Abstract
Oxidative stress is a major risk factor for Alzheimer's disease (AD), which is characterized by brain atrophy, amyloid plaques, neurofibrillary tangles, and loss of neurons. 8-Oxoguanine, a major oxidatively generated nucleobase highly accumulated in the AD brain, is known to cause neurodegeneration. In mammalian cells, several enzymes play essential roles in minimizing the 8-oxoguanine accumulation in DNA. MUTYH with adenine DNA glycosylase activity excises adenine inserted opposite 8-oxoguanine in DNA. MUTYH is reported to actively contribute to the neurodegenerative process in Parkinson and Huntington diseases and some mouse models of neurodegenerative diseases by accelerating neuronal dysfunction and microgliosis under oxidative conditions; however, whether or not MUTYH is involved in AD pathogenesis remains unclear. In the present study, we examined the contribution of MUTYH to the AD pathogenesis. Using postmortem human brains, we showed that various types of MUTYH transcripts and proteins are expressed in most hippocampal neurons and glia in both non-AD and AD brains. We further introduced MUTYH deficiency into AppNL-G-F/NL-G-F knock-in AD model mice, which produce humanized toxic amyloid-β without the overexpression of APP protein, and investigated the effects of MUTYH deficiency on the behavior, pathology, gene expression, and neurogenesis. MUTYH deficiency improved memory impairment in AppNL-G-F/NL-G-F mice, accompanied by reduced microgliosis. Gene expression profiling strongly suggested that MUTYH is involved in the microglial response pathways under AD pathology and contributes to the phagocytic activity of disease-associated microglia. We also found that MUTYH deficiency ameliorates impaired neurogenesis in the hippocampus, thus improving memory impairment. In conclusion, we propose that MUTYH, which is expressed in the hippocampus of AD patients as well as non-AD subjects, actively contributes to memory impairment by inducing microgliosis with poor neurogenesis in the preclinical AD phase and that MUTYH is a novel therapeutic target for AD, as its deficiency is highly beneficial for ameliorating AD pathogenesis.
Highlights
Alzheimer’s disease (AD) is pathologically characterized by brain atrophy, amyloid plaques, neurofibrillary tangles (NFTs), and loss of neurons, thereby causing a progressive decline in the cognitive function [1]
We further examined the effects of MUTYH deficiency on neurogenesis and found that the density of BrdU-positive cells in the subgranular zone (SGZ) and granule cell layer (GCL) in six-month-old female AppNL-G-F/NL-G-F·Mutyh-/mice had recovered to the level seen in wild-type mice (Figure 10(b))
Our results strongly suggest that MUTYH actively contributes to AD pathogenesis by activating microglia and impairing neurogenesis in the hippocampus, resulting in the mild cognitive impairment seen in AppNL-G-F/NL-G-F mice
Summary
Alzheimer’s disease (AD) is pathologically characterized by brain atrophy, amyloid plaques, neurofibrillary tangles (NFTs), and loss of neurons, thereby causing a progressive decline in the cognitive function [1]. Accumulating evidence indicates that aging and gender are major risk factors for AD [2, 3], and it has been established that those risk factors are tightly associated with increased oxidative stress in AD brains [4]. 8-oxo-7,8-dihydroguanine (8-oxoguanine, 8oxoG), an oxidized form of guanine, a major oxidation product in DNA, highly accumulates in AD brains and is recognized as the most pronounced marker of oxidative stress [4, 8,9,10,11,12]. 8-OxoG accumulated in cellular DNA can pair with adenine as well as cytosine during replication or transcription, causing mutagenesis or cell death [13,14,15,16]. There are three enzymes that play major roles in minimizing the accumulation of 8-oxoG in DNA. MTH1, known as NUDT1, with 8-oxo-2′-deoxyguanosine triphosphatase (8-oxo-dGTPase) efficiently hydrolyzes the 8oxo-dGTP generated in the nucleotide pool to 8-oxodGMP and pyrophosphate, thereby preventing the incorporation of 8-oxoG into DNA [17]; OGG1 with 8-oxoG DNA glycosylase excises 8-oxoG opposite cytosine in DNA, thereby preventing the accumulation of 8-oxoG in DNA [18]; and MUTYH, with its adenine DNA glycosylase activity, excises adenine inserted opposite 8-oxoG in DNA, initiating base excision repair [19]
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