Socodato R, Portugal CC, Canedo T, Rodrigues A, Almeida TO, Henriques JF, Vaz SH, Magalhães J, Silva CM, Baptista FI, Alves RL, Coelho-Santos V, Silva AP, Paes-de-Carvalho R, Magalhães A, Brakebusch C, Sebastião AM, Summavielle T, Ambrósio AF, Relvas JB. Microglia Dysfunction Caused by the Loss of Rhoa Disrupts Neuronal Physiology and Leads to Neurodegeneration. Cell Rep. 2020 Jun 23;31(12):107796. PubMed.
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IBMC/i3S
We very much appreciate the attention given by Alzforum to our recent paper. Concerning Dr. Ransohoff's comments on statins and RhoGTPases, we would like to draw attention to the following:
1. Besides RhoA, statins impact several other signaling pathways, including those regulated by Rac1 and cdc42 (and most likely other RhoGTPases), and by members of the Rab and Ras GTPase subfamilies. Therefore, any effect of statins in microglia is ultimately the net result of changing the localization and activities of many small GTPase proteins simultaneously. In this context, it is nearly impossible to draw any valid conclusion about the role of microglial Rhoa signaling (or any other small GTPase) in microglial function, inflammation, or during AD pathogenesis, progression, and/or memory deficits. We feel that elucidating the specific functions of RhoGTPase signaling in microglia in health or disease requires stringent, careful, and thorough examination of the individual functions of RhoGTPases using different methodological approaches, including inducible conditional transgenesis as we have done in our publication. To understand RhoGTPase function in human microglia and in AD will require direct assessment of the activation status of the different RhoGTPase proteins, which rely on posttranslational modifications, an information that is unavailable in human brain transcriptomic datasets. Unfortunately, the present lack of reliable antibodies recognizing active, GTP-bound RhoGTPases has hampered our capacity to investigate microglial RhoGTPase activation in human tissue by immunohistochemistry or related methodologies.
2. It is not very clear if statins will cause inhibition or activation of RhoA-dependent signaling, and how this would compare to our reported RhoA phenotype. As a matter of fact, in microglia-like cells, statins increase the GTP load of RhoA (Cordle et al., 2005), and even though statins can prevent RhoA prenylation and some form of membrane targeting, unprenylated (but GTP-loaded) RhoA can still be partially functional and activate downstream targets (Turner et al., 2008). Moreover, statins regulate microglia phagocytosis of Aβ, likely via inhibition of Rac1 function (Cordle et al., 2005), whereas we showed that activation of RhoA increased Aβ engulfment. On the other hand, statins have also been demonstrated to cause microglia inflammation (TNF production) in hippocampal slices by a mechanism requiring Rho prenylation (Bi et al., 2004).
3. Statins are not cell-type specific and, upon entering the brain, will modulate RhoA and the activity of many other small GTPases in different cell types (including oligodendrocytes, astrocytes, and neurons). As pointed out by Dr. Butovsky, this is particularly problematic if one considers that RhoA exerts nonredundant and context-specific roles in different CNS cell types that interact and crosstalk continuously.
4. From an AD point of view, several reports have indicated that prolonged use of statins can lead to reversible cognitive impairment, whereas other studies showed beneficial effects of statins in decreasing the risk of developing AD (Schultz et al., 2018).
References:
Bi X, Baudry M, Liu J, Yao Y, Fu L, Brucher F, Lynch G. Inhibition of geranylgeranylation mediates the effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors on microglia. J Biol Chem. 2004 Nov 12;279(46):48238-45. PubMed.
Bi X, Baudry M, Liu J, Yao Y, Fu L, Brucher F, Lynch G. Inhibition of geranylgeranylation mediates the effects of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors on microglia. J Biol Chem. 2004 Nov 12;279(46):48238-45. PubMed.
Schultz BG, Patten DK, Berlau DJ. The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms. Transl Neurodegener. 2018;7:5. Epub 2018 Feb 27 PubMed.
Socodato R, Portugal CC, Canedo T, Rodrigues A, Almeida TO, Henriques JF, Vaz SH, Magalhães J, Silva CM, Baptista FI, Alves RL, Coelho-Santos V, Silva AP, Paes-de-Carvalho R, Magalhães A, Brakebusch C, Sebastião AM, Summavielle T, Ambrósio AF, Relvas JB. Microglia Dysfunction Caused by the Loss of Rhoa Disrupts Neuronal Physiology and Leads to Neurodegeneration. Cell Rep. 2020 Jun 23;31(12):107796. PubMed.
Turner SJ, Zhuang S, Zhang T, Boss GR, Pilz RB. Effects of lovastatin on Rho isoform expression, activity, and association with guanine nucleotide dissociation inhibitors. Biochem Pharmacol. 2008 Jan 15;75(2):405-13. Epub 2007 Sep 1 PubMed.
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