Park, S.; Shahapal, A.; Yoo, S.; Hwang, J.-I.; Seong, J. Y.

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/FAM19A5LacZ+/-. Compared to control APP/PS1 mice, APP/PS1/FAM19A5LacZ+/- mice exhibited significantly lower A{beta} plaque density, suggesting that FAM19A5 reduction mitigates A{beta} plaque formation. Notably, FAM19A5 partial depletion also prolonged the lifespan of APP/PS1 mice. To further explore the therapeutic potential of FAM19A5 targeting, 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 with rapid A{beta} 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 A{beta} plaques and improving cognitive function.