Antagonism of LOTUS, a neural circuit formation factor, toward amyloid-β receptor PirB.

Abstract

Amyloid beta (Aβ) protein is well known as a primary risk factor for Alzheimer disease (AD). Aβ peptide forms amyloid plaque to interact with several cell surface receptors, leading to synaptic dysfunction and cognitive impairment in AD. Lateral olfactory tract usher substance (LOTUS) was identified as an endogenous antagonist for paired immunoglobulin-like receptor-B (PirB) as well as Nogo receptor 1 (NgR1). Previous studies have shown that LOTUS plays a crucial role in synapse formation and cognitive function through the blockade of these receptor functions. Since the deletion of PirB, reported as a receptor for Aβ, improved Aβ-induced synaptic dysfunction and restored cognitive function in AD model animals. Therefore, PirB is considered to be an important molecule mediating Aβ pathology. We assessed whether LOTUS inhibits Aβ-induced synapse elimination in primary cultured hippocampal neurons. We found that LOTUS suppressed the binding of Aβ to PirB and that cultured hippocampal neurons from LOTUS-tg mice improved the Aβ-induced decrease in dendritic spine density. On the other hand, PirB is also expressed in microglia, which is known as an immune cell in the brain and involved in Aβclearance and neuroinflammation. We also found that LOTUS suppressed Aβ-induced cytokine production and promoted Aβ phagocytosis. These findings suggest that LOTUS may have a role in suppressing disease progression of AD.