Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
Mitochondrial NADK2-dependent NADPH controls tau oligomer uptake in human neurons.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Pardo Evelyn, Kim Taylor, Wallrabe Horst, Zengeler Kristine E, Sagar Vijay Kumar, Mingledorff Garnett, Sun Xuehan, Periasamy Ammasi, Lukens John R, Bloom George S, Norambuena Andrés
Аннотация
INTRODUCTION: Reduced brain energy metabolism, mitochondria dysfunction, and extracellular tau oligomer buildup characterize Alzheimer's disease (AD), but how these phenomena cooperatively promote neurodegeneration is poorly understood. We now report that tau oligomers (TauOs) pathologically coordinate mitochondrial metabolism with increased expression of a plasma membrane (PM) tau receptor.
METHODS: Mitochondrial energy metabolism was recorded using two-photon fluorescence lifetime microscopy of mitochondrial nicotinamide adenine dinucleotide phosphate (NADPH) in live human neurons and PS19 mouse brain.
RESULTS: Recombinant or human brain-derived TauOs upregulate expression of the mitochondrial NAD+ kinase, mitochondrial NAD kinase 2 (NADK2), and by extension, de novo NADPH synthesis. This process controls expression of low-density lipoprotein receptor-related protein 1 (LRP1), a major PM receptor for tau, thereby establishing a vicious cycle for further TauO internalization. Upregulation of the NADK2-NADPH pathway was detected in live presymptomatic PS19 mouse brains and in AD patient-derived neurons.
DISCUSSION: Upregulation of mitochondrial NADK2-dependent NADPH controls a key step in TauO toxicity and may represent an early stage in human AD.
METHODS: Mitochondrial energy metabolism was recorded using two-photon fluorescence lifetime microscopy of mitochondrial nicotinamide adenine dinucleotide phosphate (NADPH) in live human neurons and PS19 mouse brain.
RESULTS: Recombinant or human brain-derived TauOs upregulate expression of the mitochondrial NAD+ kinase, mitochondrial NAD kinase 2 (NADK2), and by extension, de novo NADPH synthesis. This process controls expression of low-density lipoprotein receptor-related protein 1 (LRP1), a major PM receptor for tau, thereby establishing a vicious cycle for further TauO internalization. Upregulation of the NADK2-NADPH pathway was detected in live presymptomatic PS19 mouse brains and in AD patient-derived neurons.
DISCUSSION: Upregulation of mitochondrial NADK2-dependent NADPH controls a key step in TauO toxicity and may represent an early stage in human AD.