Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils

Etani, H.; Takatori, S.; Wang, W.; Omi, J.; Akahori, A.; Watanabe, H.; Sonn, I.; Okano, H.; Hara, N.; Hasegawa, M.; Miyashita, A.; Kikuchi, M.; Ikeuchi, T.; Morishima, M.; Saito, Y.; Murayama, S.; Saito, T.; Saido, T. C.; Takai, T.; Ohwada, T.; Aoki, J.; Tomita, T.

doi:10.1101/2024.05.08.593262

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bioRxiv · 10.1101/2024.05.08.593262

Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils

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Abstract

Microglia, the primary immune cells of the central nervous system, play a crucial role in maintaining brain homeostasis through phagocytosis of various substrates, including amyloid-{beta} (A{beta}) fibrils, a hallmark of Alzheimer disease (AD) pathology. However, the molecular mechanisms regulating microglial A{beta} uptake remain poorly understood. Here, we identified GPR34, a Gi/o-coupled receptor highly expressed in microglia, as a novel regulator of fibrillar A{beta} phagocytosis. Treatment with a selective GPR34 agonist, M1, specifically enhanced uptake of A{beta} fibrils, but not its monomer or oligomer, in both mouse and human microglia. Mechanistically, M1 reduced intracellular cAMP levels, which inversely correlated with A{beta} uptake activity. Importantly, a single intrahippocampal injection of M1 in an AD mouse model significantly increased microglial A{beta} uptake in vivo. Furthermore, single-nucleus RNA-sequencing analysis of Japanese AD patient samples revealed a significant reduction of GPR34 expression in microglia from AD patients compared to controls. We also observed an age-dependent decline in microglial GPR34 expression in both human and mouse datasets, suggesting a potential contribution of GPR34 downregulation to age-related A{beta} accumulation and AD risk. Collectively, our findings identify GPR34 as a promising target for modulating microglial A{beta} clearance and highlight the therapeutic potential of GPR34 agonists in AD. Significance statementAlzheimer disease (AD) is characterized by amyloid-{beta} (A{beta}) accumulation in the brain. Microglia, the brains immune cells, play a crucial role in the metabolism of A{beta}. We discovered that activating the microglial receptor GPR34 with a selective agonist enhances the phagocytosis of A{beta} fibrils, a key pathogenic form of A{beta}. Importantly, GPR34 expression decreases with aging and AD progression, potentially contributing to impaired A{beta} clearance. Our findings highlight GPR34 as a promising therapeutic target for AD, as boosting its activity could promote A{beta} clearance and slow disease progression. This study provides valuable insights into microglial function in AD and offers a novel strategy for developing disease-modifying therapies.

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Etani, H., Takatori, S., Wang, W., Omi, J., Akahori, A., Watanabe, H., Sonn, I., Okano, H., Hara, N., Hasegawa, M., Miyashita, A., Kikuchi, M., Ikeuchi, T., Morishima, M., Saito, Y., Murayama, S., Saito, T., Saido, T. C., Takai, T., Ohwada, T., Aoki, J., Tomita, T.. 2024-05-09. Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils. https://doi.org/10.1101/2024.05.08.593262

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