Dr. Ruixue Ai
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Representative Publications
View All Publications6 January 2022 in Nature Biomedical Engineering
Journal Article
CXChenglong Xie
Chenglong Xie
XZXu-Xu Zhuang
Xu-Xu ZhuangZNZhangming Niu
Zhangming Niu
Ruixue AiSLSofie Lautrup
Sofie Lautrup
EFEvandro Fang
Evandro Fang +23
A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer’s disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-β and tau pathologies, and improved the animals’ memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational–experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.
22 June 2022 in Frontiers in Aging
Journal Article
FNFrancisco José Naranjo-Galindo
Francisco José Naranjo-GalindoRuixue AiEFEvandro Fang
Evandro FangHNHilde Loge Nilsen
Hilde Loge NilsenTSTanima SenGupta
Tanima SenGuptaSince its introduction as a genetic model organism, Caenorhabditis elegans has yielded insights into the causes of aging. In addition, it has provided a molecular understanding of mechanisms of neurodegeneration, one of the devastating effects of aging. However, C. elegans has been less popular as an animal model to investigate DNA repair and genomic instability, which is a major hallmark of aging and also a cause of many rare neurological disorders. This article provides an overview of DNA repair pathways in C. elegans and the impact of DNA repair on aging hallmarks, such as mitochondrial dysfunction, telomere maintenance, and autophagy. In addition, we discuss how the combination of biological characteristics, new technical tools, and the potential of following precise phenotypic assays through a natural life-course make C. elegans an ideal model organism to study how DNA repair impact neurodegeneration in models of common age-related neurodegenerative diseases.
7 November 2025 in Science Advances
Journal Article
Ruixue AiLMLipeng Mao
Lipeng MaoXJXurui Jin
Xurui Jin
CCCarlos Campos-Marques
Carlos Campos-MarquesSZShiqi Zhang
Shiqi ZhangEFEvandro Fang
Evandro Fang +27
Dysfunctional alternative splicing events (ASEs) in RNA are markers of aging and Alzheimer’s disease (AD). As a key neuronal resilience metabolite, the oxidized nicotinamide adenine dinucleotide (NAD + ) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NAD + enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive. This study shows that NAD + augmentation corrects the ASEs of many genes via a key protein, EVA1C (epithelial V-like antigen 1 homolog C), which is involved in neuronal development and activities. EVA1C is reduced in the hippocampus in patients with AD compared to cognitively normal ones. NAD + -induced memory retention is partially dependent on EVA1C, as adeno-associated virus–based Eva1c knockdown in the hippocampal CA1 region annuls NAD + -induced memory improvement in pathological Tau–bearing mice. We propose that NAD + reduces AD pathologies, at least partially, via amplification of the NAD + - EVA1C splicing axis, pointing to a potential splice-switching therapy for AD.
14 May 2026 in Nature Aging
Journal Article
JPJun-Ping Pan
Jun-Ping Pan
PWPing-Jie Wang
Ping-Jie Wang
Jianying ZhangAKAnne-Brita Knapskog
Anne-Brita KnapskogLWLeiv Otto Watne
Leiv Otto WatneEFEvandro Fang
Evandro Fang +34
ULK1 (Atg1) initiates macroautophagy and mitophagy, which support neuronal growth and survival, yet how this pathway is disrupted in aging and Alzheimer's disease (AD) remains unclear. Here we report reduced ULK1 in serum and cerebrospinal fluid during aging in cognitively unimpaired participants from the COGNORM study (n = 75) and in patients with AD from the NorCog Memory Clinic Cohort (n = 316). In AD mice, ULK1 overexpression stimulates autophagic flux, reduces AD pathology and delays cognitive decline alongside increased phagocytic degradation of amyloid-β, reduced tauopathy and improved mitochondrial quality. Mechanistically, ULK1 upregulation increases autophagy and PINK1-, FUNDC1- and AMBRA1-associated mitophagy; higher autophagy and mitophagy increase cellular NAD+, which in turn deacetylates acetylated-Tau174 via the NAD+-SIRT1 axis, leading to reduced tauopathy. Using in vitro tau seeding assays and a Caenorhabditis elegans tau model, we validate the efficacy of ULK1 activators in inhibiting tauopathy. We propose that age-related decline in ULK1 leads to autophagy and mitophagy impairment and increases the progression of AD and identify ULK1 as a potential therapeutic target.
7 February 2022 in Autophagy
Journal Article
Ruixue AiXZXu-Xu Zhuang
Xu-Xu ZhuangAAAlexander Anisimov
Alexander AnisimovJLJiahong Lu
Jiahong LuEFEvandro Fang
Evandro FangFailed recognition and clearance of damaged mitochondria contributes to memory loss as well as Aβ and MAPT/Tau pathologies in Alzheimer disease (AD), for which there is an unmet therapeutic need. Restoring mitophagy to eliminate damaged mitochondria could abrogate metabolic dysfunction, neurodegeneration and may subsequently inhibit or slow down cognitive decline in AD models. We have developed a high-throughput machine-learning approach combined with a cross-species screening platform to discover novel mitophagy-inducing compounds from a natural product library and further experimentally validated the potential candidates. Two lead compounds, kaempferol and rhapontigenin, induce neuronal mitophagy and reduce Aβ and MAPT/Tau pathologies in a PINK1-dependent manner in both C. elegans and mouse models of AD. Our combinational approach provides a fast, cost-effective, and highly accurate method for identification of potent mitophagy inducers to maintain brain health.
About Me
Dr. (Alice) Ruixue Ai is a postdoctoral researcher in the Evandro Fang Lab at the University of Oslo (UiO) and Akershus University Hospital, Norway. She holds a Master’s degree in Oral Medicine from Sichuan University, China, where she studied the microenvironmental regulation of oral potentially malignant disorders. She had her doctoral degree (Dr.Philos) from UiO in 2023. Her research bridges artificial intelligence and neurodegenerative biology. She focuses on AI-driven drug screening and design for aging and Alzheimer’s disease (AD). Her co-first author work in Nature Biomedical Engineering (2022) introduced a machine learning pipeline that significantly improved the efficiency of identifying mitophagy-inducing compounds for AD treatment. She also investigates how NAD+ regulates mitophagy, mRNA splicing, and their roles in slowing down age-associated neurodegeneration. Looking forward, Dr. Ai is keen to explore the intersection of oral health and brain aging, aiming to uncover novel links between the oral microbiome, immune responses, and neurodegeneration using artificial intelligence.
She has authored nearly 20 peer-reviewed publications in high-impact journals including Nature Biomedical Engineering, Autophagy, and Acta Pharmaceutica Sinica B. She is an active member of several scientific communities, including the Genetics Society of America, Women in Autophagy, the Norwegian Artificial Intelligence Research Consortium, the NO-Age and NO-AD networks.