Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease

Fang, Evandro Fei; Y, Hou; Palikaras, Konstantinos; Adriaanse, Bryan A; Kerr, Jesse S.; Yang, Bing; Lautrup, Sofie; Hasan‐Olive, Mahdi; Caponio, Domenica; Dan, Xiuli; Rocktäschel, Paula; Croteau, Deborah L.; Akbari, Mansour; Greig, Nigel H.; Fladby, Tormod; Nilsen, Hilde; Cader, M Z; Mattson, Mark P.; Tavernarakis, Nektarios; Bohr, Vilhelm A.

doi:10.1038/s41593-018-0332-9

Cited by 1,234 publications

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“…Mitophagy is a regulated process that involves the degradation of damaged mitochondria by lysosomes. This process plays an important role in mitochondrial homeostasis, neuroprotection, and even healthy longevity in laboratory animal models [36, 37]. While we have characterized mitophagy in the CSB m/m mice [19], the changes of mitochondrial morphology and mitophagy in the animal models with CSA mutation or CSA/CSB double mutations are not known.…”

Section: Resultsmentioning

confidence: 99%

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling

Okur

Fang

Fivenson

et al. 2020

Preprint

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16Background: Cockayne syndrome (CS) is a rare premature aging disease, most 17 commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS 18 patients display cachectic dwarfism and severe neurological manifestations and have 19 an average life expectancy of 12 years. The CS proteins are involved in transcription 20 and DNA repair, with the latter including transcription-coupled nucleotide excision repair 21 (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, which 22 likely contributes to the severe premature aging phenotype of this disease. While 23 48 proteins. CSA [5, 6] and CSB [7] are DNA damage response proteins that are involved 49 in transcription-coupled nucleotide excision repair (TC-NER), as well as both nuclear 50 and mitochondrial base excision repair (BER) [8]. NER is a versatile DNA repair 51 pathway as it is responsible for the removal of a wide range of DNA adducts. CSA and 52 CSB are also important for transcription recovery after DNA damage [9][10][11]. Various 53 studies have shown that CSB plays a considerable role in transcription, and likely is a 54 transcription factor [12][13][14][15]. 55 56 Similar to other DNA repair-defective premature aging diseases, such as xeroderma 57 pigmentosum (XP) [16], ataxia-telangiectasia (AT) [17], and Werner syndrome (WS) 58[18], mitochondrial dysfunction is implicated in many CS phenotypes [3, 4, 19]. The 59 mechanisms of mitochondrial dysfunction underlying CS remain unclear but may involve 60 the impairment of the NAD + (nicotinamide adenine dinucleotide, oxidized)-mitophagy 61 axis [19][20][21][22]. NAD + is a fundamental molecule in cellular energy metabolism and 62 signaling pathways and is essential for adaptive responses of cells to bioenergetics and 63 oxidative stress; accordingly, there is an age-dependent depletion of cellular NAD + , 64 suggesting NAD + depletion as a major driver of both pathological and biological aging 65[23]. Many molecular mechanisms are involved in the multi-faceted effects of NAD + on 66 longevity and healthspan, including the induction of mitophagy, a cellular self-67 recognition, engulfment, degradation, and recycling of damaged and superfluous 68 mitochondria [24][25][26]. In CS, the accumulation of unrepaired DNA damage may lead to 69 to those observed in CS patients. After the selection of terms with p-values lower than 130 0.05 and an absolute value pathway Z-Score cut-off of 2.0, the remaining 39 GO terms 131and their respective Z-Scores were sorted by clustering in Fig 1b. Surprisingly, csa-1 132 and csb-1 worms had opposite pathway changes for a majority of the terms. Throughout 133 the dataset, csa-1;csb-1 worms partitioned more with csa-1 than csb-1 worms, 134suggesting that csa-1 drives the double mutant phenotype. However, there was a 135 shortlist of terms, including lysosome, where the csa-1;csb-1 worms segregated with 136 csb-1 worms. Other terms in this group included histidine catabolic process to glutamate 137 and formamide, oxidoreductase activity, an...

