Abd-Elrahman KS, Albaker A, de Souza JM, Ribeiro FM, Schlossmacher MG, Tiberi M, Hamilton A, Ferguson SS. Aβ oligomers induce pathophysiological mGluR5 signaling in Alzheimer's disease model mice in a sex-selective manner. Sci Signal. 2020 Dec 15;13(662) PubMed.
Recommends
Please login to recommend the paper.
Comments
Trinity College
The finding by Abd-Elrahman and co-authors that an mGluR5 negative allosteric modulator (NAM) alleviated cognitive and autophagy disruption in male, but not female, transgenic mice modelling Alzheimer’s disease amyloidosis raises important questions. In particular, can we conclude, as the authors do, that agents targeting mGluR5 may not be relevant to treating women with Alzheimer’s disease?
To underpin their findings, they report that synthetic Aβ oligomers displaced NAM binding to mGluR5 in healthy mouse brain in a sex-dependent manner. Remarkably, they found the same sex difference in Aβ-mediated mGluR5 ligand displacement in human postmortem cerebral cortex tissue. It should be noted that the four women tissue donors had no evidence of cognitive or brain pathology, whereas three of the four male donors had brain disorders, including two cases of dementia with Lewy bodies. Although the mechanism of this differential effect of Aβ is uncertain, the apparent concordance between the human and rodent data seems to provide some validation of animal models that study the deleterious actions of exogenously applied Aβ oligomers in both male and female healthy rodent brain. The similar sexual divergence in the APP/PS1 mice hints that, at least in this model, endogenously generated Aβ mediates some key sex-dependent pathological changes in early Alzheimer’s disease amyloidosis.
Consistent with a large body of evidence that certain Aβ oligomers bind potently to specific sequences in cellular prion protein (PrP) (Purro et al., 2018; Corbett et al., 2020) and thereby interfere with mGluR5 localization and function (Brody and Strittmatter, 2018), the NAM-displacing action of Aβ in male brain was absent in preparations lacking PrP. It seems likely, therefore, that the sex differences observed by Abd-Elrahman et al. may be caused by dimorphism in the ability of Aβ-bound PrP to aberrantly couple to mGluR5s, rather than a difference in the affinity of mGluR5 itself for Aβ. Human brain Aβ forms a complex with PrP equally in both men and women with Alzheimer’s disease, but Aβ-PrP complexes appear to be absent in the brains of healthy controls of either sex (Dohler et al., 2014). Taken together, these findings raise the intriguing possibility that female pathology and cognitive impairment in Alzheimer’s disease is driven at least partly by other, non-mGluR5, pathogenic partner(s), of Aβ-PrP complexes.
Clearly Aβ has a plethora of binding sites other than PrP, many of which have the potential to mediate its deleterious actions. Both these and Aβ production/clearance may at least partly be regulated by mGluR5 (e.g. Lee et al., 1995). Whether or not these putative mGluR5-mediated mechanisms are sex-dependent still needs to be investigated. Intriguingly, brief NAM treatment of healthy zebrafish only increased motor activity and brain mGluR5 number in males (Albasanz et al., 2016). If confirmed in humans (Smart et al., 2019), this finding indicates that unwanted side effects of NAMs, such as disruption of synaptic plasticity underlying cognitive function in the healthy brain (e.g. Collingridge et al., 2010; Qi et al., 2013), may also be sexually divergent. Unlike targeting mGluR5 with NAMs, using selective positive or silent allosteric modulators may exert fewer unwanted and potentially greater therapeutic effects, including PrP-mGuR5-independent. As the song goes, There’s Life in the Old (mGluR5) Girl Yet.
References:
Albasanz JL, Santana S, Guzman-Sanchez F, León D, Burgos JS, Martín M. 2-Methyl-6-(phenylethynyl)pyridine Hydrochloride Modulates Metabotropic Glutamate 5 Receptors Endogenously Expressed in Zebrafish Brain. ACS Chem Neurosci. 2016 Dec 21;7(12):1690-1697. Epub 2016 Sep 29 PubMed.
