Identifying the Main Functional Pathways Associated with Cognitive Resilience to Alzheimer’s Disease

• Main Authors: Marta Pérez-González, Sara Badesso, Elena Lorenzo, Elizabeth Guruceaga, Alberto Pérez-Mediavilla, Ana García-Osta, Mar Cuadrado-Tejedor
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: International Journal of Molecular Sciences
• Subjects: Alzheimer’s disease; cognitive resilience; inflammation; CD4⁺ cells
• Online Access: https://www.mdpi.com/1422-0067/22/17/9120

Understanding the mechanisms involved in cognitive resilience in Alzheimer’s disease (AD) represents a promising strategy to identify novel treatments for dementia in AD. Previous findings from our group revealed that the study of aged-Tg2576 cognitive resilient individuals is a suitable tool for this purpose. In the present study, we performed a transcriptomic analysis using the prefrontal cortex of demented and resilient Tg2576 transgenic AD mice. We have been able to hypothesize that pathways involved in inflammation, amyloid degradation, memory function, and neurotransmission may be playing a role on cognitive resilience in AD. Intriguingly, the results obtained in this study are suggestive of a reduction of the influx of peripheral immune cells into the brain on cognitive resilient subjects. Indeed, <i>CD4</i> mRNA expression is significantly reduced on Tg2576 mice with cognitive resilience. For further validation of this result, we analyzed <i>CD4</i> expression in human AD samples, including temporal cortex and peripheral blood mononuclear cells (PBMC). Interestingly, we have found a negative correlation between <i>CD4</i> mRNA levels in the periphery and the score in the Mini-Mental State Exam of AD patients. These findings highlight the importance of understanding the role of the immune system on the development of neurodegenerative diseases and points out to the infiltration of CD4⁺ cells in the brain as a key player of cognitive dysfunction in AD.