Biology subjects

Norambuena, A.

Publications and source records attributed to Norambuena, A..

4 recordsLinked to original sources

bioRxiv2024

Mitochondrial NADK2-dependent NADPH controls Tau oligomer uptake in human neurons

Alterations in NADH and NADPH metabolism are associated with aging, cancer, and Alzheimers Disease. Using 2P-FLIM imaging of the mitochondrial NAD(P)H in live human neurons and PS19 mouse brains, we show that tau oligomers (TauO) upregulate the mitochondrial de novo NADPH synthesis through NADK2. This process controls LRP1-mediated internalization of TauO, setting a vicious cycle for further TauO internalization. Thus, mitochondrial NADK2-dependent NADPH controls a key step in TauO toxicity.

neuroscience↗

bioRxiv2024

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAA knock-in mouse model of Alzheimer disease

IntroductionReduced brain energy metabolism, mTOR dysregulation, and extracellular amyloid-{beta} oligomer (xcA{beta}O) buildup characterize AD; how they collectively promote neurodegeneration is poorly understood. We previously reported that xcA{beta}Os inhibit Nutrient-induced Mitochondrial Activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo. MethodsBrain energy metabolism and oxygen consumption were recorded in APPSAA/+ mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy. ResultsNiMA is inhibited in APPSAA/+ mice before other defects are detected in these amyloid-{beta}-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. GSK3{beta} signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3{beta} with lithium or TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APPSAA mice. ConclusionNiMA disruption in vivo occurs before histopathological changes and cognitive decline in APPSAA mice, and may represent an early stage in human AD.

neuroscience↗

bioRxiv2023

Structural and functional damage to neuronal nuclei caused by extracellular tau oligomers

INTRODUCTIONNeuronal nuclei are normally smoothly surfaced. In Alzheimers disease (AD) and other tauopathies, though, they often develop invaginations. We investigated mechanisms and functional consequences of neuronal nuclear invagination in tauopathies. METHODSNuclear invagination was assayed by immunofluorescence in brain, and in cultured neurons before and after extracellular tau oligomers (xcTauO) exposure. Nucleocytoplasmic transport was assayed in cultured neurons. Gene expression was investigated using nanoString nCounter technology and qRT-PCR. RESULTSInvaginated nuclei were twice as abundant in human AD as in cognitively normal adults, and were increased in mouse neurodegeneration models. In cultured neurons, nuclear invagination was induced by xcTauOs by an intracellular tau-dependent mechanism. xcTauOs impaired nucleocytoplasmic transport, increased histone H3 trimethylation at lysine 9 and altered gene expression, especially by increasing tau mRNA. DISCUSSIONxcTauOs may be a primary cause of nuclear invagination in vivo, and by extension, impair nucleocytoplasmic transport and induce pathogenic gene expression changes.

neuroscience↗

bioRxiv2021

SOD1 Mediates Lysosome-to-Mitochondria Communication and its Dysregulation by Amyloid-β Oligomers

Altered mitochondrial DNA (mtDNA) occurs in neurodegenerative disorders like Alzheimers disease (AD); how mtDNA synthesis is linked to neurodegeneration is poorly understood. We discovered Nutrient-induced Mitochondrial Activity (NiMA), an inter-organelle signaling pathway where nutrient-stimulated lysosomal mTORC1 activity regulates mtDNA replication in neurons by a mechanism sensitive to amyloid-{beta} oligomers (A{beta}Os), a primary factor in AD pathogenesis. Using 5-ethynyl-2-deoxyuridine (EdU) incorporation into mtDNA of cultured neurons, along with photoacoustic and mitochondrial metabolic imaging of cultured neurons and mouse brains, we show these effects being mediated by mTORC1-catalyzed T40 phosphorylation of superoxide dismutase 1 (SOD1). Mechanistically, tau, another key factor in AD pathogenesis and other tauopathies, reduced the lysosomal content of the tuberous sclerosis complex (TSC), thereby increasing NiMA and suppressing SOD1 activity and mtDNA synthesis. A{beta}Os inhibited these actions. Dysregulation of mtDNA synthesis was observed in fibroblasts derived from TS patients, who lack functional TSC and elevated SOD1 activity was also observed in human AD brain. Together, these findings imply that tau and SOD1 couple nutrient availability to mtDNA replication, linking mitochondrial dysfunction to AD.

neuroscience↗