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/FAM19A5LacZ+/-. Compared to control APP/PS1 mice, APP/PS1/FAM19A5LacZ+/- mice exhibited significantly lower Aβ plaque density, suggesting that FAM19A5 reduction mitigates Aβ 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 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.

Inhibition of FAM19A5 restores synaptic loss and improves cognitive function in mouse models of Alzheimer’s disease

“…Building upon the established role of FAM19A5 as a physiological synaptolytic factor, we hypothesized that amyloid plaques and tau tangles in AD act as pathological drivers of excessive synapse elimination, tilting the balance toward detrimental synapse loss. Our recent observation showed that reducing FAM19A5 levels in the AD brain by crossbreeding FAM19A5LacZ+/-mice with APP/PS1 mice extended the lifespan compared to that of APP/PS1 mice, partially supporting this hypothesis 40 . Therefore, for the treatment of AD, we targeted FAM19A5 to restore synaptic balance rather than removing pathological aggregates through the monoclonal FAM19A5 antibody NS101.…”

“…Our recent observation showed that reducing FAM19A5 levels in the AD brain by crossbreeding FAM19A5LacZ+/-mice with APP/PS1 mice extended the lifespan compared to that of APP/PS1 mice, partially supporting this hypothesis 40 . Therefore, for the treatment of AD, we targeted FAM19A5 to restore synaptic balance rather than removing pathological aggregates through the monoclonal FAM19A5 antibody NS101.…”