title: Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons.
abstract: 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 dose-dependent 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-β 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.
authors.affiliation: From the Department of Chemistry and Biochemistry and.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Cifelli
authors.affiliation: the Section of Neurobiology in the Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093-0358.
authors.forename: Lara
authors.initials: L
authors.lastname: Dozier
authors.affiliation: From the Department of Chemistry and Biochemistry and.
authors.forename: Tim S
authors.initials: TS
authors.lastname: Chung
authors.affiliation: the Section of Neurobiology in the Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093-0358.
authors.forename: Gentry N
authors.initials: GN
authors.lastname: Patrick
authors.affiliation: From the Department of Chemistry and Biochemistry and jerryyang@ucsd.edu.
authors.forename: Jerry
authors.initials: J
authors.lastname: Yang
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000187:drug effects* / Q000502:physiology; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D005260:Female; D006624:Hippocampus / Q000166:cytology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D016704:Synapsins / Q000378:metabolism; D059008:Time-Lapse Imaging / Q000379:methods; D018631:ras Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D054852:Small Molecule Libraries; D016704:Synapsins; D018631:ras Proteins
keywords: Alzheimer disease; Benzothiazoles; RasGRF1; Spinogenic; dendritic spine; drug design; neurodegeneration; neuron