Abstract
Introduction Alzheimer’s disease (AD) is characterized by the dysregulation of synaptic balance, with progressive loss of synapses outpacing formation, ultimately leading to cognitive decline. However, the lack of effective strategies for restoring lost synapses poses a major barrier to improving clinical outcomes.
Methods We developed NS101, a monoclonal antibody targeting FAM19A5, a brain-secreted protein. Its preclinical efficacy in restoring synapses and cognition was evaluated using APP/PS1 and P301S mice. The clinical safety and target engagement of NS101 were examined in human participants.
Results FAM19A5 binds to LRRC4B, a postsynaptic adhesion molecule, leading to synapse reduction. Blocking this interaction with NS101 normalized the rate of synapse elimination in AD mice. This synaptic rebalancing restored the number and function of synapses, resulting in improved cognition. Systemically administered NS101 facilitated the transport of brain FAM19A5 into the bloodstream.
Discussion Targeting FAM19A5 may hold clinical promise for treating AD by restoring synaptic balance.
Competing Interest Statement
HB.K, SJ.Y, HY.K, SX.M, RH.K, MH.L, N.H, EH.C, SM.L, JW.J, WK.K, YS.P, SI.P, SG.K and JY.S are employed by Neuracle Science, Co., Ltd. MH.L, SM.L, WK.K, SW.H, HC.P, and JY.S are shareholders of Neuracle Science, Co., Ltd. The remaining authors have no conflicts of interest to declare.
Footnotes
Major changes to the manuscript include the following: 1. We have added Co-IP experiments to investigate the interaction between FAM19A5, LRRC4B, and PTPRF under physiological conditions. The results showed that FAM19A5 interacts with LRRC4B at the postsynapse, influencing synaptic connections mediated by LRRC4B and PTPRF. 2. We conducted immunocytochemistry on cultured hippocampal neurons transfected with eGFP- and FAM19A5-containing plasmids. This experiment revealed the locations of FAM19A5, LRRC4B, and PTPRF at pre- and postsynaptic sites. Furthermore, these experiments provide clearer evidence of the role of FAM19A5 in regulating synapse formation or elimination. 3. In our response sheet, we have outlined various interpretations of the studies conducted by Huang et al. (2021) and Wang et al. (2018). We obtained research findings that may contrast with their results; however, this content was not included in the current manuscript to maintain clarity and focus in the discussion. Additionally, much of this research was part of doctoral theses, which we published independently on BioRXiv, and we have cited these sources in the Background sections. 4. We incorporated changes in the pTau and Aβ levels induced by NS101 in tauopathy and amyloidopathy mouse models, respectively. Additionally, we detected alterations in the activities of astrocytes and microglia caused by NS101 in these mice.
