Neuronal structures associated with memory sprout in response to novel molecules.
Chemists at the University of California San Diego have designed a set of molecules that promote microscopic, anatomical changes in neurons associated with the formation and retention of memories. These drug candidates also prevent deterioration of the same neuronal structures in the presence of amyloid-beta, a protein fragment that accumulates in the brains of people with Alzheimer’s disease.
The study looked at the effect of drug candidates on the density of tiny thornlike structures called dendritic spines that bristle along the branching processes of neurons and receive incoming signals.
“Problems with learning and memory in many neurodegenerative and neurodevelopment disorders, such as Alzheimer’s disease and certain forms of autism or mental retardation involve either loss or misregulation of dendritic spines,” said Jerry Yang, a professor of chemistry and biochemistry who led the work. “The compounds we have developed may offer the possibility to compensate, or ideally preserve, neuronal communication in people suffering from problems with memory.”
When the researchers treated neurons from a part of the brain critical to forming and retrieving memories with their new compounds they saw an increase in the density of dendritic spines. The new compounds also prevented the loss of these spines that occurs in the presence of amyloid-beta, the substance that forms amyloid plaques in the brains of people with Alzheimer’s disease, the team reports in a forthcoming issue of the Journal of Biological Chemistry.
The greater the concentration of the drug candidate, the greater the density of spines within the range of doses the team tested. The effect is also reversible: once the compounds were washed away, the spines receded within 24 hours.
Earlier versions of these compounds, also developed by Yang’s research group, improved memory and learning in normal mice and a mouse model for Alzheimer’s disease, but were too toxic to pursue as drug candidates.
Jessica Cifelli, a graduate student in Yang’s group, worked out a way to keep the part of the molecules that they believe promoted the growth of dendritic spines, but alter the chemical features that impart toxicity. These novel compounds, called benzothiazole amphiphiles, are new tools to study relationship between dendritic spines and cognitive behavior.
We know from a wealth of prior research that spine densities on neurons change over time and that increases in the densities correlate with improved memory and learning. As potential drugs, benzothiazole amphiphiles could be useful for combatting spine loss in neurodegenerative disease, or possibly for general cognitive enhancement.
Co-authors include Lara Dozier, Tim Chung and Gentry Patrick. UC San Diego’s Shiley-Marcos Alzheimer’s Disease Research Center, funded by the National Institute on Aging, partially supported this research.
Source: Susan Brown – UCSD
Image Credit: Image is credited to Jessica Cifelli.
Original Research: Abstract for “Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons” by Jessica L. Cifelli, Lara Dozier, Tim Chung, Gentry N. Patrick, and Jerry Yang in Journal of Biological Chemistry. Published online March 28 2016 doi:10.1074/jbc.M115.701482
Abstract
Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons
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 hours 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 correlates with Ras activation. These spinogenic molecules were also capable of inhibiting a suspected mechanism of the dendritic spine loss induced by Alzheimer′s-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′s disease, and may also find use as general cognitive enhancers.
“Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons” by Jessica L. Cifelli, Lara Dozier, Tim Chung, Gentry N. Patrick, and Jerry Yang in Journal of Biological Chemistry. Published online March 28 2016 doi:10.1074/jbc.M115.701482
