Hexa (ethylene glycol) derivative of benzothiazole aniline promotes dendritic spine formation through the RasGRF1–Ras dependent pathway

Lee, Nathanael J.; Song, Jung Min; Cho, Hyun Ji; Sung, You Me; Lee, Taehee; Chung, Andrew; Hong, Sung-Ha; Cifelli, Jessica L.; Rubinshtein, Mark; Habib, Lila K.; Capule, Christina C.; Turner, R. Scott; Pak, Daniel T.S.; Yang, Jerry; Hoe, Hyang Sook

doi:10.1016/j.bbadis.2015.12.007

Cited by 10 publications

(13 citation statements)

References 39 publications

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“…Several small GTPases have been characterized as enhancers of spine density, especially Cdc42 (Tashiro et al, 2000; Wegner et al, 2008; Kim et al, 2013; Jaudon et al, 2015) and Rac1 (Tashiro et al, 2000; Penzes et al, 2001; Penzes et al, 2003; Tolias et al, 2007; Bacon et al, 2013; Ueda et al, 2013; Dhar et al, 2014; Raynaud et al, 2014; Evans et al, 2015; Jaudon et al, 2015; Kim et al, 2015; Valdez et al, 2016); others have been shown to inhibit spine density, in particular Ras (Yang et al, 2013; Lee et al, 2016) and RhoA (Tashiro et al, 2000; Margolis et al, 2010; Alder et al, 2013; Kim et al, 2015). Furthermore, modulators of activity for Ras (Pham and Rotin, 2001), Cdc42 (Hayakawa et al, 2008; Yamaguchi et al, 2008), and RhoA (Margolis et al, 2010; Lin et al, 2011; Papadimitriou et al, 2012) have been shown to be degraded by the proteasome, as well as Rac1 (Torrino et al, 2011; Zhao et al, 2013) and RhoA themselves (Wang et al, 2003; Cheng et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…The signaling pathways linking enhanced neural activity to new spine growth are currently being elucidated; many converge upon Rho GTPases as critical regulators of spinogenesis (Tolias et al, 2011; Penzes and Cahill, 2012; Saneyoshi and Hayashi, 2012; Lai and Ip, 2013; Um et al, 2014; Kim et al, 2015; Nishiyama and Yasuda, 2015; Lee et al, 2016). In addition, we recently identified the proteasome as a key regulator of activity-dependent spine outgrowth (Hamilton et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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A dual role for the RhoGEF Ephexin5 in regulation of dendritic spine outgrowth

Hamilton

Lambert

Parajuli

et al. 2017

Molecular and Cellular Neuroscience

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The outgrowth of new dendritic spines is closely linked to the formation of new synapses, and is thought to be a vital component of the experience-dependent circuit plasticity that supports learning. Here, we examined the role of the RhoGEF Ephexin5 in driving activity-dependent spine outgrowth. We found that reducing Ephexin5 levels increased spine outgrowth, and increasing Ephexin5 levels decreased spine outgrowth in a GEF-dependent manner, suggesting that Ephexin5 acts as an inhibitor of spine outgrowth. Notably, we found that increased neural activity led to a proteasome-dependent reduction in the levels of Ephexin5 in neuronal dendrites, which could facilitate the enhanced spine outgrowth observed following increased neural activity. Surprisingly, we also found that Ephexin5-GFP levels were elevated on the dendrite at sites of future new spines, prior to new spine outgrowth. Moreover, lowering neuronal Ephexin5 levels inhibited new spine outgrowth in response to both global increases in neural activity and local glutamatergic stimulation of the dendrite, suggesting that Ephexin5 is necessary for activity-dependent spine outgrowth. Our data support a model in which Ephexin5 serves a dual role in spinogenesis, acting both as a brake on overall spine outgrowth and as a necessary component in the site-specific formation of new spines.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A dual role for the RhoGEF Ephexin5 in regulation of dendritic spine outgrowth

Hamilton

Lambert

Parajuli

et al. 2017

Molecular and Cellular Neuroscience

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“…Previous work has reported that BTA-EG 4 and BTA-EG 6 could promote spine density increases in vitro in murine primary hippocampal neurons (37) and BTA-EG 4 could promote spine density increases in vivo in the hippocampus of wt mice and a 3ϫ tg mouse model for AD (18,19). The increase in spine density in neurons by BTA-EG 4,6 correlated with an increase in expression of RasGRF1 compared with control cells (37). In order to test whether the spinogenic activity induced by compounds 1-3 operated along a similar mechanistic path as BTA-EG 4,6 , we analyzed the effects of these compounds on the expression level of both RasGRF1 and active Ras in rat-dissoci- M BAM1-EG 6 on spine density.…”

