title: 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: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
authors: Jung Min
authors: JM
authors: Song
authors: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
authors: Amanda Marie
authors: AM
authors: DiBattista
authors: College of Pharmacy, Seoul National University, South Korea.
authors: You Me
authors: YM
authors: Sung
authors: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA.
authors: Joo Myung
authors: JM
authors: Ahn
authors: Department of Neurology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors: R Scott
authors: RS
authors: Turner
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Jerry
authors: J
authors: Yang
authors: Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20057, USA.
authors: Daniel T S
authors: DT
authors: Pak
authors: Department of Neuroscience, Johns Hopkins University, Baltimore, MD 20218, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Hey-Kyoung
authors: HK
authors: Lee
authors: Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20057, USA; Department of Neurology, Georgetown University Medical Center, Washington, DC 20057, USA. Electronic address: sookhoe72@kbri.re.kr.
authors: Hyang-Sook
authors: HS
authors: Hoe
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000150:complications* / Q000188:drug therapy / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology*; D049229:Dendritic Spines / Q000187:drug effects*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D016875:tau Proteins / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D000814:Aniline Compounds; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins
keywords: 3xTg AD mice; AD; Alzheimer's disease; Aβ; BTA-EG(4); Dendritic spine; Ras signaling; amyloid-β