Protection of excitatory synapses by DHA through preserving function of NMDA-Tiam1-PAK signal pathway in Alzheimer models

Abstract

Defects in dendritic spines and excitatory synapses contribute to cognitive deficits in mental retardation syndromes and Alzheimer's disease (AD), in which the Rho family GTPases Rac and its downstream p21-activeated kinases (PAKs) have been involved as a key player. We previously found that beta-Amyloid (Aβ) oligomers dysregulated Rac/PAK signaling but little is known which signal pathway is involved and whether DHA can prevent its dysregulation. In this study, we investigated whether Aβ oligomers can disrupt the NMDA-Tiam1-PAK signal pathway to inhibit dendritic spine morphogenesis and whether DHA can protect. Cultured primary neurons and 3xTg-AD transgenic mice were used and investigated using Westerns. Our results indicated that Aβ oligomers inhibited dendritic spine or Ephrin-stimulated dendritic spine morphogenesis through the dysregulation of NMDA-Tiam1-PAK signal pathway that was prevented by ω-3 fatty acid docosahexaenoic acid (DHA). Tyrosine kinase fyn participated in the processing as an upstream regulator of the signal pathway that was also protected by DHA. In cultured rat primary hippocampal neurons, Aβ42 oligomers significantly reduced membrane PSD-95, drebrin, NR2B, pNR2B, Tiam1 and Fyn. These losses were significantly protected by pretreatment with DHA. Similarly, simultaneous treatment of 3xTg-AD transgenic mice with high fat diet and dietary fish oil/DHA for four months, DHA elevated brain hippocampal membrane levels of PSD-95, drebrin, NR2B, pNR2B, Tiam1 and fyn, accompanied by improvement of cognitive function in Y-maze performance. Tiam1 significantly correlated with NR2B and Fyn in AD brain. Since dysregulation of NMDA receptors and fyn by Aβ oligomers is implicated in AD and associated with the morphogenesis of dendritic spines and cognitive deficits, our results suggest the NMDA-Tiam1-PAK signal pathway is intimately involved in Aβ oligomer-induced synaptic impairment in AD pathogenesis and demonstrate a possible protective mechanism of DHA on synaptic plasticity in early stage AD through preserving function of this signal transduction pathway.