Nanoscale reorganisation of synaptic proteins in Alzheimer's disease

Abstract

AimsSynaptic strength depends strongly on the subsynaptic organisation of presynaptic transmitter release and postsynaptic receptor densities, and their alterations are expected to underlie pathologies. Although synaptic dysfunctions are common pathogenic traits of Alzheimer's disease (AD), it remains unknown whether synaptic protein nano‐organisation is altered in AD.Here, we systematically characterised the alterations in the subsynaptic organisation in cellular and mouse models of AD.MethodsWe used immunostaining and super‐resolution stochastic optical reconstruction microscopy imaging to quantitatively examine the synaptic protein nano‐organisation in both Aβ1–42‐treated neuronal cultures and cortical sections from a mouse model of AD, APP23 mice.ResultsWe found that Aβ1–42‐treatment of cultured hippocampal neurons decreased the synaptic retention of postsynaptic scaffolds and receptors and disrupted their nanoscale alignment to presynaptic transmitter release sites. In cortical sections, we found that while GluA1 receptors in wild‐type mice were organised in subsynaptic nanoclusters with high local densities, receptors in APP23 mice distributed more homogeneously within synapses. This reorganisation, together with the reduced overall receptor density, led to reduced glutamatergic synaptic transmission. Meanwhile, the transsynaptic alignment between presynaptic release‐guiding RIM1/2 and postsynaptic scaffolding protein PSD‐95 was reduced in APP23 mice. Importantly, these reorganisations were progressive with age and were more pronounced in synapses in close vicinity of Aβ plaques with dense cores.ConclusionsOur study revealed a spatiotemporal‐specific reorganisation of synaptic nanostructures in AD and identifies dense‐core amyloid plaques as the major local inductor in APP23 mice.

Loss of postsynaptic NMDARs drives nanoscale reorganization of Munc13-1 and PSD-95

“…The results of this study may also shed light on synaptic rearrangement that occurs during pathological states associated with a decrease either in NMDAR number or activity at the synapse. Several examples of pathological NMDAR downregulation include: NMDAR hypofunction in schizophrenia (Balu, 2016), NMDAR antibody binding induced receptor internalization in Anti-NMDAR encephalitis (Dalmau and Graus, 2018), as well as reduction of NMDAR activation (Sinnen et al, 2016) and increased endocytosis (Kurup et al, 2010) in Alzheimer's disease models involving Amyloid β, which was recently and independently associated with synaptic nanostructural rearrangement (Zhu et al, 2023). Our results suggest that disease states that differentially impact NMDAR function or presence at the synapse may yield distinct nanostructural states that contribute to the unique functional status of synapses in these disorders.…”