Synaptic Adhesion Molecule Pcdh-γC5 Mediates Synaptic Dysfunction in Alzheimer's Disease

Abstract

Synaptic dysfunction and neuronal excitatory/inhibitory imbalance have been implicated in Alzheimer's disease (AD) pathogenesis. Although intensive studies have been focused on the excitatory synaptic system, much less is known concerning the mechanisms mediating inhibitory synaptic dysfunction in AD. We reported previously that protocadherin-γC5 (Pcdh-γC5), a member of clustered Pcdh-γ subfamily of cadherin-type synaptic adhesion proteins, functions to promote GABAergic synaptic transmission. We reveal here that Pcdh-γC5 is enriched in vesicular GABA transporter-positive synaptic puncta and its expression levels are increased in neuronal hyperexcitation conditions, upon β-amyloid (Aβ) treatment, and in amyloid precursor protein (APP)/presenilin-1 (PS1)-transgenic mice of both sexes. This is associated with elevated levels of GABAergic proteins and enhanced synaptic inhibition. Genetic knock-down experiments showed that Pcdh-γC5 modulates spontaneous synaptic currents and Aβ-induced synaptic alterations directly. Our results support a model in which Pcdh-γC5 senses neuronal hyperexcitation to augment GABAergic inhibition. This adaptive mechanism may be dysregulated under chronic excitation conditions such as AD, leading to aberrant Pcdh-γC5 expression and associated synaptic dysfunction. Synaptic dysfunction is causal for Alzheimer's disease (AD). Here, we reveal a novel pathway that contributes GABAergic synaptic dysfunction in AD mediated by protocadherin-γC5. Our study not only identifies a new mechanism mediating excitatory/inhibitory balance in AD, but may also offer a new target for potential therapeutic intervention.

Neuroligin-1 is altered in the hippocampus of Alzheimer’s disease patients and mouse models, and modulates the toxicity of amyloid-beta oligomers

“…In contrast with other isoforms, the isoform of NLGN1 not containing any insert is located equally at glutamatergic and www.nature.com/scientificreports www.nature.com/scientificreports/ gamma-aminobutyric acid (GABA) synapses 67 . This could suggest that the negative impact on NLGN1 could play a role in GABAergic synapse dysfunctions observed in AD and animal models 68,69 , as well as in glutamatergic synapse modifications 8,12,21 . Besides, the initial increase in Nlgn1 expression after 2 days of Aβo exposure might belong to a neuroprotective pathway similar to other pathways driven by Aβ in the hippocampus 70 .…”

Protocadherins at the Crossroad of Signaling Pathways

“…Both Pcdhs regulate membrane expression of the GABA A R subunits, possibly by facilitating their trafficking to the cell surface (Li et al, 2012a;Bassani et al, 2018) (Figure 6D). Recently, a model for Alzheimer's Disease (AD) was postulated whereby PcdhγC5 could increase inhibitory neurotransmission by enhancing synaptic GABAergic signaling and thus counterbalance the hyperexcitation caused by β-amyloid plaques (Li et al, 2017). Taken together, these findings suggest the involvement of several Pcdhs in synaptic transmission, although their specific action mechanisms in this context remain to be further examined.…”

The firstAntechinusreference genome provides a resource for investigating the genetic basis of semelparity and age-related neuropathologies

“…Antechinus displayed similar numbers of putative Pcdh-γ genes as humans and mouse (20-21 genes) in comparison to the other marsupials which showed only 6-9 genes in this family, and the platypus only 2 ( Figure 6). Pcdh-γ genes specifically have been implicated in neuronal processes [80] and have previously been associated with Alzheimer's disease [82]. These genes are most highly expressed in the brain in humans and also showed highest levels of expression in the brain and adrenal gland in the antechinus (Supplementary Table 7).…”