SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-β oligomers

Norambuena, Andrés; Sun, Xuehan; Wallrabe, Horst; Cao, Ruofan; Sun, Naidi; Pardo, Evelyn; Shivange, Nutan; Wang, Dora Bigler; Post, Lisa A.; Ferris, Heather A.; Hu, Song; Periasamy, Ammasi; Bloom, George S.

doi:10.1016/j.nbd.2022.105737

Cited by 15 publications

(12 citation statements)

References 104 publications

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“…It is reasonable to speculate that during AD progression the combination of Aβ production and insulin resistance leads to an imbalance in mTORC1 activity favoring its ectopic and toxic activity at the plasma membrane over its normal physiological functions on lysosomes. By extension, these events also lead to NiMA disruption, as we previously showed for cultured neurons [7,10], and as reported in the current study, in vivo as well. This hypothesis is consistent with the facts that mTORC1 activity is elevated in AD brain [37], and that decreasing mTOR expression in an AD mouse model ameliorates AD-like pathology and behavior [38].…”

Section: Discussionsupporting

confidence: 90%

“…At one level, AβOs trigger ectopic activation of mTORC1 at the plasma membrane by a mechanism that is dependent on tau expression, and thereby causes re-entry of neurons into the cell cycle, a prelude to most neuron death in AD [9]. At a second, parallel level, AβOs reduces mTORC1 activity on lysosomes by inhibiting insulin signaling [10]. It is reasonable to speculate that during AD progression the combination of Aβ production and insulin resistance leads to an imbalance in mTORC1 activity favoring its ectopic and toxic activity at the plasma membrane over its normal physiological functions on lysosomes.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, we also found that xcAβOs block NiMA in cultured neurons [7]. The mechanism involves xcAβO-mediated ectopic activation of mTORC1 at the neuronal plasma membrane [9] and upregulation of superoxide dismutase 1 (SOD1), a major regulator of cellular redox and a pathogenic factor in ALS [10]. Whether NiMA is disrupted in live AD brain, however, was not explored.…”

Section: Introductionmentioning

confidence: 99%

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Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP^SAAknock-in mouse model of Alzheimer’s disease

Norambuena,

Sagar,

Wang

et al. 2024

Preprint

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Introduction: Reduced brain energy metabolism, mTOR dysregulation, and extracellular amyloid-β oligomer (xcAβO) buildup characterize AD; how they collectively promote neurodegeneration is poorly understood. We previously reported that xcAβOs 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 APPSAA/+ mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy. Results: NiMA is inhibited in APPSAA/+ mice before other defects are detected in these amyloid-β-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. GSK3β signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with lithium or TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APPSAA mice. Conclusion: NiMA disruption in vivo occurs before histopathological changes and cognitive decline in APPSAA mice, and may represent an early stage in human AD.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP^SAAknock-in mouse model of Alzheimer’s disease

Norambuena,

Sagar,

Wang

et al. 2024

Preprint

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“…NiMA is initiated by trophic factors, like insulin, and nutrients, like amino acids, which activate lysosomal mTORC1 (Norambuena et al, 2018). The activated mTORC1 then phosphorylates SOD1, which coincidently is a major pathogenic factor for amyotrophic lateral sclerosis (ALS), as a necessary step for mitochondrial activation (Norambuena et al, 2022). Remarkably, the AβO‐induced, tau‐dependent CCR pathway inhibits NiMA (Norambuena et al, 2018).…”

Section: Mtor Dysregulation By Taumentioning

confidence: 99%

“…Much remains to be learned about the neuronal CCR pathway in AD, but a more recent study from our lab uncovered a previously unknown, fundamental cell biological phenomenon common to many cell types, nutrient‐induced mitochondrial activity, or NiMA, that is inhibited in neurons by a mechanism that closely parallels the neuronal CCR pathway in AD (Norambuena et al, 2018). NiMA involves activation of lysosomal mTORC1 by nutrients or insulin (Norambuena et al, 2022), which leads to a still mysterious lysosome‐to‐mitochondrion signaling process manifest as upregulation of mitochondrial activity and downregulation of mitochondrial DNA synthesis (Norambuena et al, 2022). Remarkably, NiMA is inhibited in neurons exposed to AβOs in a tau‐dependent manner because of the aforementioned activation of plasma membrane mTORC1.…”

Section: Mtor Dysregulation By Taumentioning

confidence: 99%

Dysregulation of mTOR by tau in Alzheimer's disease

Bloom,

Norambuena

2023

Cytoskeleton

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Tau was discovered in the mid 1970's as a microtubule‐associated protein that stimulates tubulin polymerization, and subsequently was shown to be expressed primarily in neurons, where it is most concentrated in axons. Interest in tau rose by the late 1980's, when it was shown to be the principal subunit of the neurofibrillary tangles (NFTs) that accumulate in Alzheimer's disease (AD) brain, and achieved new heights by the late 1990's, when numerous tau mutations were found to be highly penetrant for AD‐related disorders that also are associated with NFTs and came to be known as non‐Alzheimer's tauopathies. The role of tau in neurodegeneration is far more complex than whatever effects on neurons may be caused by NFTs, however, and here we review our work on dysregulation of mTOR by tau in AD. mTOR is a protein kinase and master regulator of myriad aspects of cellular behavior. We have defined a complex signaling network whereby aberrant tau phosphorylation provoked by amyloid‐β oligomers (AβOs), the building blocks of the amyloid plaques that form in AD brain, cause post‐mitotic neurons to re‐enter the cell cycle, but to die eventually instead of dividing, which may account for most neuron death in AD. Remarkably, we found that this same neuronal signaling network also poisons a fundamental cell biological process that we discovered, nutrient‐induced mitochondrial activation, or NiMA. Tau‐dependent cell cycle re‐entry and NiMA inhibition occur in cultured neurons within a few hours of exposure to AβOs, and thus may represent seminal processes in AD pathogenesis.

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Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP^SAA knock‐in mouse model of Alzheimer's disease

Norambuena,

Sagar,

Wang

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONReduced brain energy metabolism, mammalian target of rapamycin (mTOR) dysregulation, and extracellular amyloid beta (Aβ) oligomer (xcAβO) buildup are some well‐known Alzheimer's disease (AD) features; how they promote neurodegeneration is poorly understood. We previously reported that xcAβOs 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 heterozygous amyloid precursor protein knock‐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 Aβ‐producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. Glycogen synthase kinase 3 (GSK3β) signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APPSAA mice.DISCUSSIONNiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APPSAA 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 (APPSAA/+) mice. NiMA is disrupted long before learning and memory deficits in APPSAA/+ mice. Pharmacological interventions can rescue AD‐related NiMA disruption in vivo.

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SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-β oligomers

Cited by 15 publications

References 104 publications

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP^SAAknock-in mouse model of Alzheimer’s disease

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP^SAAknock-in mouse model of Alzheimer’s disease

Dysregulation of mTOR by tau in Alzheimer's disease

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP^SAA knock‐in mouse model of Alzheimer's disease

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SOD1 mediates lysosome-to-mitochondria communication and its dysregulation by amyloid-β oligomers

Cited by 15 publications

References 104 publications

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAAknock-in mouse model of Alzheimer’s disease

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAAknock-in mouse model of Alzheimer’s disease

Dysregulation of mTOR by tau in Alzheimer's disease

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

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Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP^SAAknock-in mouse model of Alzheimer’s disease

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP^SAAknock-in mouse model of Alzheimer’s disease

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APP^SAA knock‐in mouse model of Alzheimer's disease