Biology subjects

Hurst, C. D.

Publications and source records attributed to Hurst, C. D..

3 recordsLinked to original sources

bioRxiv2024

Nomination of a novel plasma protein biomarker panel capable of classifying Alzheimer's disease dementia with high accuracy in an African American cohort

IntroductionAfrican Americans (AA) are widely underrepresented in plasma biomarker studies for Alzheimers disease (AD) and current diagnostic biomarker candidates do not reflect the heterogeneity of AD. MethodsUntargeted proteome measurements were obtained using the SomaScan 7k platform to identify novel plasma biomarkers for AD in a cohort of AA clinically diagnosed as AD dementia (n=183) or cognitively unimpaired (CU, n=145). Machine learning approaches were implemented to identify the set of plasma proteins that yields the best classification accuracy. ResultsA plasma protein panel achieved an area under the curve (AUC) of 0.91 to classify AD dementia vs CU. The reproducibility of this finding was observed in the ANMerge plasma and AMP-AD Diversity brain datasets (AUC=0.83; AUC=0.94). DiscussionThis study demonstrates the potential of biomarker discovery through untargeted plasma proteomics and machine learning approaches. Our findings also highlight the potential importance of the matrisome and cerebrovascular dysfunction in AD pathophysiology.

neuroscience↗

bioRxiv2023

Genetic background influences the 5XFAD Alzheimer's disease mouse model brain proteome

There is a pressing need to improve the translational validity of Alzheimers disease (AD) mouse models. Introducing genetic background diversity in AD mouse models has been proposed as a way to increase validity and enable discovery of previously uncharacterized genetic contributions to AD susceptibility or resilience. However, the extent to which genetic background influences the mouse brain proteome and its perturbation in AD mouse models is unknown. Here we crossed the 5XFAD AD mouse model on a C57BL/6J (B6) inbred background with the DBA/2J (D2) inbred background and analyzed the effects of genetic background variation on the brain proteome in F1 progeny. Both genetic background and 5XFAD transgene insertion strongly affected protein variance in hippocampus and cortex (n=3,368 proteins). Protein co-expression network analysis identified 16 modules of highly co-expressed proteins common across hippocampus and cortex in 5XFAD and non-transgenic mice. Among the modules strongly influenced by genetic background were those related to small molecule metabolism and ion transport. Modules strongly influenced by the 5XFAD transgene were related to lysosome/stress response and neuronal synapse/signaling. The modules with the strongest relationship to human disease--neuronal synapse/signaling and lysosome/stress response--were not significantly influenced by genetic background. However, other modules in 5XFAD that were related to human disease, such as GABA synaptic signaling and mitochondrial membrane modules, were influenced by genetic background. Most disease-related modules were more strongly correlated to AD genotype in hippocampus compared to cortex. Our findings suggest that genetic diversity introduced by crossing B6 and D2 inbred backgrounds influences proteomic changes related to disease in the 5XFAD model, and that proteomic analysis of other genetic backgrounds in transgenic and knock-in AD mouse models is warranted to capture the full range of molecular heterogeneity in genetically diverse models of AD.

neuroscience↗

bioRxiv2022

Integrated Proteomics Identifies Neuritin (NRN1) as a Mediator of Cognitive Resilience to Alzheimer's Disease

We present an integrative proteomic strategy for the nomination and validation of proteins associated with cognitive resilience to Alzheimers disease (AD). Correlation network analysis across distinct stages of AD was used to prioritize protein modules linked to resilience. Neuritin (NRN1), a hub protein in a module associated with synaptic biology, was identified as a top candidate of resilience and selected for functional validation in cultured neurons. NRN1 provided dendritic spine resilience against amyloid-{beta} (A{beta}), and NRN1 blocked A{beta}-induced neuronal hyperexcitability. The impact of exogenous NRN1 on the proteome of cultured neurons was assessed and integrated with the AD brain network. This revealed over-lapping synapse-related biology that linked NRN1-induced changes in cultured neurons with human pathways associated with AD resilience. Collectively, this highlights the utility of integrating the proteome from human brain and model systems to prioritize therapeutic targets that mediate resilience to AD.

neuroscience↗