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Kim E, Kim H, Jedrychowski MP, Bakiasi G, Park J, Kruskop J, Choi Y, Kwak SS, Quinti L, Kim DY, Wrann CD, Spiegelman BM, Tanzi RE, Choi SH. Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling. Neuron. 2023 Nov 15;111(22):3619-3633.e8. Epub 2023 Sep 8 PubMed.
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Texas A&M University School of Medicine
In this study, the authors investigated how irisin could affect Aβ pathology in Alzheimer’s disease. They report that irisin treatment causes a reduction in Aβ pathology by stimulating increased neprilysin release from astrocytes. Additional analysis revealed that increased neprilysin release from astrocytes by irisin is mediated through ERK-STAT3 signaling. The results also suggest that irisin’s effects on astrocytes occur through integrin aV/b5 receptors. Another interesting finding is that irisin significantly reduced gene expression levels of the astrocyte reactivity markers, implying that irisin could potentially help restrain the activity of reactive astrocytes known to contribute to AD pathogenesis.
Overall, the results are exciting, and the in vitro experiments were well done and analyzed appropriately. The results suggest irisin treatment could reduce Aβ plaques in amyloidosis or AD.
The entire study was performed in three-dimenesional cultures of REN cells expressing FAD-associated mutations. While the reported results from three-dimenesional cultures are valuable and provide mechanistic insights, it remains to be determined whether similar results could be obtained through systemic or localized irisin administration into brain regions in mouse models of amyloidosis or AD.
Three-dimenesional cultures in the study were maintained with recombinant irisin protein for 1.5 weeks, which could be considered a continuous long-term exposure. Providing such continuous exposure to irisin in the brain will be challenging. Future studies need to determine whether intermittent irisin treatment commencing in the early stage of the disease would be sufficient to reduce Aβ plaques long-term.
Queen's University
This is a beautiful study that adds insight into the neuroprotective mechanisms of irisin in Alzheimer’s experimental models. In my opinion, the main takeaway of this study is that irisin triggers the release of neprilysin by binding integrins on astrocytes. This explains how irisin may decrease Aβ levels in 3D cultures, as observed by authors.
The release of neprilysin by irisin is an important contribution to the field. It is in harmony with our findings showing that recombinant irisin reduced the binding of Aβ oligomers to neurons and that FNDC5/irisin overexpression reduced hippocampal soluble Aβ42 levels in APP/PS1 M146L mice (Lourenco et al., 2019).
In our study, we further observed that surface FNDC5/irisin and Aβ oligomers did not colocalize in dendrites of hippocampal neurons, which can be explained by the current study showing that irisin acts on astrocytes.
References:
Lourenco MV, Frozza RL, de Freitas GB, Zhang H, Kincheski GC, Ribeiro FC, Gonçalves RA, Clarke JR, Beckman D, Staniszewski A, Berman H, Guerra LA, Forny-Germano L, Meier S, Wilcock DM, de Souza JM, Alves-Leon S, Prado VF, Prado MA, Abisambra JF, Tovar-Moll F, Mattos P, Arancio O, Ferreira ST, De Felice FG. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nat Med. 2019 Jan;25(1):165-175. Epub 2019 Jan 7 PubMed.
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