LOTUS suppresses amyloid β‑induced dendritic spine elimination through the blockade of amyloid β binding to PirB

Molecular Medicine, 2022 · DOI: https://doi.org/10.1186/s10020-022-00581-7 · Published: December 1, 2022

Simple Explanation

Alzheimer’s disease (AD) is a neurodegenerative disease with no effective treatment. Amyloid beta (Aβ) protein accumulates in the brain of AD patients. Paired immunoglobulin-like receptor B (PirB) has been identified as a receptor of Aβ, causing synapse elimination and synaptic dysfunction. Inhibiting the Aβ–PirB molecular interaction could be a successful approach for combating AD pathology. Lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of type1 Nogo receptor and PirB. This study implied that LOTUS improved Aβ-induced synapse elimination by suppressing Aβ-PirB interaction in rodents and inhibited Aβ–LilrB2 interaction in humans. Our findings revealed that LOTUS may be a promising therapeutic agent in counteracting Aβ-induced AD pathologies.

Study Duration

Not specified

Participants

WT or LOTUS-tg mice on embryonic day 17.5 (E17.5)

Evidence Level

Not specified

Key Findings

1
LOTUS inhibits the binding of Aβ to PirB overexpressed in Cos7 cells.
2
Aβ-induced dephosphorylation of cofilin and Aβ-induced decrease in post-synaptic density-95 expression were suppressed in cultured hippocampal neurons from LOTUS-overexpressing transgenic (LOTUS-tg) mice compared with that in wild-type mice.
3
Human LOTUS inhibited the binding of Aβ to LilrB2 in a similar manner.

Research Summary

This study implied that LOTUS improved Aβ-induced synapse elimination by suppressing Aβ-PirB interaction in rodents and inhibited Aβ–LilrB2 interaction in humans. PirB has been implicated in this pathology as a receptor of Aβ and has thus been regarded as a novel therapeutic target against AD. LOTUS inhibits the binding of Aβ to PirB in rodents or LilrB2 in humans and that LOTUS suppressively regulates Aβ-induced intracellular responses, including dephosphorylation of cofilin and the reduction of PSD95, and that LOTUS suppresses the Aβ-induced synaptotoxic phenomenon, such a decrease in spine density.

Practical Implications

Therapeutic Potential

LOTUS may be a promising therapeutic agent in counteracting Aβ-induced AD pathologies.

Drug Development

LOTUS could be a template for developing drugs that target the Aβ-PirB interaction.

Further Research

Future studies should explore how LOTUS affects cognitive function in AD model animals and the expression levels of LOTUS in patients with AD.

Study Limitations

1
The detailed molecular mechanism in inhibiting Aβ binding to PirB by LOTUS requires further investigation.
2
The domains of human LOTUS and LilrB2 that interact with each other remain unclear.
3
Further studies are required to determine if LOTUS inhibits Aβ-induced synapse elimination via NgR1.

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