Abstract
Genetic polymorphisms of immune genes that associate with higher risk to develop Alzheimer's disease (AD) have led to an increased research interest on the involvement of the immune system in AD pathogenesis. A link between amyloid pathology and immune gene expression was suggested in a genome‐wide gene expression study of transgenic amyloid mouse models. In this study, the gene expression of lysozyme, a major player in the innate immune system, was found to be increased in a comparable pattern as the amyloid pathology developed in transgenic mouse models of AD. A similar pattern was seen at protein levels of lysozyme in human AD brain and CSF, but this lysozyme pattern was not seen in a tau transgenic mouse model. Lysozyme was demonstrated to be beneficial for different Drosophila melanogaster models of AD. In flies that expressed Aβ1‐42 or AβPP together with BACE1 in the eyes, the rough eye phenotype indicative of toxicity was completely rescued by coexpression of lysozyme. In Drosophila flies bearing the Aβ1‐42 variant with the Arctic gene mutation, lysozyme increased the fly survival and decreased locomotor dysfunction dose dependently. An interaction between lysozyme and Aβ1‐42 in the Drosophila eye was discovered. We propose that the increased levels of lysozyme, seen in mouse models of AD and in human AD cases, were triggered by Aβ1‐42 and caused a beneficial effect by binding of lysozyme to toxic species of Aβ1‐42, which prevented these from exerting their toxic effects. These results emphasize the possibility of lysozyme as biomarker and therapeutic target for AD.
Highlights
Two of the main pathological hallmarks of Alzheimer’s disease (AD) are extracellular accumulation of amyloid plaques, which consists of amyloid-b (Ab) peptides, and intracellular neurofibrillary tangles composed of hyperphosphorylated tau [1]
This study demonstrates that both mRNA and protein levels of lysozyme were upregulated in AD mouse models and in human AD cases and that lysozyme associated with Ab-plaques in mice brain tissue
A similar lysozyme mRNA profile was detected in humans, with increased lysozyme expression in visual cortex and prefrontal cortex in AD patients, and again, no apparent change in cerebellum
Summary
Two of the main pathological hallmarks of Alzheimer’s disease (AD) are extracellular accumulation of amyloid plaques, which consists of amyloid-b (Ab) peptides, and intracellular neurofibrillary tangles composed of hyperphosphorylated tau [1]. The amyloid plaques were previously considered the foremost neurotoxic agents in AD, but increasing evidence suggests that small diffusible Ab aggregates (referred to as oligomers) are the principal cytotoxic species as these correlate better with synaptic loss and cognitive impairment than the plaques [2]. Activated astrocytes and microglia cells surround Ab plaques together with various inflammatory mediators [5,6]. Genetic studies show upregulation of several genes involved in inflammation, especially complement activation and prostaglandin synthesis, during incipient AD [7] and there is data which demonstrate inflammatory processes before tangles and neurodegeneration are apparent [8]. Microglial activation demonstrates a protective function of a triggered immune response in AD, as microglial activation mediates phagocytosis and clearance of Ab [9]
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