A Small Molecule Treatment that Boosts Memory in Mice

Researchers involved in one of the very the early portions of drug discovery, in which as many types of molecule are tested as possible, have discovered a way to improve memory in mice:

Memory improved in mice injected with a small, drug-like molecule discovered [by] researchers studying how cells respond to biological stress. The memory-boosting chemical was singled out from among 100,000 chemicals screened at the Small Molecule Discovery Center at UCSF for their potential to perturb a protective biochemical pathway within cells that is activated when cells are unable to keep up with the need to fold proteins into their working forms.

The chemical acts within the cell beyond the biochemical pathway that activates this unfolded protein response, to more broadly impact what's known as the integrated stress response. In this response, several biochemical pathways converge on a single molecular lynchpin, a protein called eIF2 alpha. "Among other things, the inactivation of eIF2 alpha is a brake on memory consolidation." The chemical identified by the UCSF researchers is called ISRIB, which stands for integrated stress response inhibitor. ISRIB counters the effects of eIF2 alpha inactivation inside cells.

In one memory test included in the study, normal mice were able to relocate a submerged platform about three times faster after receiving injections of the potent chemical than mice that received sham injections. The mice that received the chemical also better remembered cues associated with unpleasant stimuli - the sort of fear conditioning that could help a mouse avoid being preyed upon. "It appears that the process of evolution has not optimized memory consolidation; otherwise I don't think we could have improved upon it the way we did in our study with normal, healthy mice."

Evolution has failed to optimize many individually desirable and arguably advantageous aspects of mouse biology, such as life span, for example. That tells us something about the details of the way in which natural selection operates.

Link: http://www.newswise.com/articles/memory-boosting-chemical-is-identified-in-mice

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https://elifesciences.org/articles/62048

Small molecule cognitive enhancer reverses age-related memory decline in mice

Abstract
With increased life expectancy age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition i) rescues intrinsic neuronal electrophysiological properties, ii) restores spine density and iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.

Posted by: Robert Read at December 6th, 2020 10:42 AM

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