Inhibition of FAM19A5 reverses synaptic loss and cognitive decline in mouse models of Alzheimer's disease.

Background: FAM19A5 is a secretory protein primarily expressed in neurons. Although its role in synaptic function has been suggested, the precise molecular mechanisms underlying its effects at the synapse remain unclear. Given that synaptic loss is a critical hallmark of Alzheimer's disease (AD), elucidating the mechanisms involving FAM19A5 could provide valuable insights into reversing synaptic loss in AD.

Methods: The binding partner of FAM19A5 was identified through co-immunoprecipitation experiments of mouse brain tissue. The effect of FAM19A5 on spine density in hippocampal neurons was evaluated using immunocytochemistry by overexpressing FAM19A5, treating neurons with FAM19A5 protein, and/or an anti-FAM19A5 antibody NS101. Target engagement of NS101 was determined by measuring FAM19A5 levels in mouse, rat, and human plasma at specific time points post NS101 injection using ELISA. Changes in spine density and dynamics in P301S tauopathy mice were assessed via Golgi staining and two-photon microscopy after NS101 administration. The synaptic strengthening of hippocampal neurons in APP/PS1 amyloidopathy mice after NS101 treatment was assessed by measuring miniature excitatory postsynaptic currents (mEPSCs) and field excitatory postsynaptic potentials (fEPSPs). Cognitive performance in AD mice after NS101 treatment was measured using the Y-maze and Morris water maze tests.

Results: FAM19A5 binds to LRRC4B, a postsynaptic adhesion molecule, leading to reductions in spine density in mouse hippocampal neurons. Inhibiting FAM19A5 function with NS101 increased spine density. Intravenous administration of NS101 increased spine density in the prefrontal cortex of P301S mice, which initially showed reduced spine density compared to wild-type (WT) mice. NS101 normalized the spine elimination rate in P301S mice, restoring the net spine count to levels comparable to WT mice. NS101 treatment enhanced the frequency of mEPSCs and fEPSPs in the hippocampal synapses of APP/PS1 mice, leading to improved cognitive function. The increases in plasma FAM19A5 levels upon systemic NS101 administration suggest that the antibody effectively engages its target and facilitates the transport of FAM19A5 from the brain.

Conclusions: This study demonstrated that inhibiting FAM19A5 function with an anti-FAM19A5 antibody restores synaptic integrity and enhances cognitive function in AD, suggesting a novel therapeutic strategy for AD.

Trial registration: https://clinicaltrials.gov/study/NCT05143463 , Identifier: NCT05143463, Release date: 3 December 2021.