FAM19A5 Deficiency Mitigates the Aβ Plaque Burden and Improves Cognition in Mouse Models of Alzheimer’s Disease

ABSTRACT FAM19A5, a novel secretory protein highly expressed in the brain, is potentially associated with the progression of Alzheimer’s disease (AD). However, its role in the AD brain remains unclear. Here, we investigated the potential function of FAM19A5 in the context of AD. We generated APP/PS1 mice with partial FAM19A5 deficiency, termed APP/PS1/FAM19A5+/LacZ mice. Compared to control APP/PS1 mice, APP/PS1/FAM19A5+/LacZ mice exhibited significantly lower Aβ plaque density, suggesting that FAM19A5 reduction mitigates Aβ plaque formation. Notably, partial FAM19A5 depletion also prolonged the lifespan of the APP/PS1 mice. To further explore the therapeutic potential of targeting FAM19A5, we developed an anti-FAM19A5 antibody. Administration of this antibody to APP/PS1 mice significantly improved their performance in the novel object recognition test, demonstrating enhanced cognitive function. This effect was reproduced in 5XFAD mice, a model of early-onset AD characterized by rapid Aβ accumulation. Additionally, anti-FAM19A5 antibody treatment in 5XFAD mice led to increased spontaneous alternation behavior in the Y-maze test, indicating improved spatial working memory. These findings suggest that anti-FAM19A5 antibodies may be a promising therapeutic strategy for AD by reducing Aβ plaques and improving cognitive function. Competing Interest Statement The authors have declared no competing interest. Footnotes A reference list has been updated: [12]Kim, H.B., Yoo, S., Kwak, H., Ma, S.X., Kim, R., Lee, M., Ha, N., Pyo, S., Kwon, S.G., Cho, E.H., Lee, S.M., Jang, J., Kim, W., Park, H.C., Baek, M., Park, Y., Park, J.Y., Park, J.W., Hwang, S.W., Hwang, J.I., Seong, J.Y. (2023) Inhibition of FAM19A5 restores synaptic loss and improves cognitive function in mouse models of Alzheimer's disease, bioRxiv, 2023.11.22.568357.