Price BR, Sudduth TL, Weekman EM, Johnson S, Hawthorne D, Woolums A, Wilcock DM. Therapeutic Trem2 activation ameliorates amyloid-beta deposition and improves cognition in the 5XFAD model of amyloid deposition. J Neuroinflammation. 2020 Aug 14;17(1):238. PubMed.
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Washington University School of Medicine
This new paper by Wilcock and colleagues shows that intracranial injection or systemic administration of an agonist antibody specific for mouse TREM2, AL002a, induces pro-inflammatory and anti-inflammatory/repair gene expression, enhancing microglial responses to Aβ plaques, and improving impaired cognitive functions in the 5XFAD mouse model of Aβ accumulation. Overall, this study corroborates a protective effect of anti-TREM2 mAbs on amyloid plaque pathology. A reduction of Aβ load was recently reported by Denali with a different anti-mouse TREM2 antibody in a different mouse model (Schlepckow et al., 2020). Moreover, treatment with AL002a was also recently found to promote myelin debris clearance in the cuprizone model of CNS demyelination, as reported by Laura Piccio, Ilaria Tassi, and colleagues (Cignarella et al., 2020), suggesting a broad beneficial effect of TREM2 activation by AL002a in neurodegenerative and demyelinating diseases.
Our group recently reported that prolonged systemic administration of an anti-human TREM2, AL002c, reduced filamentous plaques and neurite dystrophy, impacted behavior, and tempered microglial inflammatory response in 5XFAD mice carrying either the human TREM2 common variant or the R47H variant associated with risk for Alzheimer’s Disease (Wang et al., 2020). However, we did not observe significant reduction of Aβ loads, and microglial clustering around plaques did not change upon treatment. Such discrepancy might be due to the different doses and duration of the antibody treatment. In our experiments, mice were treated with 30 mg/Kg of mAb for 12 weeks starting from 5 months of age. In the Wilcock paper, a dose of 50 mg/Kg for 14 weeks was used. Another important difference is that in our experiments 5XFAD mice carried human TREM2, whereas in the Wilcock study 5XFAD mice carried the endogenous mouse TREM2. Finally, the antibodies were different, which may impact specificity, mechanism of action, and pharmacokinetics. While all these preliminary studies support the potential value of anti-TREM2 antibodies in the treatment of Alzheimer’s disease, it will be important to extend our studies comparing different antibodies, treatment regimens, and mouse models.
References:
Schlepckow K, Monroe KM, Kleinberger G, Cantuti-Castelvetri L, Parhizkar S, Xia D, Willem M, Werner G, Pettkus N, Brunner B, Sülzen A, Nuscher B, Hampel H, Xiang X, Feederle R, Tahirovic S, Park JI, Prorok R, Mahon C, Liang CC, Shi J, Kim DJ, Sabelström H, Huang F, Di Paolo G, Simons M, Lewcock JW, Haass C. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol Med. 2020 Apr 7;12(4):e11227. Epub 2020 Mar 10 PubMed.
Cignarella F, Filipello F, Bollman B, Cantoni C, Locca A, Mikesell R, Manis M, Ibrahim A, Deng L, Benitez BA, Cruchaga C, Licastro D, Mihindukulasuriya K, Harari O, Buckland M, Holtzman DM, Rosenthal A, Schwabe T, Tassi I, Piccio L. TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of multiple sclerosis. Acta Neuropathol. 2020 Oct;140(4):513-534. Epub 2020 Aug 9 PubMed.
Wang S, Mustafa M, Yuede CM, Salazar SV, Kong P, Long H, Ward M, Siddiqui O, Paul R, Gilfillan S, Ibrahim A, Rhinn H, Tassi I, Rosenthal A, Schwabe T, Colonna M. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model. J Exp Med. 2020 Sep 7;217(9) PubMed.
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