Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease

Traxler, Larissa; Herdy, Joseph R.; Stefanoni, Davide; Eichhorner, Sophie; Pelucchi, Silvia; Szűcs, Attila; Santagostino, Alice; Kim, Yongsung; Agarwal, R. K.; Schlachetzki, J; Glass, Christopher K.; Lagerwall, Jessica; Galasko, Douglas; Gage, Fred H.; D’Alessandro, Angelo; Mertens, Jérôme

doi:10.1016/j.cmet.2022.07.014

Cited by 96 publications

(90 citation statements)

References 72 publications

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“…Our data are consistent with the results of previous studies on the reduction of normal cell irradiation sensitivity by PTL via the ROS/KEAP1/NRF2 pathway. Besides, some studies revealed that blocking the nuclear translocation of PKM2 and inhibiting the expression of apoptosis-regulated genes can alleviate AD neuronal lesions ( Traxler et al, 2022 ), and PTL may also play an anti-apoptotic role by promoting the formation of PKM2 tetramers and inhibiting dimerization into the nucleus. Above all, PTL is potentially protective against irradiation-induced acute cerebellum injury.…”

Section: Discussionmentioning

confidence: 99%

Parthenolide promotes expansion of Nestin+ progenitor cells via Shh modulation and contributes to post-injury cerebellar replenishment

et al. 2022

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Background: Regeneration of injuries occurring in the central nervous system is extremely difficult. Studies have shown that the developing cerebellum can be repopulated by a group of Nestin-expressing progenitors (NEPs) after irradiation injury, suggesting that modulating the mobilization of NEPs is beneficial to promoting nerve regeneration. To date, however, effect of exogenous pharmaceutical agonist on NEPs mobilization remains unknown. Parthenolide (PTL), a sesquiterpene lactone isolated from shoots of feverfew. Although it has been shown to possess several pharmacological activities and is considered to have potential therapeutic effects on the regeneration of peripheral nerve injury, its efficacy in promoting central nervous system (CNS) regeneration is unclear. In this study, we aimed to elucidate the role and possible mechanism of PTL on regeneration in injured CNS after irradiation using a developing cerebellum model.Methods: We investigated the radioprotective effects of PTL on the developing cerebellum by immunoblotting as well as immunofluorescence staining and ROS detection in vivo and in vitro experiments, and then determined the effects of PTL on NEPs in Nestin CFP and Nestin GFP fluorescent mice. Inducible lineage tracing analysis was used in Nestin-CreERT2×ROSA26-LSL YFP mice to label and track the fate of NEPs in the cerebellum after irradiation. Combined with cell biology and molecular biology techniques to determine changes in various cellular components in the cerebellum and possible mechanisms of PTL on NEPs mobilization in the injured developing cerebellum.Results: We found that PTL could attenuate radiation-induced acute injury of granule neuron progenitors (GNPs) in irradiated cerebellar external granule layer (EGL) by alleviating apoptosis through regulation of the cells’ redox state. Moreover, PTL increased cerebellar Shh production and secretion by inhibiting the PI3K/AKT pathway, thus promoting expansion of NEPs, which is the compensatory replenishment of granule neurons after radiation damage.Conclusion: Collectively, our results indicate that activation and expansion of NEPs are critical for regeneration of the injured cerebellum, and that PTL is a promising drug candidate to influence this process.

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Section: Discussionmentioning

confidence: 99%

Parthenolide promotes expansion of Nestin+ progenitor cells via Shh modulation and contributes to post-injury cerebellar replenishment

et al. 2022

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“…This rewiring triggered by the virus will ultimately contribute to a lower availability of ATP (Medini et al, 2021), leading to higher levels of ROS and oxidative damage in the host cell (Mohiuddin & Kasahara, 2021), further increasing cell death. Dysregulated bioenergetics has also been observed in cellular aging (Baltanas et al, 2013; Traxler et al, 2022). Infection by RNA viruses can lead to increased generation of ROS and their release into the cytoplasm, which supports the observation that SARS‐CoV‐2 infection is accompanied by elevated ROS, a typical consequence of OXPHOS dysregulation (Gatti et al, 2020; Li et al, 2021; Schwarz, 1996).…”

Section: Figurementioning

confidence: 99%

COVID‐19 and neurodegeneration: The mitochondrial connection

et al. 2022

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There is still a significant lack of knowledge regarding many aspects of the etiopathology and consequences of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in humans. For example, the variety of molecular mechanisms mediating this infection, and the long‐term consequences of the disease remain poorly understood. It first seemed like the SARS‐CoV‐2 infection primarily caused a serious respiratory syndrome. However, over the last years, an increasing number of studies also pointed towards the damaging effects of this infection has on the central nervous system (CNS). In fact, evidence suggests a possible disruption of the blood–brain barrier and deleterious effects on the CNS, especially in patients who already suffer from other pathologies, such as neurodegenerative disorders. The molecular mechanisms behind these effects on the CNS could involve the dysregulation of mitochondrial physiology, a well‐known early marker of neurodegeneration and a hallmark of aging. Moreover, mitochondria are involved in the activation of the inflammatory response, which has also been broadly described in the CNS in COVID‐19. Here, we critically review the current bibliography regarding the presence of neurodegenerative symptoms in COVID‐19 patients, with a special emphasis on the mitochondrial mechanisms of these disorders.

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“…Dysfunction in the production of ATP as a result of mitochondrial damage and a metabolic switch from oxidative phosphorylation to glycolysis, reminiscent of the Warburg effect observed in cancer cells, has recently been proposed to act as a driver of neurodegeneration in AD. Traxler et al, [ 53 ] found that increased production of pyruvate kinase (PKM) 2 (an essential glycolytic enzyme, which catalyses the conversion of phosphoenolpyruvate to pyruvate) as opposed to PKM1 in patient-derived induced neurons may be responsible for initiating this switch, correlating with an increase in the PKM2 to PKM1 ratio in the prefrontal cortex of AD patients. Evidence for increased glycolytic flux in AD has been reported in further studies, which have observed early alterations in glucose metabolism in rodent models of AD [ 193 ] and significant increases in glycolytic-associated enzymes including PKM2 and lactate dehydrogenase in frontal and temporal brain regions of AD patients [ 194 ].…”

Section: Neuromodulator Function In the Central Nervous System And Dy...mentioning

confidence: 99%

“…The accumulation of metal ions with Aβ exacerbates excitotoxicity and oxidative stress [ 45 , 46 , 47 , 48 ], and contributes to the production of toxic ROS [ 49 , 50 , 51 , 52 ]. Increased extracellular and reduced intracellular ATP as a result of metabolic switching [ 53 , 54 ] and Aβ-induced pore production in the neuronal membrane [ 55 ] underlie dysfunction of P-ATPases, [ 56 ], P2-R overactivation, excess calcium influx, mitochondrial dysfunction, abnormal mitophagy, excitotoxicity and cell death [ 57 , 58 , 59 ]. Reduced neurotrophin activation of TrK-Rs leads to increased apoptosis and LTD and reduced cell survival and LTP [ 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 ].…”

Section: Figurementioning

confidence: 99%

Alternative Pharmacological Strategies for the Treatment of Alzheimer’s Disease: Focus on Neuromodulator Function

et al. 2022

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Alzheimer’s disease (AD) is a neurodegenerative disorder, comprising 70% of dementia diagnoses worldwide and affecting 1 in 9 people over the age of 65. However, the majority of its treatments, which predominantly target the cholinergic system, remain insufficient at reversing pathology and act simply to slow the inevitable progression of the disease. The most recent neurotransmitter-targeting drug for AD was approved in 2003, strongly suggesting that targeting neurotransmitter systems alone is unlikely to be sufficient, and that research into alternate treatment avenues is urgently required. Neuromodulators are substances released by neurons which influence neurotransmitter release and signal transmission across synapses. Neuromodulators including neuropeptides, hormones, neurotrophins, ATP and metal ions display altered function in AD, which underlies aberrant neuronal activity and pathology. However, research into how the manipulation of neuromodulators may be useful in the treatment of AD is relatively understudied. Combining neuromodulator targeting with more novel methods of drug delivery, such as the use of multi-targeted directed ligands, combinatorial drugs and encapsulated nanoparticle delivery systems, may help to overcome limitations of conventional treatments. These include difficulty crossing the blood-brain-barrier and the exertion of effects on a single target only. This review aims to highlight the ways in which neuromodulator functions are altered in AD and investigate how future therapies targeting such substances, which act upstream to classical neurotransmitter systems, may be of potential therapeutic benefit in the sustained search for more effective treatments.

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Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer’s disease

Cited by 96 publications

References 72 publications

Parthenolide promotes expansion of Nestin+ progenitor cells via Shh modulation and contributes to post-injury cerebellar replenishment

Parthenolide promotes expansion of Nestin+ progenitor cells via Shh modulation and contributes to post-injury cerebellar replenishment

COVID‐19 and neurodegeneration: The mitochondrial connection

Alternative Pharmacological Strategies for the Treatment of Alzheimer’s Disease: Focus on Neuromodulator Function

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