A tetra(ethylene glycol) derivative of benzothiazole aniline ameliorates dendritic spine density and cognitive function in a mouse model of Alzheimer's disease.

Abstract

We recently reported that the tetra(ethylene glycol) derivative of benzothiazole aniline, BTA-EG4, acts as an amyloid-binding small molecule that promotes dendritic spine density and cognitive function in wild-type mice. This raised the possibility that BTA-EG4 may benefit the functional decline seen in Alzheimer's disease (AD). In the present study, we directly tested whether BTA-EG4 improves dendritic spine density and cognitive function in a well-established mouse model of AD carrying mutations in APP, PS1 and tau (APPswe;PS1M146V;tauP301L, 3xTg AD mice). We found that daily injections of BTA-EG4 for 2 weeks improved dendritic spine density and cognitive function of 3xTg AD mice in an age-dependent manner. Specifically, BTA-EG4 promoted both dendritic spine density and morphology alterations in cortical layers II/III and in the hippocampus at 6-10 months of age compared to vehicle-injected mice. However, at 13-16 months of age, only cortical spine density was improved without changes in spine morphology. The changes in dendritic spine density correlated with Ras activity, such that 6-10 month old BTA-EG4 injected 3xTg AD mice had increased Ras activity in the cortex and hippocampus, while 13-16 month old mice only trended toward an increase in Ras activity in the cortex. Finally, BTA-EG4 injected 3xTg AD mice at 6-10 months of age showed improved learning and memory; however, only minimal improvement was observed at 13-16 months of age. This behavioral improvement corresponds to a decrease in soluble Aβ 40 levels. Taken together, these findings suggest that BTA-EG4 may be beneficial in ameliorating the synaptic loss seen in early AD.

• Authors: Jung Min Song, Amanda Marie DiBattista, You Me Sung, Joo Myung Ahn, R Scott Turner, Jerry Yang, Daniel T S Pak, Hey-Kyoung Lee, Hyang-Sook Hoe
• Journal: Experimental neurology (Exp Neurol) Vol. 252 Pg. 105-13 (Feb 2014) ISSN: 1090-2430 [Electronic] United States
• PMID: 24316432 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013. Published by Elsevier Inc.

Chemical References

• Amyloid beta-Protein Precursor
• Aniline Compounds
• PSEN1 protein, human
• Presenilin-1
• tau Proteins

Topics

• Age Factors
• Alzheimer Disease (complications, drug therapy, genetics)
• Amyloid beta-Protein Precursor (genetics)
• Aniline Compounds (pharmacology, therapeutic use)
• Animals
• Cognition Disorders (drug therapy, etiology)
• Dendritic Spines (drug effects)
• Disease Models, Animal
• Hippocampus (pathology, ultrastructure)
• Humans
• Male
• Maze Learning (drug effects)
• Mice
• Mice, Transgenic
• Mutation (genetics)
• Presenilin-1 (genetics)
• tau Proteins (genetics)