Identification of Genetic Networks Reveals Complex Associations and Risk Trajectory Linking Mild Cognitive Impairment to Alzheimer’s Disease

Abstract

Amnestic mild cognitive impairment (aMCI) and sporadic Alzheimer’s disease (AD) are multifactorial conditions resulting from a complex crosstalk among multiple molecular and biological processes. The present study investigates the association of variants localized in genes and miRNAs with aMCI and AD, which may represent susceptibility, prognostic biomarkers or multi-target treatment options for such conditions. We included 371 patients (217 aMCI and 154 AD) and 503 healthy controls, which were genotyped for a panel of 120 single nucleotide polymorphisms (SNPs) and, subsequently, analyzed by statistical, bioinformatics and machine-learning approaches. As a result, 21 SNPs were associated with aMCI and 13 SNPs with sporadic AD. Interestingly, a set of variants shared between aMCI and AD displayed slightly higher Odd Ratios in AD with respect to aMCI, highlighting a specific risk trajectory linking aMCI to AD. Some of the associated genes and miRNAs were shown to interact within the signaling pathways of APP (Amyloid Precursor Protein), ACE2 (Angiotensin Converting Enzyme 2), miR-155 and PPARG (Peroxisome Proliferator Activated Receptor Gamma), which are known to contribute to neuroinflammation and neurodegeneration. Overall, results of this study increase insights concerning the genetic factors contributing to the neuroinflammatory and neurodegenerative mechanisms underlying aMCI and sporadic AD. They have to be exploited to develop personalized approaches based on the individual genetic make-up and multi-target treatments.

Activation of ACE2/Ang-(1-7)/Mas axis improve cognitive dysfunction induced by isoflurane in mice via oxidative stress

“…and plays an important role in balancing Ang II by converting excess Ang II to Ang -(1-7) in the central nervous system. Ang -(1-7) acts on its receptor Mas, in recent studies, ACE 2/Ang-(1-7)/Mas axis has been shown to play a neuroprotective role in a variety of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease [17,18] , and may be associated with mild cognitive impairment and susceptibility to Alzheimer's disease [19] . However, it remains uncertain whether the ACE2/Ang -(1-7)/Mas axis participates in t he development of cognitive impairment induced by long-term isoflurane anesthesia.…”