Glycogen Phosphorylase Inhibition Improves Cognitive Function in Old Mice Only

Today's open access paper provides an interesting example of a pharmacological strategy that is beneficial to specific aspects of memory function in old mice, but detrimental to that same function in young mice. This is certainly possible, as the biochemistry of cells and tissues is nothing if not exceedingly complex, but this outcome tends to be unusual. More commonly, a therapy targeting causative mechanisms of aging, one that improves function in aged individuals, will do little to nothing for younger individuals, but will not be actively harmful.

Here, clearly, the biochemistry of memory formation changes in meaningful ways with age. At present far too little is understood of the fine details of how neural function gives rise to the mind, for all that chemical and structural features relating to memory formation are quite well mapped at the high level. That less well understood details change with age in ways that give rise a treatment that only works in old individuals is a painful reminder that mammalian neural biochemistry is far more complex than we'd like it to be, at least when it comes to the task of developing biotechnologies to maintain its function over time.

Glycogen phosphorylase inhibition improves cognitive function of aged mice

Glycogen phosphorylase (Pyg) catalyzes the first and rate-limiting step in the process of glycogen degradation (glycogenolysis). Inhibition of Pyg was shown to block memory formation in young chickens and induction of the Long Term Potentiation (LTP, a cellular/molecular mechanism of memory formation) in hippocampi and hippocampal slices isolated from young rodents. It was also shown that impairment of synaptic plasticity after Pyg inhibition was associated with decreased transport of glycogen-derived lactate from astrocytes to neurons in a process called the astrocyte-neuronal lactate shuttle (ANLS). The impact of the astrocytic glycogen-derived lactate on neuronal metabolism is the subject of ongoing debate and the mechanism by which this pool of lactate stimulates the LTP is not fully understood. However, it is commonly accepted that disruption of the ANLS affects memory formation.

In contrast to the young animals, inhibition of glycogen breakdown in hippocampal sections isolated from adult and aged rodents was shown to improve the LTP formation, elevating significantly its magnitude. Moreover, in hippocampal slices isolated from old animals, significant alterations in morphology of dendritic spines were observed after inhibition of Pyg, indicating changes in dendritic spines maturation. Mechanisms underlying this different response to Pyg inhibition remain to be discovered but they might be associated with a different organization of hippocampal formation in young and aged animals and global changes in the expression of hippocampal proteins, and in the NAD+/NADH metabolism during aging.

Here, we report that a 2-week treatment with glycogen phosphorylase inhibitor BAY U6751 alleviated memory deficits and stimulated neuroplasticity in old mice. Using the 2-Novel Object Recognition and Novel Object Location tests, we discovered that the prolonged intraperitoneal administration of BAY U6751 improved memory formation in old mice. This was accompanied by changes in morphology of dendritic spines in hippocampal neurons, and by "rejuvenation" of hippocampal proteome. In contrast, in young animals, inhibition of glycogen degradation impaired memory formation; however, as in old mice, it did not alter significantly the morphology and density of cortical dendritic spines. Our findings provide evidence that prolonged inhibition of glycogen phosphorolysis improves memory formation of old animals. This could lead to the development of new strategies for treatment of age-related memory deficits.


Might it also be a good test to see if an anti aging treatment is actually working?

Posted by: Rob at August 20th, 2023 8:02 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.