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

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.

SorCS1 inhibits amyloid-β binding to neurexin and rescues amyloid-β–induced synaptic pathology

“…We found that axonal expression of either SorCS1b or SorCS1bΔVPS10 did not significantly affect Slitrk2-induced VGLUT1 accumulation regardless of AβO treatment (Fig 4E and F). This finding is in line with the results of our previous study showing that RPTP-mediated presynaptic differentiation is insensitive to AβOs (Naito et al, 2017;Lee et al, 2020) and suggests that it is also insensitive to SorCS1, consistent with our binding results showing that SorCS1-Fc does not interact with any RPTPs or Slitrks (Fig 1A). In conclusion, these findings suggest that axonal SorCS1b expression rescues AβO-induced impairment of NRXmediated presynaptic organization through cis-interaction with β-NRXs.…”

SorCS1 inhibits amyloid-β binding to neurexin and rescues amyloid-β-induced synaptic pathology

“…We found that axonal expression of either SorCS1b or SorCS1bΔVPS10 did not significantly affect Slitrk2-induced VGLUT1 accumulation regardless of AβO treatment (Fig 4E and F). This finding is in line with the results of our previous study showing that RPTP-mediated presynaptic differentiation is insensitive to AβOs (Lee et al, 2020;Naito et al, 2017) and suggests that it is also insensitive to SorCS1, consistent with our binding results showing that SorCS1-Fc does not interact with any RPTPs or Slitrks (Fig 1A). In conclusion, these findings suggest that axonal SorCS1 expression rescues AβO-induced impairment of NRX-mediated presynaptic organization through cis-interaction with β-NRXs.…”

Key Disease Mechanisms Linked to Alzheimer’s Disease in the Entorhinal Cortex

“…Fluctuations in NRXN1 levels and other neurexins are implicated in disrupting the balance of excitatory and inhibitory signals at synapses, resulting in damage and cognitive impairment seen early in AD [ 40 ]. NRXN1 has been found to interact with the Aβ plaques in AD leading to synaptic transmission impairment [ 41 ]. Presenilins, proteases involved in Aβ formation, proteolytically process neurexins, and the dysfunction of this pathway may be associated with AD [ 42 ].…”