Paper
- Alzforum Recommends
Spurrier J, Nicholson L, Fang XT, Stoner AJ, Toyonaga T, Holden D, Siegert TR, Laird W, Allnutt MA, Chiasseu M, Brody AH, Takahashi H, Nies SH, Cañamás AP, Sadasivam P, Lee S, Li S, Zhang L, Huang YH, Carson RE, Cai Z, Strittmatter SM. Reversal of synapse loss in Alzheimer mouse models by targeting mGluR5 to prevent synaptic tagging by C1Q. Sci Transl Med. 2022 Jun;14(647):eabi8593. PubMed.
Recommends
Please login to recommend the paper.
Comments
University of Ottawa
The most interpretable result of the Phase 2 trial of the experimental complement inhibitor compound ANX005 in patients with Huntington’s disease (HD) is that there is target engagement for the proposed mechanism of C1q Target Inhibition.
Safety data warrants some reflection for future trials considering the total number of discontinuations and those explained by treatment-emergent serious adverse events in such a small trial.
The efficacy results should be interpreted with abundant reservation, as the trial was not designed to determine efficacy. This is a small, open-label trial, with no placebo arm in subjects at risk of or with early stage Huntington’s disease. We know from HD and other neurodegenerative disorders how the power of placebo can be reflected in efficacy outcomes, even after months of treatment.
In addition, any extrapolation of clinical and biomarker data on disease progression data from other HD cohorts needs to take into consideration that study participants were at a very early stage of the disease.
Overall, it is exciting news that a new compound warrants further investigation to address the enormous gap of disease modification in HD, and the HD community will follow the next chapter in its history with enthusiasm. Likely the company is advancing for a larger Phase 3 trial to address the question of efficacy of ANX005 that the current trial data is not able to solve.
View all comments by Tiago MestreUniversity of Texas Health at San Antonio
The Spurrier study shows that an mGluR5-targeted AD therapeutic can normalize neuronal gene signatures and reduce C1q synaptic localization without altering total C1q amount, which further reinforces the concept that neuronal genes can regulate complement and microglia-mediated synapse loss.
This important work also highlights the gap in our understanding of how C1q is recruited to the synapse, and provides further evidence that C1q is a promising therapeutic target in neurodegenerative diseases.
View all comments by Gek Ming SiaChildren's Hospital
Boston Children's Hospital
In their study, Spurrier et al., follow up on earlier work carried out by the same group (Haas et al., 2017). They recapitulate previous observations that treatment with a silent allosteric modulator of mGluR5 can increase synaptic density in AD mouse models, as well as rescue a variety of behavioral phenotypes. They extend this finding to other relevant disease models and expand their previous search into the underlying cellular and molecular mechanisms driving these beneficial phenotypes.
The strength of the current study lies in the pharmacokinetic profiling of BMS-984923, including investigations of receptor occupancy in nonhuman primates and studies of selectivity and toxicity across multiple species.
Furthermore, from a translational perspective, the demonstration in a preclinical rodent model that a key pathological hallmark of AD, namely the loss of synaptic populations, can to some extent be rescued by treatment with BMS-984923 and that this can be observed non-invasively with a clinically relevant SV2A PET tracer is another important finding. Imaging with this tracer in patients with neurodegenerative or neurodevelopmental disorders has already shown statistically significant associations between SV2A signal and clinically relevant disease transitions (Delva et al., 2022; Onwordi et al., 2020).
The authors' efforts to uncover mechanisms that might underlie the beneficial actions of BMS-984923 have yielded some interesting questions. At the same time, the data they present showing that C1Q association with synaptic proteins is diminished in AD models following treatment with BMS-984923—while itself intriguing, particularly in light of other work showing this protein to be important in synaptic elimination in other contexts—is insufficient on its own to support the claim that the reversal of synapse loss is mediated through this mechanism. The authors themselves acknowledge this in their discussion.
