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

Marta Pérez-González,Elena Lorenzo,Sara Badesso,Ana García-Osta,Alberto Pérez-Mediavilla,Elizabeth Guruceaga,Mar Cuadrado-Tejedor

doi:10.3390/ijms22179120

Abstract

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, CD4 mRNA expression is significantly reduced on Tg2576 mice with cognitive resilience. For further validation of this result, we analyzed CD4 expression in human AD samples, including temporal cortex and peripheral blood mononuclear cells (PBMC). Interestingly, we have found a negative correlation between CD4 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.

Highlights

Alzheimer’s disease (AD), which is the most common form of dementia in the elderly, is characterized by the presence in the brain of extracellular deposition of amyloid-β (Aβ) in the form of plaques and intracellular accumulation of hyper-phosphorylated Tau protein as neurofibrillary tangles
Aβ42 levels are higher in the prefrontal cortex than in the hippocampus of Tg2576 mice and, taking into account the implication of this area on memory function [10], we used the prefrontal cortex of this model to perform a transcriptomic analysis in order to shed some light into the key players on cognitive resilience
The RNASeq analysis performed on the prefrontal cortex of cognitive resilient and impaired Tg2576 mice revealed the activation of the peripheral immune system as one of the possible mediators of cognitive resilience mechanisms

Summary

Introduction

Alzheimer’s disease (AD), which is the most common form of dementia in the elderly, is characterized by the presence in the brain of extracellular deposition of amyloid-β (Aβ) in the form of plaques and intracellular accumulation of hyper-phosphorylated Tau (pTau) protein as neurofibrillary tangles. Like many other drugs focused on clearing pathological β-amyloid, this new therapy has revealed a very modest effect on slowing disease progression [2] These drug failures combined with the socioeconomic burden associated with the disease, highlight the urgent need of finding alternative approaches to the search of new effective AD treatments. In line with this idea, a very exciting fact is that several clinical studies have shown that some elderly people accumulate a significant number of histopathological AD lesions in their brains despite the absence of signs of dementia [3,4]. Understanding the mechanisms underlying this cognitive resilience appears to be a promising line of research

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