{"doi":"10.1101/2025.09.07.674780","title":"The interaction between aging and DNA damage influences the accumulation of APP in Alzheimer’s disease","abstract":"ABSTRACT DNA damage is a major driver of the aging process, and the progression of Alzheimer’s disease (AD) worsens the situation. Neurons of the AD brain show significantly elevated levels of DNA damage compared to controls. AD is also associated with altered processing of the amyloid precursor protein (APP), best known for its Aβ proteolytic peptide fragment. In the current work we find that these three elements – age, DNA damage, and APP – are associated with each other. We present evidence from the mouse brain supporting the hypothesis that DNA damage drives increased levels of APP. Using the TUNEL reaction to track DNA damage, we show that TUNEL staining increases significantly with age (6 months to 24 months, 8 females and 14 males total in this study), in lockstep with intracellular APP. To separate correlation from causality we analyzed tissue from mice genetically deficient in ATM (ataxia-telangiectasia mutated), a protein kinase that promotes DNA damage repair. Compared to 6-month wild type mice, the increased TUNEL signal in neurons of 6-month Atm −/− animals was equivalent to that seen in 24-month wild type. Significantly, the APP signal in the Atm −/− cells was also increased, and this correlation was found in both neuronal and non-neuronal cells. These results suggest that the loss of genomic integrity associated with aging is a cellular stressor that increases the levels of APP and thus increases vulnerability to the pathogenesis of AD. SIGNIFICANCE STATEMENT Our work links the genetics of Alzheimer’s disease (dominant disease-causing mutations in the APP gene) with DNA damage and aging – two factors known as risk factors in AD. The evidence suggests that the enhanced DNA damage associated with the normal aging process, increases the levels of APP thus potentially contributing to Aβ production and plaque formation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":574690,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9526,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1267707,"name":"Gnanesh Gutta","orcid":"0009-0009-8566-727X","position":1,"is_corresponding":false},{"id":1103146,"name":"Fiona Stauffer","orcid":"0009-0009-5171-2968","position":2,"is_corresponding":false},{"id":1267708,"name":"Jay P. Mehta","orcid":"0000-0001-9951-4906","position":3,"is_corresponding":false},{"id":722371,"name":"Rody Kingston","orcid":"0000-0002-2396-4027","position":4,"is_corresponding":false},{"id":1482741,"name":"Mike Bagnell","orcid":null,"position":5,"is_corresponding":false},{"id":1042864,"name":"Fulin Ma","orcid":"0000-0002-0333-3180","position":6,"is_corresponding":false},{"id":819267,"name":"Karl Herrup","orcid":"0000-0001-7786-5844","position":7,"is_corresponding":false},{"id":1482380,"name":"Elizabeth Zinzell","orcid":"0009-0001-3068-3477","position":8,"is_corresponding":false},{"id":1267710,"name":"Eliana Brenner","orcid":"0009-0004-5879-5018","position":0,"is_corresponding":true}],"reference_count":38,"raw_metadata":null,"created_at":"2026-07-19T02:57:44.572630Z","pmid":"40964273","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}