Impaired Innate Immunity Mechanisms in the Brain of Alzheimer's Disease.

Martina Romagnoli,Elisa Porcellini,Federico Licastro,Robert Veerhuis,Ilaria Carbone

doi:10.3390/ijms21031126

Abstract

Among environmental factors likely associated with Alzheimer’s disease (AD), persistent virus infections, and age-related progressive decline of immune competence might play a pivotal role. However, AD antimicrobial brain immune responses are poorly investigated. The present study focused on genes involved in antimicrobial defenses, especially against virus infections, in the AD brain. In particular, mRNA levels of IRF7, MED23, IL28B, and IFN-α genes were analyzed in hippocampus and temporal cortex brain samples from AD and non-demented controls. All subjects were also genotyped for APOE ε, IRF7, MED23, and IL28B gene polymorphisms. Most AD patients showed decreased mRNA levels of all investigated genes in the hippocampus and temporal cortex. However, a small group of AD patients showed increased hippocampal mRNA expression of MED23, IL28B, and IFN-α. mRNA levels of MED23, IL28B, IFN-α from the hippocampus and those of MED23 from the temporal cortex were further decreased in APOE ε4 allele AD carriers. Moreover, rs6598008 polymorphism of IRF7 was significantly associated with decreased hippocampal expression of IRF7, MED23, IL28B, and IFN-α. These findings suggest that AD brains show impaired innate antimicrobial gene expression profiles, and individual genetic makeup, such as positivity for the APOE ε4 and IRF7 A alleles, might affect brain immune efficiency.

Highlights

Alzheimer’s disease (AD) is a chronic neurodegenerative disease and the most frequent form of dementia in the elderly [1]
We previously suggested that the concomitant presence of a set of single nucleotide polymorphisms (SNPs) associated with AD might result in a genetic signature predisposing to AD via complex and diverse mechanisms, each contributing to modulate individual susceptibility to herpes virus infection [5]
Our findings showed that impaired mRNA levels of IRF7, MED23, IL28B, and IFN-α were present in AD hippocampus and temporal cortex samples

Summary

Introduction

Alzheimer’s disease (AD) is a chronic neurodegenerative disease and the most frequent form of dementia in the elderly [1]. Neuroinflammation has emerged as a relevant component of AD brain pathology [3] Pathogens, such as viruses of the herpes family, through frequent cycles of reactivation and latency, constantly trigger the immune system, which is not able to completely eradicate these microbes. The amyloid-β (Aβ) peptide, which is associated with neurodegenerative processes of AD, showed antimicrobial activity against eight common and clinically relevant microorganisms [6]. Aβ peptide showed a protective activity against in vitro infection by the neurotropic virus, herpes simplex virus 1 (HSV-1) [7] This observation reinforces the notion that persistent and latent herpes virus infections may lead to Aβ overproduction that, in turn, contributes to amyloid plaque formation [7]

Methods

Discussion

Conclusion