (p > .05). Clinical/cognitive test scores were the most common reason for screen failure across all participants (41.7%), followed by medical history (26.0%). There were differences across racial/ethnic groups; compared with White participants, Black (odds ratio (OR), 2.6, 95% CI, 1.1‐5.6; p < .05) and Hispanic/Latino (OR, 2.7; 95% CI, 1.0‐6.1; p < .05) were more likely to meet exclusion criteria for cognition.ConclusionWhile efforts have been made to broaden recruitment strategies, create a Spanish‐language cohort, and revise exclusion criteria, racial/ethnic differences in recruitment and screen failure of HABS participants persist. This reflects a continued need to identify more culturally appropriate cognitive tests, norms, and cutoffs. Discovering and analyzing disparities by race/ethnicity will inform future efforts to create inclusive cohorts, leading to more representative AD research.
Background: The balance between production, clearance, and toxicity of Aβ peptides is central to Alzheimer's disease (AD) pathobiology. Though highly variable in terms of age at symptom onset (AAO), hundreds of variants in PSEN1 cause autosomal dominant forms of AD (ADAD) with nearly complete penetrance. PSEN1 forms the catalytic core of the γ-secretase complex and thereby directly mediates the production of longer, aggregation-prone Aβ peptides relative to shorter, non-aggregating peptides. We hypothesized that the broad AAO and biomarker heterogeneity seen across ADAD would be predictable based on mutation-specific differences in the production of Aβ species. Methods: Aβ-37, 38, 40, 42, and 43 production was quantified from 162 unique PSEN1 variants expressed in HEK293 cells. Prediction of AAO was carried out in 107 variants with available AAO and then replicated in 55 variants represented across 190 PSEN1 mutation carriers who have detailed cognitive and biomarker data from the Dominantly Inherited Alzheimer's Network (DIAN). Results: Variations in Aβ production across the 162 mutations examined in cell-based models were highly predictive of AAO. In those with corresponding in vivo data from the DIAN study, our cell-based γ-secretase composite was strongly associated with biomarker and cognitive trajectories. Conclusions: These findings elucidate the critical link between γ-secretase function, Aβ production, and AD progression and offer mechanistic support for the amyloid hypothesis. The approach used here represents a powerful tool to account for heterogeneity in disease progression in ADAD clinical trials and to assess the pathogenicity of variants of unknown significance or with limited family history.
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