by Maria Giulia Manzione
As humans age, besides the wrinkles and the white hair, a decline in our cognitive abilities such as learning, memorising, and focusing can also occur. According to the World Health Organization (WHO) “By 2050, the world’s population aged 60 years and older is expected to total 2 billion”, challenging the healthcare systems due to the high costs associated with the care of cognitive impairments such as dementia.
Multiple factors and certain pharmacological (e.g. medications) and non-pharmacological (e.g. cognitive stimulating activities) interventions seem to influence the speed of cognitive decline during ageing. Neurobiologists have identified a variety of molecular mechanisms and/or cellular processes whose alterations contribute to age-related cognitive decline. For example, loss of protein homeostasis (proteostasis) — a process by which the cell makes sure there is the right supply of proteins needed for all cellular functions while defective proteins (damaged or misfolded) are removed — has been associated with cognitive decline.
It is well established that protein synthesis is essential for memory consolidation — when short-term memories are converted into long-term memories in the brain. During ageing, defective proteins can accumulate and activate the integrated stress response (ISR), which inhibits most protein synthesis while allowing the production of specific proteins (such as the activating transcription factor 4, ATF4) that promote cellular recovery. The activation of ISR has been associated with cognitive dysfunction and neurodegenerative disorders such as Alzheimer’s disease. Recently, a team led by Prof. Susanna Rosi at the Department of Neurological Surgery and of Physical Therapy and Rehabilitation Science of the University of California San Francisco (UCSF) showed that pharmacological inhibition of ISR can restore memory deficits in old mice.
At the molecular level, the authors found that the treatment of old mice with an integrated stress response inhibitor (ISRIB), a drug-like small-molecule able to reach the brain, reduced the protein levels of ATF4 (known to increase with ISR) to the levels of ATF4 that are typically found in the brain of young mice. To test the effects of ISRIB on cognitive functions such as spatial learning and memory, old mice were trained in a radial arm water maze (RAWM). The RAWM is like a pool with an array of eight arms radiating from a central starting point where the mice need to find an escape platform hidden under opaque water. The authors recorded the number of errors (e.g. wrong arm = no escape) before the mice were able to escape. Old mice made an average of three errors compared to one error made by young mice. However, after treatment with ISRIB, old mice made only two mistakes before finding the escape platform indicating an improvement of spatial memory. Then, the authors used the so-called delayed-matching-to-place paradigm (DMP) to test working and episodic memory (working memory is a “temporary” memory while episodic memory is a long-term memory) a few weeks after ISRIB treatment. The DMP maze consists of a round table with 40 escape holes arranged in three concentric rings and an escape tunnel connected to one of the outer holes. The authors measured the time taken for the mice to escape. After 23 days post-ISRIB treatment old mice were able to find the escape tunnel 20 seconds faster than the control group demonstrating again the beneficial effects of ISRIB on cognitive functions.
Representative image of memory tests before and after treatment of old mice with ISRIB
Prompted by the promising results, the authors analyzed the electrophysiological and cellular changes occurring in the brain of old mice after ISRIB treatment. Firstly, they found that a single injection of ISRIB restored the excitability of old neurons — nerve cells that communicate with each other through electrical impulses and chemical neurotransmitters — to levels almost indistinguishable from those in young mice. Secondly, the number of synapses (the connections between neurons) that are usually reduced in old brains were increased after ISRIB treatment. Thirdly, administration of ISRIB reduced the levels of inflammatory biomarkers observed in old mice. Thus, ISRIB treatment rejuvenated the brain of old mice by improving the communication between neurons and by counteracting inflammation resulting in enhancement of cognitive performance.
One of the most important findings of the work published by Karen Krukowski et al. is the identification of the molecular mechanism that can be targeted to improve age-related memory deficits. Pharmacological inhibition of ISR seems to be effective in recovering the behavior and mitigating the cognitive defects of old mice after only a few weeks of ISRIB treatment.
Interestingly, ISRIB could be potentially used to treat other diseases associated with ISR activation, including Alzheimer's Disease, Parkinson’s disease and Down Syndrome. Further research is needed to evaluate the pharmacological use and the potential benefits of ISRIB in humans.
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