Reduced ULK1 links impaired autophagy and mitophagy to Alzheimer's disease pathology.

Jun-Ping Pan, Ping-Jie Wang, Jianying Zhang, Anne-Brita Knapskog, Leiv Otto Watne, He-Ling Wang, Maria Jose Lagartos-Donate, Sofie Lautrup, Li-Peng Mao, Qian Wang, Zhi-Peng Ling, Shi-Qi Zhang, Tomás Schmauck-Medina, Ruixue Ai, Trine Holt Edwin, Tianjiao Zhang, Ingvild Saltvedt, Rannveig Sakshaug Eldholm, Annabel Smith, Kateřina Veverová, Domenica Caponio, Asgeir Kobro-Flatmoen, Huanhuan Pang, Zijian Wang, Haoyun Wang, Li-Juan Gao, Nathalie Bodd Halaas, Garry Wong, Martin Vyhnalek, Oscar Junhong Luo, William A McEwan, Jon Storm-Mathisen, Li Gan, Zeping Hu, Henrik Zetterberg, Menno P Witter, Dag Aarsland, Geir Selbæk, Guobing Chen, Evandro Fei Fang

Department of Microbiology and Immunology, School of Medicine; Institute of Geriatric Immunology, School of Medicine, Jinan University, Guangzhou, China. · pubmed

Paper

Abstract

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

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Research summary

Reduced ULK1 levels are linked to impaired autophagy and mitophagy, which contribute to Alzheimer's disease pathology. The paper is relevant as it explores the mechanisms underlying autophagy and mitophagy in the context of aging and Alzheimer's disease, addressing potential root causes of age-related decline rather than merely treating symptoms.

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