The authors have shown that synapse loss can be reversed and C1Q association with synaptic proteins reduced following treatment with BMS-984923, but these observations are only correlative. One way to test the necessity of reducing C1Q deposition with respect to the restoration of synaptic numbers would be to block this process through conditional genetic ablation of C1Q. Another would be to use pharmacological approaches, either together with, or in the absence of, the SAM, and to then assess whether blocking complement deposition alone is sufficient to rescue synapse density, as has been demonstrated in more acute paradigms earlier in disease progression and following genetic ablation of complement components from birth, and to assess whether there are any additive or synergistic effects of treatment with both agents.
It would also be interesting to look at how BMS-984923 might be acting to inhibit C1Q association with synaptic proteins or other functions of C1Q independent of classical complement pathway activation. Are downstream signaling or activation events in the complement cascade reversed or impacted by this compound?
Some interesting questions that arise not only from this work but also that of others are: What molecular mechanisms drive enhanced C1Q association with synaptic proteins in AD models? How specific is this phenotype to certain types of synapses or synaptic populations, and how are these associations reversed or impacted by treatment with BMS-984923? Given the role neuronal activity has been shown to play in microglial engulfment during developmental pruning events, could it be that altered patterns of activity within circuits are in some way acting as an instructive cue to prompt this process? This is intriguing given these authors' previous work showing the normalization of oligomeric Aβ-induced impaired LTD phenotypes in slice culture following treatment with BMS-984923 (Haas et al., 2017).
Finally, a caveat of the conclusions the authors draw is that mGluR5 is also expressed by specific populations of astrocytes under certain contexts. This includes AD models, where it has been implicated in synaptogenesis and changes in neuronal activity (Danjo et al., 2022; Grolla et al., 2013; Shrivastava et al., 2013).
Taken together with the authors' results showing reduced engulfment of synaptic material by astrocytes in the APP/PS1 model following treatment with the SAM, it’s possible that at least some of the phenotypes they observe are a result of it binding directly to astrocytic mGluR5, which may then subsequently feed back to alter neuronal biology or impact this cell's engulfment phenotype. This may be something worth exploring in future studies.
References:
Haas LT, Salazar SV, Smith LM, Zhao HR, Cox TO, Herber CS, Degnan AP, Balakrishnan A, Macor JE, Albright CF, Strittmatter SM. Silent Allosteric Modulation of mGluR5 Maintains Glutamate Signaling while Rescuing Alzheimer's Mouse Phenotypes. Cell Rep. 2017 Jul 5;20(1):76-88. PubMed.
Delva A, Michiels L, Koole M, Van Laere K, Vandenberghe W. Synaptic Damage and Its Clinical Correlates in People With Early Huntington Disease: A PET Study. Neurology. 2022 Jan 4;98(1):e83-e94. Epub 2021 Oct 18 PubMed.
Onwordi EC, Halff EF, Whitehurst T, Mansur A, Cotel MC, Wells L, Creeney H, Bonsall D, Rogdaki M, Shatalina E, Reis Marques T, Rabiner EA, Gunn RN, Natesan S, Vernon AC, Howes OD. Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats. Nat Commun. 2020 Jan 14;11(1):246. PubMed.
Danjo Y, Shigetomi E, Hirayama YJ, Kobayashi K, Ishikawa T, Fukazawa Y, Shibata K, Takanashi K, Parajuli B, Shinozaki Y, Kim SK, Nabekura J, Koizumi S. Transient astrocytic mGluR5 expression drives synaptic plasticity and subsequent chronic pain in mice. J Exp Med. 2022 Apr 4;219(4) Epub 2022 Mar 23 PubMed.
Grolla AA, Sim JA, Lim D, Rodriguez JJ, Genazzani AA, Verkhratsky A. Amyloid-β and Alzheimer's disease type pathology differentially affects the calcium signalling toolkit in astrocytes from different brain regions. Cell Death Dis. 2013;4:e623. PubMed.
Shrivastava AN, Kowalewski JM, Renner M, Bousset L, Koulakoff A, Melki R, Giaume C, Triller A. β-amyloid and ATP-induced diffusional trapping of astrocyte and neuronal metabotropic glutamate type-5 receptors. Glia. 2013 Oct;61(10):1673-86. PubMed.
View all comments by Daniel WiltonMake a Comment
To make a comment you must login or register.