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

Lee, Annie; Kondapalli, Chandana; Virga, Daniel M.; Lewis, Tommy L.; Koo, So Yeon; Ashok, Archana; Mairet-Coello, Georges; Herzig, Sébastien; Foretz, Marc; Viollet, Benoı̂t; Shaw, Reuben J.; Sproul, Andrew A.; Polleux, Franck

doi:10.1038/s41467-022-32130-5

Cited by 43 publications

(60 citation statements)

References 124 publications

(204 reference statements)

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“…Two recent studies are particularly relevant in this regard: The first study ( Bold et al, 2022 ) showed that APPsα (the proteolytic cleavage product of APP along the nonamyloidogenic pathway, i.e., the one not producing Aβ) rescued abnormally low spine density in tauopathy model mice, even when applied at nanomolar concentrations. In contrast, the second study ( Lee et al, 2022 ) as well as many others, showed that soluble forms of oligomeric Aβ (the proteolytic APP cleavage product along the amyloidogenic pathway) drove excitatory synapse loss. Intriguingly, this study provided compelling evidence for causal links between Aβ-triggered loss of postsynaptic specializations (comparable both in extent and time course to Figure 6 above) and an upstream loss of dendritic mitochondria biomass, and by extension, compromised energy production capacity.…”

Section: Discussionmentioning

confidence: 91%

Synapse integrity and function: Dependence on protein synthesis and identification of potential failure points

Cohen

Ziv²,

Ziv

2022

Front. Mol. Neurosci.

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Synaptic integrity and function depend on myriad proteins - labile molecules with finite lifetimes that need to be continually replaced with freshly synthesized copies. Here we describe experiments designed to expose synaptic (and neuronal) properties and functions that are particularly sensitive to disruptions in protein supply, identify proteins lost early upon such disruptions, and uncover potential, yet currently underappreciated failure points. We report here that acute suppressions of protein synthesis are followed within hours by reductions in spontaneous network activity levels, impaired oxidative phosphorylation and mitochondrial function, and, importantly, destabilization and loss of both excitatory and inhibitory postsynaptic specializations. Conversely, gross impairments in presynaptic vesicle recycling occur over longer time scales (days), as does overt cell death. Proteomic analysis identified groups of potentially essential ‘early-lost’ proteins including regulators of synapse stability, proteins related to bioenergetics, fatty acid and lipid metabolism, and, unexpectedly, numerous proteins involved in Alzheimer’s disease pathology and amyloid beta processing. Collectively, these findings point to neuronal excitability, energy supply and synaptic stability as early-occurring failure points under conditions of compromised supply of newly synthesized protein copies.

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Section: Discussionmentioning

confidence: 91%

Synapse integrity and function: Dependence on protein synthesis and identification of potential failure points

Cohen

Ziv²,

Ziv

2022

Front. Mol. Neurosci.

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“…A potential confounding factor in the variation observed in the literature regarding mitochondrial length is recent data reporting differential mitochondria morphologies in different brain regions. It is now clear that both distinct neuron types and even the compartments within the same neuron (soma, dendrites, and axon) regulate mitochondria morphology to different levels ( Faits et al, 2016 ; Lewis et al, 2018 ; Chandra et al, 2019 ; Janickova et al, 2020 ; Faitg et al, 2021 ; Lee et al, 2022 ). However, it is unclear if or how these different mitochondrial populations would be affected by the different fixatives and perfusion methods.…”

Section: Discussionmentioning

confidence: 99%

Neuronal mitochondrial morphology is significantly affected by both fixative and oxygen level during perfusion

Kim

Strucinska²,

Osei³

et al. 2022

Front. Mol. Neurosci.

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Neurons in the brain have a uniquely polarized structure consisting of multiple dendrites and a single axon generated from a cell body. Interestingly, intracellular mitochondria also show strikingly polarized morphologies along the dendrites and axons: in cortical pyramidal neurons (PNs), dendritic mitochondria have a long and tubular shape, while axonal mitochondria are small and circular. Mitochondria play important roles in each compartment of the neuron by generating adenosine triphosphate (ATP) and buffering calcium, thereby affecting synaptic transmission and neuronal development. In addition, mitochondrial shape, and thereby function, is dynamically altered by environmental stressors such as oxidative stress or in various neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. Although the importance of altered mitochondrial shape has been claimed by multiple studies, methods for studying this stress-sensitive organelle have not been standardized. Here we address pertinent steps that influence mitochondrial morphology during experimental processes. We demonstrate that fixative solutions containing only paraformaldehyde (PFA), or that introduce hypoxic conditions during the procedure, induce dramatic fragmentation of mitochondria both in vitro and in vivo. This disruption was not observed following the use of glutaraldehyde (GA) addition or oxygen supplementation, respectively. Finally, using pre-formed fibril α-synuclein treated neurons, we show fixative choice can alter experimental outcomes. Specifically, α-synuclein-induced mitochondrial remodeling could not be observed with PFA only fixation as fixation itself caused mitochondrial fragmentation. Our study provides optimized methods for examining mitochondrial morphology in neurons and demonstrates that fixation conditions are critical when investigating the underlying cellular mechanisms involving mitochondria in physiological and neurodegenerative disease models.

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“…Importantly, a strong correlation between microglial activation and metabolic dysfunction in AD has been demonstrated in both basic research and clinical studies [ 5 , 18 , 19 ]. In AD, a series of mitochondrial abnormalities have been identified, including structure alteration, age-dependent accumulation of mitochondrial DNA (mtDNA) changes, altered mitochondrial membrane potential, excessive mitochondrial ROS production, reduced mitochondrial adenosine triphosphate (ATP), disrupted electron transport chain (ETC), and increased mitochondrial fragmentation, leading to defective mitophagy in microglia and other brain cells [ 13 , 22 – 29 ]. In addition, chronic exposure to Aβ and p-Tau induces dysregulated expression of late-onset AD-associated genes [ 30 ], mitochondrial toxicity, and metabolic dysfunction in microglia [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of Alzheimer’s disease

Xia

Wang

et al. 2022

J Neuroinflammation

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Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly globally. Emerging evidence has demonstrated microglia-driven neuroinflammation as a key contributor to the onset and progression of AD, however, the mechanisms that mediate neuroinflammation remain largely unknown. Recent studies have suggested mitochondrial dysfunction including mitochondrial DNA (mtDNA) damage, metabolic defects, and quality control (QC) disorders precedes microglial activation and subsequent neuroinflammation. Therefore, an in-depth understanding of the relationship between mitochondrial dysfunction and microglial activation in AD is important to unveil the pathogenesis of AD and develop effective approaches for early AD diagnosis and treatment. In this review, we summarized current progress in the roles of mtDNA, mitochondrial metabolism, mitochondrial QC changes in microglial activation in AD, and provide comprehensive thoughts for targeting microglial mitochondria as potential therapeutic strategies of AD.

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

Cited by 43 publications

References 124 publications

Synapse integrity and function: Dependence on protein synthesis and identification of potential failure points

Synapse integrity and function: Dependence on protein synthesis and identification of potential failure points

Neuronal mitochondrial morphology is significantly affected by both fixative and oxygen level during perfusion

Mitochondrial dysfunction in microglia: a novel perspective for pathogenesis of Alzheimer’s disease

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