Section: Design and Evaluation Of Benzothiazole Amphiphiles (Bams) 1-mentioning

confidence: 97%

“…Effects of BAMs 1-3 on Dendritic Spine Density-BTA-EG 6 was first used to assess increases in spine density in primary hippocampal neurons as a control due to its previously published ability to increase spine density (37). To visualize all spines, we used a virally transfected membrane-targeting pal-GFP that is known to reliably fluorescently label dendritic spines (38 -40).…”

Section: Design and Evaluation Of Benzothiazole Amphiphiles (Bams) 1-mentioning

confidence: 99%

Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons

Cifelli

Dozier

Chung

et al. 2016

Journal of Biological Chemistry

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The majority of excitatory synapses in the brain exist on dendritic spines. Accordingly, the regulation of dendritic spine density in the hippocampus is thought to play a central role in learning and memory. The development of novel methods to control spine density could, therefore, have important implications for treatment of a host of neurodegenerative and developmental cognitive disorders. Herein, we report the design and evaluation of a new class of benzothiazole amphiphiles that exhibit a dosedependent response leading to an increase in dendritic spine density in primary hippocampal neurons. Cell exposure studies reveal that the increase in spine density can persist for days in the presence of these compounds, but returns to normal spine density levels within 24 h when the compounds are removed, demonstrating the capability to reversibly control spinogenic activity. Time-lapse imaging of dissociated hippocampal neuronal cultures shows that these compounds promote a net increase in spine density through the formation of new spines. Biochemical studies support that promotion of spine formation by these compounds is accompanied by Ras activation. These spinogenic molecules were also capable of inhibiting a suspected mechanism for dendritic spine loss induced by Alzheimer-related aggregated amyloid-␤ peptides in primary neurons. Evaluation of this new group of spinogenic agents reveals that they also exhibit relatively low toxicity at concentrations displaying activity. Collectively, these results suggest that small molecules that promote spine formation could be potentially useful for ameliorating cognitive deficiencies associated with spine loss in neurodegenerative diseases such as Alzheimer disease, and may also find use as general cognitive enhancers.

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“…To date, relatively few compounds have been shown to increase dendritic spine density [14][15][16][17][18][19][20][21][22]. For instance, we have previously reported that benzothiazole amphiphiles (BAMs) can increase dendritic spine density in primary rat hippocampal neuronal culture [15] as well as in vivo in wild-type mice and in a 3xTg mouse model for AD [23][24][25]. These initial reports showed that BAMs are able to improve memory and learning in rodents by a RasGRF1 (a guanine nucleotide release factor involved in regulation of dendritic spine formation)-associated mechanism for promoting dendritic spine formation.…”

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confidence: 99%

Benzothiazole amphiphiles promote RasGRF1‐associated dendritic spine formation in human stem cell‐derived neurons

2020

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Synaptic dysfunction has been implicated as an early cause of cognitive decline in neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD). Methods to slow down or reverse the loss of functional synapses, therefore, represent a promising avenue to explore for treating NDDs. We have previously reported the development of a class of benzothiazole amphiphiles (BAMs) that exhibited the capability to improve memory and learning both in wild‐type mice and in an AD rodent model, putatively through promoting RasGRF1‐associated formation of dendritic spines in hippocampal neurons. While these results represent a good first step in exploring a new approach to treating NDDs, the capability of these compounds to increase spine density has not been previously examined in a human neuronal model. Here, we found that neurons derived from differentiated human induced pluripotent stem cells exhibited both an increase in RasGRF1 expression and a phenotypic increase in the density of postsynaptic density protein 95‐positive puncta (which we use to provide an estimate of dendritic spine density) in BAM‐treated vs. control neurons. These results demonstrate that the previously observed spinogenic effects of BAMs in rodent neurons can be recapitulated in a human neuronal model, which further supports the potential utility of BAM agents for treating human diseases associated with spine deficits such as AD or other NDDs.

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Hexa (ethylene glycol) derivative of benzothiazole aniline promotes dendritic spine formation through the RasGRF1–Ras dependent pathway

Cited by 10 publications

References 39 publications

A dual role for the RhoGEF Ephexin5 in regulation of dendritic spine outgrowth

A dual role for the RhoGEF Ephexin5 in regulation of dendritic spine outgrowth

Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons

Benzothiazole amphiphiles promote RasGRF1‐associated dendritic spine formation in human stem cell‐derived neurons

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