Synaptic actin stabilization protein loss in Down syndrome and Alzheimer disease
| Autor: | Julie C. Lauterborn, Christine M. Gall, See Wing Chan, Conor D. Cox, Peter W. Vanderklish, Gary Lynch |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Dendritic spine Arp2/3 complex macromolecular substances Filamentous actin Article Pathology and Forensic Medicine 03 medical and health sciences 0302 clinical medicine Postsynaptic potential Alzheimer Disease medicine Humans biology General Neuroscience Middle Aged Actin cytoskeleton medicine.disease Actins 030104 developmental biology p21-Activated Kinases Synaptic plasticity Actin-Related Protein 2 Synapses biology.protein Excitatory postsynaptic potential Female Neurology (clinical) Alzheimer's disease Down Syndrome Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Brain Pathol |
| ISSN: | 1750-3639 |
| Popis: | Reduced spine densities and age-dependent accumulation of amyloid β and tau pathology are shared features of Down syndrome (DS) and Alzheimer's disease (AD). Both spine morphology and the synaptic plasticity that supports learning depend upon the actin cytoskeleton, suggesting that disturbances in actin regulatory signaling might underlie spine defects in both disorders. The present study evaluated the synaptic levels of two proteins that promote filamentous actin stabilization, the Rho GTPase effector p21-activated kinase 3 (PAK3) and Arp2, in DS vs. AD. Fluorescent deconvolution tomography was used to determine postsynaptic PAK3 and Arp2 levels for large numbers of excitatory synapses in the parietal cortex of individuals with DS plus AD pathology (DS + AD) or AD alone relative to age-matched controls. Though numbers of excitatory synapses were not different between groups, synaptic PAK3 levels were greatly reduced in DS + AD and AD individuals vs. 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 the 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|