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

Abstract

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.

Neuronal Dynamics and miRNA Signaling Differ between SH-SY5Y APPSwe and PSEN1 Mutant iPSC-Derived AD Models upon Modulation with miR-124 Mimic and Inhibitor

“…Dendritic morphogenesis and spine density were shown to be promoted by miR-124 in mouse olfactory bulb neurons [ 57 ]. Here, we profit from having our iNEU- WT or iNEU- PSEN cell models to explore the consequences of modulating miR-124 expression levels on the number of dendritic spines that receive input from a synapse of another neuron, since such an assessment cannot be realized in SH-SY5Y neuroblastoma cultures [ 58 ].…”

“…Synaptic failure is a cause of cognitive decline, and the loss of dendritic spines is associated to synaptic dysfunction [ 56 ] and the pathological accumulation of Tau in AD [ 77 ]. In the present study, the loss of dendritic spines was evidenced by the miR-124 inhibitor only in iNEU- WT and iNEU- PSEN cells once they could not be visualized in neuroblastoma cultures [ 58 ]. Increased Tau phosphorylation was observed by the miR-124-inhibitor in SH- WT cells, but its decrease was achieved by the mimic in iNEU- PSEN cells, suggesting a potential beneficial effect in AD pathology, already proposed in a previous study [ 49 ].…”

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

“…When Aβ levels are reduced by a pharmacological treatment, mRNA and protein levels of RasGRF1 are increased, promoting dendritic spine formation in hippocampal primary neurons [ 24 , 25 ]. Considering that the RasGRF1/Ras/MAPK pathway is involved in the dendritic spine formation, benzothiazole amphiphiles such as hexa(ethylene glycol), derivative of benzothiazole aniline, have been effective in modulating this pathway and in promoting dendritic spine formation in human iPSC-derived neurons [ 26 ].…”

“…Another significant example is the description of the axis RasGRF1/Ras/MAPK that controls the dendritic spine formation. Based on this, benothiazole aniline derivatives have been able to modulate this pathway in order to promote dendritic spine formation [ 26 ]. Moreover, Pyk2/RhoGAPGraf1/RhoA/ROCK2 cascade is responsible for the dendritic spine retraction in the presence of Aβ peptides [ 80 ].…”

Upregulation of RasGRF1 ameliorates spatial cognitive dysfunction in mice after chronic cerebral hypoperfusion

“…Ras guanine nucleotide releasing factor 1 (RasGRF1) is a neuron-specific guanine-nucleotide releasing factor that enhances Ras and Rac activity. RasGRF1 is widely distributed in the brain, especially in the neurons of the hippocampus and corpus striatum [13][14][15], and is closely related to spine formation and cognition [16,17]. Rasgrf1 expression promotes neurite outgrowth after neurotrophin induction [18], dendritic spine formation [19][20][21], axonal growth and branching [22], and long-term potentiation (LTP) [23].…”