Neha Mithani

Background: The modulation of the TREM2 pathway holds promise as a therapeutic strategy across various neurodegenerative conditions, including Alzheimer’s disease (AD)¹. TREM2, predominantly expressed in microglia², plays a pivotal role in regulating immune responses and phagocytosis in the central nervous system (CNS)^4,. Dysregulation of this pathway has been implicated in the pathogenesis of AD, highlighting its significance in neurodegeneration⁷.

Objective: This review aims to elucidate the role of the TREM2 pathway in neuroinflammation and its potential as a therapeutic target in neurodegenerative diseases, with a specific focus on AD³.

Search Methods: A comprehensive literature search encompassing PubMed and other databases was conducted using relevant MeSH terms and keywords such as “Alzheimer’s pathology”, “role of microglia”, and “dysfunction in TREM”. Articles from 2019 to 2024 were included to capture recent advancements in the field.

Results: The Phase I study evaluated the impact of AL002, a humanized monoclonal IgG1 antibody targeting TREM2, on cerebrospinal fluid biomarkers. Following a single dose of AL002, there was a dose-dependent reduction in soluble TREM2 (sTREM2) levels and an increase in soluble CSF-1R (sCSF-1R) within two days⁵. The decrease in sTREM2 indicates potential interference with proteolytic shedding or induction of TREM2 internalization, while the increase in sCSF-1R suggests heightened microglia proliferation. Preliminary trial data demonstrated that AL002 is safe, well-tolerated, and effectively engages its specific targets. These results support the potential of AL002 as a therapeutic intervention for Alzheimer’s disease (AD), offering broader neuroprotective effects beyond AD pathology⁶. The findings from the INVOKE Phase I trial in healthy volunteers corroborate the pharmacodynamic effects of AL002, indicating activation of the TREM2 pathway and microglial activity in response to treatment.

Conclusion: Targeting the TREM2 pathway represents a promising avenue for therapeutic intervention in neurodegenerative diseases. Understanding the intricate mechanisms underlying TREM2 modulation and its impact on microglial function is essential for developing effective treatments. Further research into TREM2-targeted therapies holds potential for addressing the unmet medical needs in neurodegenerative disorders beyond AD.

Implications and Future Research: Future research efforts should focus on elucidating the precise mechanisms by which TREM2 modulates microglial function and neuroinflammation. Clinical trials investigating TREM2-targeted therapies in diverse neurodegenerative conditions are warranted to translate preclinical findings into clinical practice. Additionally, exploring novel approaches for enhancing TREM2 activity or targeting downstream signalling pathways may yield innovative therapeutic strategies for neurodegenerative diseases.

Works Cited:

1. Rostagno AA. Pathogenesis of Alzheimer’s Disease. Int J Mol Sci . 2022;24(1):107.Published 2022 Dec 21. doi:10.3390/ijms24010107
2. Zhang C. Etiology of Alzheimer’s Disease. Discov Med . 2023;35(178):757-776. doi:10.24976/Discov.Med.202335178.71
3. Parhizkar S, Holtzman DM. APOE mediated neuroinflammation and neurodegeneration in Alzheimer’s disease. Semin Immunol. 2022;59:101594. doi:10.1016/j.smim.2022.101594
4. Miao J, Ma H, Yang Y, et al. Microglia in Alzheimer’s disease: pathogenesis, mechanisms, and therapeutic potentials. Frontiers in Aging Neuroscience. 2023;15. doi:https://doi.org/10.3389/fnagi.2023.1201982
5. Wang C, Xiong M, Gratuze M, et al. Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia. Neuron. 2021;109(10):1657-1674.e7. doi:10.1016/j.neuron.2021.03.024
6. Ellwanger, D. C., Wang, S., Brioschi, S., Shao, Z., Green, L., Case, R., Yoo, D., Weishuhn, D., Rathanaswami, P., Bradley, J., Rao, S., Cha, D., Luan, P., Sambashivan, S., Gilfillan, S., Hasson, S. A., Foltz, I. N., & Colonna, M. (2021). Prior activation state shapes the microglia response to antihuman TREM2 in a mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences, 118(3), e2017742118. https://doi.org/10.1073/pnas.2017742118
7. Wang S, Mustafa M, Yuede CM, et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J Exp Med. 2020;217(9):e20200785. doi:10.1084/jem.20200785