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<p>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 (<i>n</i> = 75) and in patients with AD from the NorCog Memory Clinic Cohort (<i>n</i> = 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<sup>+</sup>, which in turn deacetylates acetylated-Tau174 via the NAD<sup>+</sup>–SIRT1 axis, leading to reduced tauopathy. Using in vitro tau seeding assays and a <i>Caenorhabditis elegans</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月14日

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  • 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

摘要

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.