Synaptic Actin Stabilization Protein Loss in Down Syndrome and Alzheimer Disease.

Reduced spine densities and an age-dependent accumulation of amyloid β and tau pathology are shared features of Down syndrome (DS) and Alzheimer's disease (AD). Spine morphology and the synaptic plasticity that supports learning both depend upon the actin cytoskeleton, suggesting that disturbances in actin regulatory signaling might underlie spine defects in both disorders. The present study evaluated synaptic levels of two proteins that promote filamentous actin stabilization, the Rho GTPase effector p21-activated kinase 3 (PAK3) and Arp2, in DS versus AD. Fluorescent deconvolution tomography was used to determine postsynaptic PAK3 and Arp2 levels for large numbers of excitatory synapses in parietal cortex of individuals with DS plus AD pathology or AD alone relative to age-matched controls. Although numbers of excitatory synapses were not different between groups, synaptic PAK3 levels were greatly reduced in DS+AD and AD individuals versus controls. Synaptic Arp2 levels also were reduced in both disorders, but to a greater degree in AD. Western blotting detected reduced Arp2 levels in the AD group, but there was no correlation with phosphorylated tau levels suggesting that Arp2 loss does not contribute to mechanisms that drive tau pathology progression. Overall, the results demonstrate marked synaptic disturbances in two actin regulatory proteins in adult DS and AD brains, with greater effects in individuals with AD alone. As both PAK and the Arp2/3 complex play roles in the actin stabilization that supports synaptic plasticity, reductions in these proteins at synapses may be early events in spine dysfunction that contribute to cognitive impairment in these disorders. This article is protected by copyright. All rights reserved.