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Section: Resultsmentioning

confidence: 99%

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling

Okur

Fang

Fivenson

et al. 2020

Preprint

Self Cite

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“…This loss of connectivity is thought to be responsible for the early cognitive defects characterizing AD patients including defective learning and memory (Sheng et al, 2012;Terry et al, 1991). Recently, mitochondrial remodeling and dysfunction in PNs have emerged as a prominent cellular phenotype in AD (Cho et al, 2009;Fang et al, 2019;Wang et al, 2009a;Wang et al, 2009b;Zhang et al, 2016). However, whether this structural remodeling of dendritic mitochondria is causally linked to excitatory synaptic loss was unknown, in part because the molecular mechanism mediating Aβ42o-dependent mitochondrial remodeling are currently unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Results from our lab as well as others demonstrated that in neurons, Aβ42o over-activates AMP-activated kinase (AMPK) in a Calcium/calmodulin Kinase Kinase protein 2 (CAMKK2)-dependent manner and preventing CAMKK2 or AMPK over-activation either pharmacologically or genetically protects hippocampal neurons from Aβ42o-dependent synaptic loss in vitro and in the hAPP SWE, IND transgenic mouse model (J20) in vivo (Ma et al, 2014;Mairet-Coello et al, 2013;Son et al, 2012;Thornton et al, 2011). Importantly, AMPK is over-activated in the brain of AD patients where catalytically active AMPK accumulates in pyramidal neurons of the cortex and hippocampus (Fang et al, 2019;Vingtdeux et al, 2011). In non-neuronal cells, AMPK is a key metabolic sensor that is catalytically activated upon increasing levels of AMP/ADP (when ATP levels drop) and regulates various downstream effectors involved in maintaining mitochondrial integrity in part via two recently identified downstream effectors: mitochondrial fission factor (MFF) and Unc-51 like autophagy activating kinases 1/2 (ULK1/2) (Egan et al, 2011;.…”

Section: Introductionmentioning

confidence: 99%

Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy

Lee

Kondapalli

et al. 2019

Preprint

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During the early stages of Alzheimer's disease (AD) in both mouse models and human patients, soluble forms of Amyloid-β1-42 oligomers (Aβ42o) trigger loss of excitatory synapses (synaptotoxicity) in cortical and hippocampal pyramidal neurons (PNs) prior to the formation of insoluble Aβ plaques. We observed a spatially restricted structural remodeling of mitochondria in the apical tufts of CA1 PNs dendrites in the hAPP SWE,IND transgenic AD mouse model (J20), corresponding to the dendritic domain receiving presynaptic inputs from the entorhinal cortex and where the earliest synaptic loss is detected in vivo. We also observed significant loss of mitochondrial biomass in human neurons derived from a new model of human ES cells where CRISPR-Cas9-mediated genome engineering was used to introduce the 'Swedish' mutation biallelically (APP SWE/SWE ). Recent work uncovered that Aβ42o mediates synaptic loss by overactivating the CAMKK2-AMPK kinase dyad, and that AMPK is a central regulator of mitochondria homeostasis in non-neuronal cells. Here, we demonstrate that Aβ42o-dependent over-activation of CAMKK2-AMPK mediates synaptic loss through coordinated MFF-dependent mitochondrial fission and ULK2-dependent mitophagy in dendrites of PNs. We also found that the ability of Aβ42o-dependent mitochondrial remodeling to trigger synaptic loss requires the ability of AMPK to phosphorylate Tau on Serine 262. Our results uncover a unifying stress-response pathway triggered by Aβo and causally linking structural remodeling of dendritic mitochondria to synaptic loss.

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“…Mitophagy specifically has been proposed to contribute to several neurodegenerative diseases 18 . Evidence of early mitophagy induction and dysfunction has been observed in AD brains and in cells derived from patients with familial and sporadic forms of AD, which may exacerbate mitochondrial oxidative stress 12, 19–22 .…”

Section: Mainmentioning

confidence: 99%

ECSIT prevents Alzheimer’s disease pathology by regulating neuronal mitochondrial ROS and mitophagy

Lepelley

Vaughn

Staniszewski

et al. 2020

Preprint

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Altered mitochondrial fitness is a potential triggering factor in Alzheimer’s disease (AD). Mitochondrial quality control pathways are dysfunctional and mitochondrially-derived reactive oxygen species (mROS) levels are increased in AD patient brains. However, the pathways responsible for dysregulated mROS accumulation have remained relatively unclear. In this study, we demonstrate that levels of ECSIT, a mitochondrial oxidative phosphorylation (OxPhos) complex I (CI)-associated protein, are reduced in AD-affected brains. Neuronal ECSIT downregulation increased mROS generation and impaired mitophagy of defective mitochondria. Consequently, decreasing neuronal ECSIT caused AD-like changes, including memory loss and neuropathology. In contrast, augmented neuronal expression of ECSIT protected against the development of an AD-like phenotype. Decreased levels of ECSIT in AD patient brains therefore likely contribute to oxidative stress, neuroinflammation and AD pathogenesis.

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Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease

Cited by 1,234 publications

References 66 publications

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling

Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy

ECSIT prevents Alzheimer’s disease pathology by regulating neuronal mitochondrial ROS and mitophagy

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Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer’s disease

Cited by 1,234 publications

References 66 publications

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+signaling

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+signaling

Aβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy

ECSIT prevents Alzheimer’s disease pathology by regulating neuronal mitochondrial ROS and mitophagy

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Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling