Dysregulation of antimicrobial peptide expression distinguishes Alzheimer's disease from normal aging.

Min Wang,Simin Li,Xianda Hu,I-Feng Peng

doi:10.18632/aging.102650

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disease with unknown mechanism that is characterized by the aggregation of abnormal proteins and dysfunction of immune responses. In this study, an integrative approach employing in silico analysis and wet-lab experiment was conducted to estimate the degrees of innate immune system relevant gene expression, neurotoxic Aβ42 generation and neuronal apoptosis in normal Drosophila melanogaster and a transgenic model of AD. Results demonstrated mRNA levels of antimicrobial peptide (AMP) genes gradually increased with age in wild-type flies, while which exhibited a trend for an initial decrease followed by subsequent increase during aging in the AD group. Time series and correlation analysis illustrated indicated a potential relationship between variation in AMP expression and Aβ42 concentration. In conclusion, our study provides evidence for abnormal gene expression of AMPs in AD flies with age, which is distinct from the expression profiles in the normal aging process. Aberrant AMP expression may participate in the onset and development of AD by inducing or accelerating Aβ deposition. These findings suggest that AMPs may serve as potential diagnostic biomarkers and therapeutic targets. However, further studies are required to elucidate the pathological effects and underlying mechanisms of AMP dysregulation in AD progression.

Highlights

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects a growing proportion of the aging population
The degree of expression of other inducible and constitutive effector molecules in the host defense system of Drosophila, such as C-type lectins or lysozymes; pattern recognition receptors (PRRs), including peptidoglycan recognition proteins (PGRPs) and gram-negative binding proteins (GNBPs); major molecules involved in Toll, immune deficiency (IMD), and Janus kinase - signal transducer and activator of transcription (JAK-STAT) pathways, essentially remained unchanged
There is a lack of adaptive immunity in Drosophila, immune defense in the human brain under normal circumstances relies entirely on the innate immune system [5]

Summary

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects a growing proportion of the aging population. Patients with AD manifest with gradual decline of cognitive and functional abilities and shortened lifespan [1]. Due to the complex and multifactorial nature of AD, the etiology of which remains poorly understood, effective interventional means for prevention and treatment are lacking [2, 3]. There is growing recognition that the pathological mechanisms underlying AD do involve the aggregation of abnormal proteins, such as amyloid beta peptide (Aβ) and tau, and include dysfunction of immune responses in the brain [4]. Since there is a lack of adaptive immune system in human brains under normal circumstances, impaired innate immune function has been proposed to be a key mechanism in the initiation and progression of AD [5]. The innate immune system has been considered a potential therapeutic target and has drawn substantial attention in biological and pharmaceutical studies, it is still disputed whether innate immunity is increased or decreased in AD [6, 7]

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Results

Conclusion