Molecular & cellular proteomics : MCPApr 6, 2023

Proteins linked to how Neuritin (NRN1) may support thinking resilience in Alzheimer's disease

Updated Apr 22, 2026

Abstract

A total of 109 cases of asymptomatic Alzheimer's disease (AsymAD) were analyzed to identify resilience-associated pathways.

Asymptomatic individuals with Alzheimer's disease pathology exhibit cognitive resilience, meaning they remain cognitively normal despite high levels of disease indicators.
Neuritin (NRN1) was identified as a central protein in a network linked to synaptic function and cognitive resilience.
In cellular models of Alzheimer's disease, NRN1 demonstrated protective effects against amyloid-β-induced damage, preserving dendritic spines and preventing neuronal hyperexcitability.
Proteomic analysis showed that NRN1 influences synaptic-related biological processes, suggesting a connection between NRN1's effects in cultured neurons and cognitive resilience pathways in humans.
The research emphasizes the importance of combining human brain proteomic data with model systems to explore mechanisms that promote resilience to Alzheimer's disease.

Simplified

The molecular mechanisms and pathways enabling certain individuals to remain cognitively normal despite high levels of Alzheimer's disease (AD) pathology remain incompletely understood. These cognitively normal people with AD pathology are described as preclinical or asymptomatic AD (AsymAD) and appear to exhibit cognitive resilience to the clinical manifestations of AD dementia. Here we present a comprehensive network-based approach from cases clinically and pathologically defined as asymptomatic AD to map resilience-associated pathways and extend mechanistic validation. Multiplex tandem mass tag MS (TMT-MS) proteomic data (n = 7787 proteins) was generated on brain tissue from Brodmann area 6 and Brodmann area 37 (n = 109 cases, n = 218 total samples) and evaluated by consensus weighted gene correlation network analysis. Notably, neuritin (NRN1), a neurotrophic factor previously linked to cognitive resilience, was identified as a hub protein in a module associated with synaptic biology. To validate the function of NRN1 with regard to the neurobiology of AD, we conducted microscopy and physiology experiments in a cellular model of AD. NRN1 provided dendritic spine resilience against amyloid-β (Aβ) and blocked Aβ-induced neuronal hyperexcitability in cultured neurons. To better understand the molecular mechanisms of resilience to Aβ provided by NRN1, we assessed how exogenous NRN1 alters the proteome by TMT-MS (n = 8238 proteins) of cultured neurons and integrated the results with the AD brain network. This revealed overlapping synapse-related biology that linked NRN1-induced changes in cultured neurons with human pathways associated with cognitive resilience. Collectively, this highlights the utility of integrating the proteome from the human brain and model systems to advance our understanding of resilience-promoting mechanisms and prioritize therapeutic targets that mediate resilience to AD.

Full Text

We can’t show the full text here under this license.

View Full Text ↗

Funding

Competing interests

Conflict of interest The authors declare no competing interests.

PubMed

Abstract

Full Text

Funding

Competing interests

Related papers

What Lands in Your Inbox Each Week: