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 63 publications

(48 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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“…In both in vitro and in vivo models of outer retinal apoptotic stress, a tetramerization-inducing PKM2-activating small molecule was found to inhibit apoptosis in photoreceptors [41]. Furthermore, induced tetramerization with a PKM2 inhibitor inhibited apoptosis and prevented nuclear translocation of PKM2 in human neurons derived from patients with Alzheimer's disease [42]. PKM2 has been shown to be regulated in the brain in response to hypoxia in different settings.…”

Section: Glucose Metabolism and Its Relation To Cell Death Pathwaysmentioning

confidence: 99%

“…PKM2 has been shown to be upregulated in Alzheimer's disease in humans and in mice, and to mediate γ-secretase activity in hypoxic neurons [45]. Moreover, inhibition of PKM2 decreased cell death in neurons derived from patients with Alzheimer's disease [42].…”

Section: Glucose Metabolism and Its Relation To Cell Death Pathwaysmentioning

confidence: 99%

Reinventing the Penumbra — the Emerging Clockwork of a Multi-modal Mechanistic Paradigm

Walther

Kirsch

Hellwig

et al. 2022

Transl. Stroke Res.

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The concept of the ischemic penumbra was originally defined as the area around a necrotic stroke core and seen as the tissue at imminent risk of further damage. Today, the penumbra is generally considered as time-sensitive hypoperfused brain tissue with decreased oxygen and glucose availability, salvageable tissue as treated by intervention, and the potential target for neuroprotection in focal stroke. The original concept entailed electrical failure and potassium release but one short of neuronal cell death and was based on experimental stroke models, later confirmed in clinical imaging studies. However, even though the basic mechanisms have translated well, conferring brain protection, and improving neurological outcome after stroke based on the pathophysiological mechanisms in the penumbra has yet to be achieved. Recent findings shape the modern understanding of the penumbra revealing a plethora of molecular and cellular pathophysiological mechanisms. We now propose a new model of the penumbra, one which we hope will lay the foundation for future translational success. We focus on the availability of glucose, the brain’s central source of energy, and bioenergetic failure as core pathophysiological concepts. We discuss the relation of mitochondrial function in different cell types to bioenergetics and apoptotic cell death mechanisms, autophagy, and neuroinflammation, to glucose metabolism in what is a dynamic ischemic penumbra.

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

Cited by 63 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

Reinventing the Penumbra — the Emerging Clockwork of a Multi-modal Mechanistic Paradigm

COVID‐19 and neurodegeneration: The mitochondrial connection

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