How Much of Cognitive Decline is Actively Maintained via Dysfunctional Cell States or Signaling, and is thus Quickly Reversible?

Demonstrations in which researchers adjust cell state or signaling to reverse cognitive decline in old mice suggest that a meaningfully large fraction of this age-related cognitive decline is actively maintained via dysfunctions in cell signaling and cell activity. Senescent cells and their inflammatory signaling are a likely culprit, though it is challenging to join the dots between signaling and specific mechanisms inside cells in the highly complex environment of cellular biochemistry. The important point is that much of the decline in cognitive function could be quickly reversed if specific signals and mechanisms can be addressed. The work here is hopeful evidence on that front, though we should not forget that there remain the late stages of neurodegenerative conditions in which too much damage has been done, too many cells have died in the brain, for there to be a solution of this nature.

Just a few doses of an experimental drug can reverse age-related declines in memory and mental flexibility in mice, according to a new study. The drug, called integrated stress response inhibitor (ISRIB), targeting eIF2α phosphorylation, has already been shown in laboratory studies to restore memory function months after traumatic brain injury (TBI), reverse cognitive impairments in Down Syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer and even enhance cognition in healthy animals. In the new study, researchers showed rapid restoration of youthful cognitive abilities in aged mice, accompanied by a rejuvenation of brain and immune cells that could help explain improvements in brain function.

"ISRIB's extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological "blockage" rather than more permanent degradation. The data suggest that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress. Our work with ISRIB demonstrates a way to break that cycle and restore cognitive abilities that had become walled off over time."



Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer's disease

Restoring protein synthesis and cognition
The loss of protein synthesis caused by chronic activation of the integrated stress response (ISR) is observed in hippocampal neurons and correlates with cognitive loss in mouse models of Alzheimer's disease. The compound ISRIB blocks the translation inhibition arm of the ISR but failed to confer cognitive benefit and caused mortality in mouse models of Alzheimer's disease in previous studies. However, Oliveira et al. found that daily systemic administration of low-dose ISRIB, which did not cause mortality or obvious side effects, rescued protein synthesis and synaptic plasticity in the hippocampus and restored performance on long-term memory tests both in wild-type mice in which translation had been pharmacologically inhibited and in two mouse models of Alzheimer's disease, although there was no effect on amyloid plaque load. The findings suggest that restoring protein synthesis in the brain may delay cognitive deficits in Alzheimer's disease patients.

Posted by: Robert Read at February 2nd, 2021 2:08 PM
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