Nanoscale reorganisation of synaptic proteins in Alzheimer's disease

Aims Synaptic 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. Methods We 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. Results We 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. Conclusions Our 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. AMPA receptors and PSD‐95 scaffold organise in local high‐density nanoclusters opposite presynaptic glutamate release sites, which is believed to optimise synaptic transmission. Using super‐resolution imaging, we found that these nanoscale organisations were greatly disrupted in APP23 mice, with postsynaptic proteins showing lower density, distributing more homogeneously and aligning less with release sites. These reorganizations were progressive with age and was more pronounced in synapses in close vicinity of Aβ plaques with dense cores.