JCI Xiamen University multi-unit cooperation, Wang Xin/Xu Huaxi/Song Weihong discovered potential targets for the treatment of Alzheimer's disease

iNature Down syndrome (DS) or trisomy 21 is one of the key risk factors for early-onset Alzheimer's disease (AD), and the gene encoded by chromosome 21 plays a key role in the pathogenesis of AD
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The role of the deubiquitinase USP25, encoded on chromosome 21, in regulating microglial homeostasis in AD brains has been previously identified; however, whether USP25 affects amyloid pathology remains unclear
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On March 1, 2022, Wang Xin, Xu Huaxi of Xiamen University, and Song Weihong of Wenzhou Medical University jointly published a research titled "USP25 inhibition ameliorates Alzheimer's pathology through regulating APP processing and Aβ generation" in the Journal of Clinical Investigation (IF=15) online.
In this study, by crossing 5×FAD and Dp16DS mice, we observed that trisomy 21 exacerbates amyloid pathology in the brains of 5×FAD mice
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Furthermore, bacterial artificial chromosome (BAC) transgene-mediated overexpression of USP25 increased amyloid deposition in the brains of 5×FAD mice, whereas genetic deletion of Usp25 reduced amyloid deposition
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This study found that USP25 promotes β-cleavage of APP and Aβ generations by reducing ubiquitination and lysosomal degradation of APP and BACE1
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Importantly, pharmacological inhibition of USP25 ameliorated amyloid pathology in the brains of 5×FAD mice
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In conclusion, this study identifies the DS-related gene USP25 as a key regulator of AD pathology, and the findings suggest that USP25 is a potential pharmacological target for AD drug development
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Down syndrome (DS), the most common form of intellectual disability, is caused by full or partial triploidy of chromosome 21
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As one of the key risk factors for early-onset Alzheimer's disease (AD), trisomy 21 not only increases the dose of the amyloid precursor protein (APP) gene, but also by altering APP processing and expression in AD mouse brains Amyloid plaque deposition promotes the amyloidogenic pathway in AD human brain
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In addition to APP and BACE2, whether other genes on chromosome 21 are also involved in AD pathology in DS and their underlying molecular mechanisms remain to be determined
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By age 40, nearly all DS patients exhibit AD neuropathology, including amyloid plaques and neurofibrillary tangles
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In addition, approximately two-thirds of DS patients will develop clinical Alzheimer's disease before the age of 60
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As the main pathological hallmark of Alzheimer's disease, amyloid plaques are composed of aggregated amyloid beta (Aβ), a polypeptide that is sequentially decomposed by β-secretase BACE1 and γ-secretase
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Accumulating evidence suggests that accumulation of Aβ polypeptides in vulnerable brain regions is a trigger for tau pathology and gliosis/neuroinflammation
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Thus, beta targeting can include key disease-modifying strategies to treat or prevent AD progression
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Targeting USP25 ameliorates the pathological changes of amyloid in the brain of Alzheimer's disease patients (image from Journal of Clinical Investigation) The ubiquitin-specific proteolytic enzyme USP25 is encoded by a gene located at 21q11.
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As a negative regulator of IL-17-mediated inflammation, USP25 plays a crucial role in innate immunity
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Previous studies have found that USP25 regulates microglial homeostasis and neuroinflammation during neurodegeneration
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However, it is unclear whether and how the three replications of USP25 in DS brains lead to AD-like neuropathological features such as amyloid deposition
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In this study, we demonstrate that triploidy of the chromosome 21 gene exacerbates AD-associated amyloid pathology in 5×FAD mice
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Furthermore, overexpression of chromosome 21-encoded USP25 significantly increased amyloid deposition, and USP25 deficiency ameliorated amyloid pathology in 5 × FAD mice by regulating APP processing and Aβ production
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Furthermore, pharmacological inhibition of USP25 significantly reduced amyloid plaque burden in 5×FAD mice
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Taken together, the findings of this study identify a critical role for ubiquitin-proteasome system signaling in regulating amyloid deposition and provide a potential new strategy for improving neuropathology in AD
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