Amyloid β / PKC-dependent alterations in NMDA receptor composition are detected in early stages of Alzheimer´s disease

Abstract

Amyloid beta (Aβ)-mediated synapse dysfunction is an early event in Alzheimer’s disease (AD) pathogenesis and previous studies suggest that NMDA receptor (NMDAR) dysregulation may contribute to these pathological effects. Although Aβ peptides impair NMDAR expression and activity, the mechanisms mediating these alterations in the early stages of AD are unclear. Here, we observed that NMDAR subunit NR2B and PSD-95 levels were aberrantly upregulated and correlated with Aβ42 load in human postsynaptic fractions of the prefrontal cortex in early stages of AD patients, as well as in the hippocampus of 3xTg-AD mice. Importantly, NR2B and PSD95 dysregulation was revealed by an increased expression of both proteins in Aβ-injected mouse hippocampi. In cultured neurons, Aβ oligomers increased the NR2B-containing NMDAR density in neuronal membranes and the NMDA-induced intracellular Ca2+ increase, in addition to colocalization in dendrites of NR2B subunit and PSD95. Mechanistically, Aβ oligomers required integrin β1 to promote synaptic location and function of NR2B-containing NMDARs and PSD95 by phosphorylation through classic PKCs. These results provide evidence that Aβ oligomers modify the contribution of NR2B to NMDAR composition and function in the early stages of AD through an integrin β1 and PKC-dependent pathway. These data reveal a novel role of Aβ oligomers in synaptic dysfunction that may be relevant to early-stage AD pathogenesis.

Recombinant Integrin β1 Signal Peptide Blocks Gliosis Induced by Aβ Oligomers

“…We have previously observed that Aβ oligomer-induced PKC phosphorylation is mediated by integrin β1 in astrocytes and in neurons [ 38 ]. Further, Aβ oligomers lead to NR2B subunit upregulation on neuronal membranes through the PKC signaling pathway [ 46 ]. Under these circumstances, integrin β1 transduces the message that Aβ oligomers brings, generating a cellular response which manifests itself in a higher permeability for calcium ions to alter cellular homeostasis [ 46 ].…”

“…Further, Aβ oligomers lead to NR2B subunit upregulation on neuronal membranes through the PKC signaling pathway [ 46 ]. Under these circumstances, integrin β1 transduces the message that Aβ oligomers brings, generating a cellular response which manifests itself in a higher permeability for calcium ions to alter cellular homeostasis [ 46 ]. Hence, depending on the stimulus or ligands, the same receptor along with its intracellular signaling molecules can switch on/off different pathways that lead to antagonistic cellular responses.…”

“…We and others have described a key molecular relationship between integrin β1 and Aβ peptides required to modulate neuronal and glial biology [ 27 , 38 , 42 , 46 ]. The findings point out the molecular mechanism by which recombinant R s peptide works in order to block Aβ oligomer intracellular signaling both in vitro and in vivo.…”

Aberrant protein S-nitrosylation contributes to hyperexcitability-induced synaptic damage in Alzheimer’s disease: Mechanistic insights and potential therapies

“…Prior studies indicate that this increased excitation is due at least in part to dysfunction in the glutamatergic system in the cortex and hippocampus ( Danysz and Parsons, 2012 ; Ghatak et al, 2019 ; Yuan et al, 2022 ). Elevated glutamate levels in the cerebrospinal fluid (CSF), increased glutamate receptor expression and activity, and decreased glutamate clearance as well as increased release, have all been found to contribute to the neuronal hyperactivation observed in AD ( Figure 1 ; Li et al, 2009 ; Pirttimaki et al, 2013 ; Talantova et al, 2013 ; Madeira et al, 2018 ; Ghatak et al, 2019 ; Zott et al, 2019 ; Ortiz-Sanz et al, 2022 ).…”

“…In addition to AMPA receptors and mGluRs, NMDA receptors play arguably the most important role in excitotoxic damage and E/I imbalance. While glutamatergic neurotransmission via synaptic NMDA receptors is critical for induction of long-term potentiation (LTP) and survival of neurons in several brain areas, excessive NMDA receptor activity (especially extrasynaptic NMDA receptors) contributes to aberrant gene transcription and excitotoxic pathways leading to synaptic damage, neurodegeneration and cognitive decline in AD and in other neurologic diseases ( Hardingham et al, 2002 ; Lipton, 2006 ; Alberdi et al, 2010 ; Danysz and Parsons, 2012 ; Talantova et al, 2013 ; Wang and Reddy, 2017 ; Ghatak et al, 2021b ; Ortiz-Sanz et al, 2022 ). In contrast, physiological synaptic NMDA receptor activity leads to gene expression that opposes these destructive processes ( Hardingham et al, 2002 ; Hardingham and Bading, 2010 ).…”