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

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.

Integrated analysis and identification of hub genes as novel biomarkers for Alzheimer’s disease

“…However, in AD, clinical and experimental studies have demonstrated that peripheral immune cells (macrophages, monocytes, and neutrophils) participate in inflammatory responses and Aβ metabolism ( Ennerfelt and Lukens, 2020 ). CD4 + cells, numbers of which are positively correlated with AD, have been revealed to be a hub factor of cognitive dysfunction in AD ( Pérez-González et al, 2021 ), as have CD8 + cells ( Unger et al, 2020 ). Immunoglobulin accumulation around Aβ plaques, caused by the infiltration of B cells into the brain parenchyma, could be reduced by the therapeutic depletion of B cells; this could retard disease progression in mice ( Kim et al, 2021 ).…”

Docosahexaenoic Acid Ameliorates Contextual Fear Memory Deficits in the Tg2576 Alzheimer’s Disease Mouse Model: Cellular and Molecular Correlates

“…The task was carried out in a StartFear system (Panlab), as described by the authors in [ 68 ]. Briefly, during the training phase (visible platform, no visible cues) the animals learned to find a platform raised above the surface of the water during three consecutive days with eight trials per day.…”

“…RNA was extracted from the hippocampal tissue using Trizol Reagent (Sigma-Aldrich) and its integrity was confirmed via Agilent RNA Nano LabChips (Agilent Technologies, Santa Clara, CA, USA). A total of 1 μg of the total RNA was used to construct cDNA libraries with the TruSeq Stranded mRNA Kit (Illumina, San Diego, CA, USA), as described by Perez-Gonzalez et al, 2021 [ 68 ] and RNA sequencing data analysis was performed using the same workflow [ 69 ]. Genes were selected as differentially expressed using a p -value cut-off of p < 0.01.…”

Negative interpretation of ambiguous bodily symptoms among illness-anxious individuals: Exploring the role of developmental and maintenance constructs

“…Some studies propose a developmental perspective to explain susceptibility or resilience to mental problems ( 9 ). Furthermore, studies suggest that long-term exposure to stress can result in changes in physiological functioning, which can lead to long-lasting effects and the development of long-term consequences ( 10 , 11 ). According to the cognitive behavioral approach to illness anxiety ( 12 ), the core feature of illness anxiety is the catastrophic interpretation of ambiguous bodily symptoms and changes, known as interpretation bias.…”