| First Author | Norambuena A | Year | 2024 |
| Journal | Alzheimers Dement | Volume | 20 |
| Issue | 10 | Pages | 6844-6859 |
| PubMed ID | 39171353 | Mgi Jnum | J:354794 |
| Mgi Id | MGI:7736441 | Doi | 10.1002/alz.14144 |
| Citation | Norambuena A, et al. (2024) Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP(SAA) knock-in mouse model of Alzheimer's disease. Alzheimers Dement |
| abstractText | INTRODUCTION: Reduced brain energy metabolism, mammalian target of rapamycin (mTOR) dysregulation, and extracellular amyloid beta (Abeta) oligomer (xcAbetaO) buildup are some well-known Alzheimer's disease (AD) features; how they promote neurodegeneration is poorly understood. We previously reported that xcAbetaOs inhibit nutrient-induced mitochondrial activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo. METHODS: Brain energy metabolism and oxygen consumption were recorded in heterozygous amyloid precursor protein knock-in (APP(SAA)) mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy. RESULTS: NiMA is inhibited in APP(SAA) mice before other defects are detected in these Abeta-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. Glycogen synthase kinase 3 (GSK3beta) signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3beta with TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APP(SAA) mice. DISCUSSION: NiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APP(SAA) mice, and may represent an early stage in human AD. HIGHLIGHTS: Amyloid beta blocks communication between lysosomes and mitochondria in vivo. Nutrient-induced mitochondrial activity (NiMA) is disrupted long before the appearance of Alzheimer's disease (AD) histopathology in heterozygous amyloid precursor protein knock-in (APP(SAA/+)) mice. NiMA is disrupted long before learning and memory deficits in APP(SAA/+) mice. Pharmacological interventions can rescue AD-related NiMA disruption in vivo. |