Brody AH, Strittmatter SM. Synaptotoxic Signaling by Amyloid Beta Oligomers in Alzheimer's Disease Through Prion Protein and mGluR5. Adv Pharmacol. 2018;82:293-323. Epub 2017 Oct 25 PubMed.
Collingridge GL, Peineau S, Howland JG, Wang YT. Long-term depression in the CNS. Nat Rev Neurosci. 2010 Jul;11(7):459-73. PubMed.
Corbett GT, Wang Z, Hong W, Colom-Cadena M, Rose J, Liao M, Asfaw A, Hall TC, Ding L, DeSousa A, Frosch MP, Collinge J, Harris DA, Perkinton MS, Spires-Jones TL, Young-Pearse TL, Billinton A, Walsh DM. PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins. Acta Neuropathol. 2020 Mar;139(3):503-526. Epub 2019 Dec 18 PubMed.
Dohler F, Sepulveda-Falla D, Krasemann S, Altmeppen H, Schlüter H, Hildebrand D, Zerr I, Matschke J, Glatzel M. High molecular mass assemblies of amyloid-β oligomers bind prion protein in patients with Alzheimer's disease. Brain. 2014 Mar;137(Pt 3):873-86. Epub 2014 Feb 10 PubMed.
Lee RK, Wurtman RJ, Cox AJ, Nitsch RM. Amyloid precursor protein processing is stimulated by metabotropic glutamate receptors. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):8083-7. PubMed.
Purro SA, Nicoll AJ, Collinge J. Prion Protein as a Toxic Acceptor of Amyloid-β Oligomers. Biol Psychiatry. 2018 Feb 15;83(4):358-368. Epub 2017 Nov 21 PubMed.
Qi Y, Hu NW, Rowan MJ. Switching off LTP: mGlu and NMDA receptor-dependent novelty exploration-induced depotentiation in the rat hippocampus. Cereb Cortex. 2013 Apr;23(4):932-9. Epub 2012 Apr 5 PubMed.
Smart K, Cox SM, Scala SG, Tippler M, Jaworska N, Boivin M, Séguin JR, Benkelfat C, Leyton M. Sex differences in [11C]ABP688 binding: a positron emission tomography study of mGlu5 receptors. Eur J Nucl Med Mol Imaging. 2019 May;46(5):1179-1183. Epub 2019 Jan 9 PubMed.
View all comments by Michael RowanUniversity of Arkansas for Medical Sciences
It is worth noting that the responses of mice to scrapie forms of PrP are reportedly sex-dependent (Loeuillet et al., 2010). In that case, greater virulence (a shorter incubation period) was observed in females, but it is easy to imagine that the structural requirements for scrapie propagation are distinct from those that permit this Aβ-mGluR5 interaction. The sex-dependency of scrapie latency appears to be dependent on the major androgen receptor (AR); similar to Ferguson’s group, Loeuillet et al. found no effect from manipulating estrogen receptors. It is somewhat curious that the scrapie effect seemed to involve some interaction in the periphery (peripheral interactions of PrP with the product of an AR-induced gene would be a reasonable hypothesis, given the effects of both AR mutation and castration); latency after direct CNS injections was not sex-dependent. Effects on mGluR5 were observed in dissociated cell cultures, again suggesting a distinction between scrapie propagation and this neurotransmission hypothesis. At any rate, manipulation of AR in this AD model would be intriguing.
References:
Loeuillet C, Boelle PY, Lemaire-Vieille C, Baldazza M, Naquet P, Chambon P, Cesbron-Delauw MF, Valleron AJ, Gagnon J, Cesbron JY. Sex effect in mouse and human prion disease. J Infect Dis. 2010 Aug 15;202(4):648-54. PubMed.
View all comments by Steve BargerMake a Comment
To make a comment you must login or register.