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ISRIB Applications for TBI, Alzheimer's

By Chris Keim

The human brain has a tremendous capacity to learn from past experiences, and store experiences as memories. In his day, the famous neuroscientist Santiago Ramón y Cajal theorized that memories are stored in synapses, or connections, that neurons make with each other in the brain. Almost half a century past his time Ramón y Cajal’s predictions were brought through, in large by Dr. Eric Kandel’s work on the molecular underpinnings of learning and memory. Kandel’s work has shown the tremendous flexibility that synapses in the hippocampus, a key brain region for memories of things like personal experiences and words, undergo as a result of learning. Indeed, it is widely known now that inhibiting these changes in how neurons connect stops memories from forming.

Over 1.7 million Americans experience a traumatic brain injury (TBI) each year, and TBI is actually one of the most predictive risk factors for developing both Alzheimer's disease and dementia. Most patients who survive mild to severe TBI present with long lasting problems with cognition and memory, but the connection between TBI and memory has been mysterious. The brains of deceased patients who sustained a TBI in their life and presented cognitive deficits usually don’t show any direct lesions to memory supporting regions. Besides a couple of small tears, they look normal.

Recent clarity into the ties between TBI and the biological systems that support our learning and memory, and the motivation behind the recent work by Austin Chou et al., at the the University of California in San Francisco, is that these changes are molecular in nature. TBI causes chronic activation of a cellular signaling pathway called the integrated stress response (ISR) in hippocampal neurons. The ISR is an evolutionarily conserved pathway that generally inhibits protein synthesis by the α subunit phosphorylation of a molecule known as eukaryotic translation initiation factor 2 (eIF2α). In the brain however, the ISR directly regulates long term memory formation with the eIF2α phosphorylation by disrupting long term potentiation (LTP). Austin Chou’s team championed a drug called ISRIB (ISR inhibitor) which both readily crosses the blood brain barrier and formidably stops the ISR, reversing the deficits to cognition and memory.

It is no surprise that a signaling pathway that inhibits protein synthesis would disrupt memory - we understand in present times that memory formation requires protein synthesis. The real profundity here is that administration of ISRIB reverses cognitive and memory deficits up to 4 weeks after the TBI, opening the door for treatment available well after the time of injury. What’s more, is that ISRIB likely directly supports dendritic spine remodeling, a process integral to learning and memory but also disrupted by a wide range of chronic disorders that affect cognition and memory.

While further time needs to be spent with the drug mechanistically, animals that have experimentally reduced eIF2α phosphorylation show improved long term memory. It is too soon to say, but this work harkens towards a near future where haunting diseases of memory, like Alzheimer's disease, may start to look amenable.

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