Repurposing Proteostasis-Modifying Drugs to Prevent or Treat Age-Related Dementia: A Systematic Review

Heard, Daniel S.; Tuttle, Camilla; Lautenschlager, Nicola T.; Maier, Andrea B.

doi:10.3389/fphys.2018.01520

Cited by 16 publications

(11 citation statements)

References 68 publications

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“…The MBH 2 ‐mediated H 2 O 2 generation, according to these authors, is caused by a nonenzymatic reaction of MBH 2 with O 2 . There is a strong increase in interest to MB as a neuroprotective compound and the mechanism of its interaction with mitochondria, especially because MB is currently being used in clinical trials for the treatment of Alzheimer's disease . However, guinea pigs are not a commonly used animal model in ageing and neurological disease studies; mice are.…”

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confidence: 99%

Methylene blue does not bypass Complex III antimycin block in mouse brain mitochondria

et al. 2019

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Methylene blue (MB) is a promising prodrug to treat mitochondrial dysfunctions that is currently being used in clinical trials for Alzheimer's disease. MB can penetrate the blood brain barrier, accumulating in brain mitochondria where it acts as a redox mediator in the electron transfer chain (ETC). Mitochondrial flavins are thought to reduce MB, which is then oxidized by cytochrome c, thereby bypassing inhibited Complex I of ETC. We found that in mouse brain mitochondria, MB fails to restore the membrane potential and respiration inhibited by antimycin. Furthermore, antimycin inhibits MB‐induced H2O2 generation. Our data suggest that the acceptor of electrons from MB is a Qo ubiquinol‐binding site of Complex III; thus, MB‐based drugs might not be helpful in mitochondrial dysfunctions involving Complex III inhibition.

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confidence: 99%

Methylene blue does not bypass Complex III antimycin block in mouse brain mitochondria

et al. 2019

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“…Although we did not observe any obvious negative effects of our anti-PI recycling treatments in mice, it remains to be seen whether longer term anti-PI recycling treatments might eventually lead to some effects on angiogenically active normal tissues. However, some hints to the long-term sustainability and effectiveness of anti-PI recycling therapies may possibly be gleaned from the historically welltolerated and continued use of LiCl for management of bipolar disorder and cognitive impairment in human patients 30,[46][47][48] . Fig.…”

Section: Discussionmentioning

confidence: 99%

Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling

et al. 2020

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Anti-angiogenic therapies have generated significant interest for their potential to combat tumor growth. However, tumor overproduction of pro-angiogenic ligands can overcome these therapies, hampering success of this approach. To circumvent this problem, we target the resynthesis of phosphoinositides consumed during intracellular transduction of proangiogenic signals in endothelial cells (EC), thus harnessing the tumor's own production of excess stimulatory ligands to deplete adjacent ECs of the capacity to respond to these signals. Using zebrafish and human endothelial cells in vitro, we show ECs deficient in CDPdiacylglycerol synthase 2 are uniquely sensitive to increased vascular endothelial growth factor (VEGF) stimulation due to a reduced capacity to re-synthesize phosphoinositides, including phosphatidylinositol-(4,5)-bisphosphate (PIP2), resulting in VEGF-exacerbated defects in angiogenesis and angiogenic signaling. Using murine tumor allograft models, we show that systemic or EC specific suppression of phosphoinositide recycling results in reduced tumor growth and tumor angiogenesis. Our results suggest inhibition of phosphoinositide recycling provides a useful anti-angiogenic approach.

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“…Lithium has also been reported to enhance autophagy and reduce protein translation in nematodes and Drosophila (Sarkar et al 2005;Sarkar and Rubinsztein 2006;Sofola et al 2010;Sofola-Adesakin et al 2014;Tam et al 2014). A recent systematic review by Heard et al (2018) found that lithium produced statistically significant benefits on cognition in animal models of AD (5 mice, 2 rats, 1 Drosophila, and 1 zebrafish; P < 0.05). The results in humans with AD were mixed however with three randomized controlled studies showing a statistically significant benefit of lithium on cognition, while two other open-label and one randomized controlled study did not (Heard et al 2018).…”

Section: Combination Therapy For Admentioning

confidence: 99%

Drug synergy as a strategy for compression of morbidity in a Caenorhabditis elegans model of Alzheimer’s disease

et al. 2020

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Alzheimer's disease (AD) is the most common cause of dementia worldwide. AD is a multifactorial disease with simultaneous occurrence of several connected pathological processes including mitochondrial dysfunction and impaired proteostasis. Most of these are also implicated in organismal aging per se. The presence of separable pathological conditions poses the opportunity to try combination treatments that target these different processes separately. This approach may provide an effective strategy to target AD; therefore, we investigated whether a combination of metformin (targeting mitochondria and energy metabolism) and lithium (targeting proteostasis) could result in synergistic benefits. In this perspective paper, we looked for benefits in lifespan and healthspan using a transgenic nematode strain, GRU102, which expresses panneuronal human amyloid-beta (Aβ). Individually, metformin and lithium extended the lifespan of both nontransgenic GRU101 controls and GRU102. Combination treatment using metformin and lithium did not result in any synergistic increase in GRU102 lifespan, but this treatment did result in a significant compression of morbidity when compared with each individual drug, resulting in relative and absolute extension of healthspan. Despite over-expressing pathogenic human Aβ in their neurons, GRU102 worms treated with the combination treatment enjoyed longer lifespans and significantly compressed morbidity, even compared with untreated non-transgenic animals. These findings suggest combination treatment as a strategy to compress morbidity, and highlight the distinction between healthspan and lifespan.

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Repurposing Proteostasis-Modifying Drugs to Prevent or Treat Age-Related Dementia: A Systematic Review

Cited by 16 publications

References 68 publications

Methylene blue does not bypass Complex III antimycin block in mouse brain mitochondria

Methylene blue does not bypass Complex III antimycin block in mouse brain mitochondria

Anti-angiogenic effects of VEGF stimulation on endothelium deficient in phosphoinositide recycling

Drug synergy as a strategy for compression of morbidity in a Caenorhabditis elegans model of Alzheimer’s disease

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