Synaptic Organizers in Alzheimer's Disease: A Classification Based on Amyloid-β Sensitivity.

Alfred Kihoon Lee,Hideto Takahashi,Husam Khaled,Nicolas Chofflet

doi:10.3389/fncel.2020.00281

Abstract

Synaptic pathology is one of the major hallmarks observed from the early stage of Alzheimer’s disease (AD), leading to cognitive and memory impairment characteristic of AD patients. Synaptic connectivity and specificity are regulated by multiple trans-bindings between pre- and post-synaptic organizers, the complex of which exerts synaptogenic activity. Neurexins (NRXs) and Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are the major presynaptic organizers promoting synaptogenesis through their distinct binding to a wide array of postsynaptic organizers. Recent studies have shown that amyloid-β oligomers (AβOs), a major detrimental molecule in AD, interact with NRXs and neuroligin-1, an NRX-binding postsynaptic organizer, to cause synaptic impairment. On the other hand, LAR-RPTPs and their postsynaptic binding partners have no interaction with AβOs, and their synaptogenic activity is maintained even in the presence of AβOs. Here, we review the current evidence regarding the involvement of synaptic organizers in AD, with a focus on Aβ synaptic pathology, to propose a new classification where NRX-based and LAR-RPTP-based synaptic organizing complexes are classified into Aβ-sensitive and Aβ-insensitive synaptic organizers, respectively. We further discuss how their different Aβ sensitivity is involved in Aβ vulnerability and tolerance of synapses for exploring potential therapeutic approaches for AD.

Highlights

Alzheimer’s disease (AD), the most common age-related neurodegenerative disease with progressive cognitive decline including memory loss, has seen a sharp increase in the number of cases and AD-related deaths over the past decades
While the underlying mechanism and the synaptic role of the LRRTM3-dependent modulation of amyloid precursor protein (APP) processing need to be addressed, these findings suggest that NRX-LRRTM3mediated synapses may be vulnerable to amyloid β (Aβ) due to local Aβ overproduction by LRRTM3 as well as Aβ binding to NRXs at the synapse level
Given the discrepancy among the studies regarding Aβ binding to NLGN1 (Dinamarca et al, 2011; Brito-Moreira et al, 2017; Naito et al, 2017b), it is important to confirm whether Aβ-insensitive synaptic organizers including LAR-RPTPs have no Aβ-binding ability by performing multiple independent experimental approaches

Summary

Frontiers in Cellular Neuroscience

Synaptic pathology is one of the major hallmarks observed from the early stage of Alzheimer’s disease (AD), leading to cognitive and memory impairment characteristic of AD patients. Recent studies have shown that amyloid-β oligomers (AβOs), a major detrimental molecule in AD, interact with NRXs and neuroligin-1, an NRX-binding postsynaptic organizer, to cause synaptic impairment. LAR-RPTPs and their postsynaptic binding partners have no interaction with AβOs, and their synaptogenic activity is maintained even in the presence of AβOs. Here, we review the current evidence regarding the involvement of synaptic organizers in AD, with a focus on Aβ synaptic pathology, to propose a new classification where NRX-based and LARRPTP-based synaptic organizing complexes are classified into Aβ-sensitive and Aβinsensitive synaptic organizers, respectively.

INTRODUCTION

Synaptic Organizers in Aβ Pathology

SYNAPTIC ORGANIZERS IN AD

THE ROLE OF SYNAPTIC ORGANIZERS IN TAU PATHOLOGY

CONCLUSION AND FUTURE DIRECTIONS