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10.1038/s41419-025-08066-1 http://scihub22266oqcxt.onion/10.1038/s41419-025-08066-1 C12533062!12533062 !41102145     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=41102145 &cmd=llinks): Failed to open stream: HTTP request failed! 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Increased nucleotide metabolism alleviates Alzheimer s disease pathology |pdf=|usr=}}{{41102145 }} gab.com Text Increased nucleotide metabolism alleviates Alzheimer s disease pathology JO: Cell Death Dis http://www.kidney.de/pget.php?&tw=1&pmid=41102145 #FOAvip Genetic information in cells flows from DNA to RNA to proteins, which form molecular machines. During normal ageing, cell intrinsic and environmental factors alter this flow of information by damaging DNA in cells, including postmitotic neurons. Damage to DNA is associated with age-related neurodegenerative diseases such as Alzheimer's disease (AD). We previously reported an increase in DNA repair mechanisms in a fly model of AD. However, the causal mechanisms underlying somatic mutations in AD remain unclear. Here, we combine in silico methods from single-cell genomics of patients with AD with experimental validation in a Drosophila model of AD to elucidate the DNA repair processes in AD. We show that the levels of poly(ADP?ribose) polymerase 1 (PARP1), which mediates multiple DNA damage repair pathways, are increased in the brains of patients with AD. We found that higher PARP1 levels in neurons from patients with AD are linked to increased disease risk and a greater burden of somatic mutations. Nucleotide imbalance can increase the frequency of somatic mutations upon activation of DNA repair processes. Using a fly model of AD, we identified a metabolic signature in AD animals characterised by decreased levels of phosphorylated nucleotides. Enhancing nucleotide metabolism via dietary supplementation or genetic manipulation protects against AD pathology in animals. Finally, Mendelian randomisation revealed that higher expression of human deoxyguanosine kinase (DGUOK) is linked to a lower risk of developing AD. Our results suggest that enhancing nucleotide metabolism could improve DNA repair and serve as an adjunct therapy to delay AD progression. Twit Text FOAVip Increased nucleotide metabolism alleviates Alzheimer s disease pathology ????Cell Death Dis http://www.kidney.de/pget.php?&tw=1&pmid=41102145 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=41102145 #FOAvip English Wikipedia <ref>{{Cite pmid|41102145 }}</ref> Increased nucleotide metabolism alleviates Alzheimer s disease pathology #MMPMID41102145 Yu Y ; Miller MB ; Huang AY ; Tan BWZ ; Celardo I ; Leal NS ; Loh SHY ; Martins LM Cell Death Dis 2025[Oct]; 16 (1 ): 724 PMID41102145 show ga Genetic information in cells flows from DNA to RNA to proteins, which form molecular machines. During normal ageing, cell intrinsic and environmental factors alter this flow of information by damaging DNA in cells, including postmitotic neurons. Damage to DNA is associated with age-related neurodegenerative diseases such as Alzheimer's disease (AD). We previously reported an increase in DNA repair mechanisms in a fly model of AD. However, the causal mechanisms underlying somatic mutations in AD remain unclear. Here, we combine in silico methods from single-cell genomics of patients with AD with experimental validation in a Drosophila model of AD to elucidate the DNA repair processes in AD. We show that the levels of poly(ADP?ribose) polymerase 1 (PARP1), which mediates multiple DNA damage repair pathways, are increased in the brains of patients with AD. We found that higher PARP1 levels in neurons from patients with AD are linked to increased disease risk and a greater burden of somatic mutations. Nucleotide imbalance can increase the frequency of somatic mutations upon activation of DNA repair processes. Using a fly model of AD, we identified a metabolic signature in AD animals characterised by decreased levels of phosphorylated nucleotides. Enhancing nucleotide metabolism via dietary supplementation or genetic manipulation protects against AD pathology in animals. Finally, Mendelian randomisation revealed that higher expression of human deoxyguanosine kinase (DGUOK) is linked to a lower risk of developing AD. Our results suggest that enhancing nucleotide metabolism could improve DNA repair and serve as an adjunct therapy to delay AD progression. |*Alzheimer Disease/pathology/metabolism/genetics [MESH] |*Nucleotides/metabolism [MESH] |Animals [MESH] |Brain/metabolism/pathology [MESH] |DNA Damage [MESH] |DNA Repair [MESH] |Disease Models, Animal [MESH] |Drosophila melanogaster/metabolism [MESH] |Humans [MESH] |Male [MESH] |Mutation/genetics [MESH] |Neurons/metabolism/pathology [MESH]Increased nucleotide metabolism alleviates Alzheimer s disease patholo(epmc).pdf DeepDyve Pubget Overpricing