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

Abstract

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.