Paper
- Alzforum Recommends
Fang J, Zhang P, Zhou Y, Chiang CW, Tan J, Hou Y, Stauffer S, Li L, Pieper AA, Cummings J, Cheng F. Endophenotype-based in silico network medicine discovery combined with insurance record data mining identifies sildenafil as a candidate drug for Alzheimer’s disease. Nat Aging. 1, 2021, pp. 1175–88. Nat Aging.
Recommends
Please login to recommend the paper.
Comments
Columbia University Medical Center
I read this manuscript with a lot of interest, as it shows human data that are consistent with the large amount of preclinical data published by my lab and others in the last 20 years, supporting the use of phosphodiesterase 5 inhibitors against Alzheimer’s disease. I still remember when I presented the first evidence at a meeting on phosphodiesterases. The major critique was that there is no phosphodiesterase 5 in the human brain. To address this issue, we published a manuscript (Teich et al., 2016) in which we demonstrated that phosphodiesterase 5 exists in human neurons and is a viable therapeutic target. I have dedicated more than 20 years to these studies; to see them supported by evidence in humans is very rewarding.
Regarding the mechanisms of the protective effect, the manuscript does not discuss the issue in depth, probably due to the fact that there is a large amount of work published on the topic, and it would have been hard to synthesize it in the discussion. We showed that phosphodiesterase 5 inhibitors counteract the reduction in activity of the NO cascade due to elevation of tau oligomers, re-establishing normal phosphorylation of the memory related molecule, CREB (Acquarone et al., 2019). The same cascade is also affected after elevation of Aβ oligomers (Puzzo et al., 2005, 2009).
Thus, the most likely scenario is that extracellular tau and Aβ oligomers downregulate the NO cascade, possibly by interacting with a transmembrane protein. Our work showed that APP is necessary for the damage of synaptic plasticity and memory by Aβ and tau oligomers (Puzzo et al., 2017).
As the authors point out, due to the nature of the use of sildenafil (mostly in a male population, without a specific regimen), the study has some limitations that will be addressed by a randomized controlled trial, possibly using inhibitors of phosphodiesterase 5 that can be administered for prolonged periods of time, as it is required in a chronic condition such as Alzheimer’s. Indeed, a prolonged use of sildenafil might incur side effects due to interaction of the drug with phosphodiesterase 6, 1, and perhaps 9, 10, and 11. A more specific phosphodiesterase 5 inhibitor could serve the purpose (see, for instance, Fiorito et al., 2013, 2017; Zuccarello et al., 2020).
References:
Teich AF, Sakurai M, Patel M, Holman C, Saeed F, Fiorito J, Arancio O. PDE5 Exists in Human Neurons and is a Viable Therapeutic Target for Neurologic Disease. J Alzheimers Dis. 2016;52(1):295-302. PubMed.
Acquarone E, Argyrousi EK, van den Berg M, Gulisano W, Fà M, Staniszewski A, Calcagno E, Zuccarello E, D'Adamio L, Deng SX, Puzzo D, Arancio O, Fiorito J. Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade. Mol Neurodegener. 2019 Jun 27;14(1):26. PubMed. Correction.
Puzzo D, Vitolo O, Trinchese F, Jacob JP, Palmeri A, Arancio O. Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity. J Neurosci. 2005 Jul 20;25(29):6887-97. PubMed.
Puzzo D, Staniszewski A, Deng SX, Privitera L, Leznik E, Liu S, Zhang H, Feng Y, Palmeri A, Landry DW, Arancio O. Phosphodiesterase 5 inhibition improves synaptic function, memory, and amyloid-beta load in an Alzheimer's disease mouse model. J Neurosci. 2009 Jun 24;29(25):8075-86. PubMed.
Puzzo D, Piacentini R, Fá M, Gulisano W, Li Puma DD, Staniszewski A, Zhang H, Tropea MR, Cocco S, Palmeri A, Fraser P, D'Adamio L, Grassi C, Arancio O. LTP and memory impairment caused by extracellular Aβ and Tau oligomers is APP-dependent. Elife. 2017 Jul 11;6 PubMed.
Fiorito J, Vendome J, Saeed F, Staniszewski A, Zhang H, Yan S, Deng SX, Arancio O, Landry DW. Identification of a Novel 1,2,3,4-Tetrahydrobenzo[b][1,6]naphthyridine Analogue as a Potent Phosphodiesterase 5 Inhibitor with Improved Aqueous Solubility for the Treatment of Alzheimer's Disease. J Med Chem. 2017 Nov 9;60(21):8858-8875. Epub 2017 Oct 23 PubMed.
Zuccarello E, Acquarone E, Calcagno E, Argyrousi EK, Deng SX, Landry DW, Arancio O, Fiorito J. Development of novel phosphodiesterase 5 inhibitors for the therapy of Alzheimer's disease. Biochem Pharmacol. 2020 Jun;176:113818. Epub 2020 Jan 21 PubMed.
View all comments by Ottavio ArancioMake a Comment
To make a comment you must login or register.