Increased Insulin Receptor Expression Improves Memory in Old Rats

This is a interesting example of modulating the metabolism of the aging brain in order to improve its function, without any attempt to address the underlying cell and tissue damage that causes loss of function. Researchers delivered recombinant insulin receptor protein to the hippocampus of old rats, and demonstrated improved memory function as an outcome of this intervention. An age-related decline in insulin metabolism has been implicated in neurodegenerative conditions, but it is somewhat hard to pick this apart from reduced blood flow, blood-brain barrier dysfunction, and other related issues that contribute to the declining function of the brain. Hence this effort to attempt to modify insulin metabolism somewhat distinctly from other mechanisms.

As demonstrated by increased hippocampal insulin receptor density following learning in animal models and decreased insulin signaling, receptor density, and memory decline in aging and Alzheimer's disease, numerous studies have emphasized the importance of insulin in learning and memory processes. This has been further supported by work showing that intranasal delivery of insulin can enhance insulin receptor signaling, alter cerebral blood flow, and improve memory recall. Additionally, inhibition of insulin receptor function or expression using molecular techniques has been associated with reduced learning.

Here, we sought a different approach to increase insulin receptor activity without the need for administering the ligand. A constitutively active, modified human insulin receptor (IRβ) was delivered to the hippocampus of young (2 months) and aged (18 months) male Fischer 344 rats in vivo. The impact of increasing hippocampal insulin receptor expression was investigated using several outcome measures, including Morris water maze and ambulatory gait performance, immunofluorescence, immunohistochemistry, and Western immunoblotting.

In aged animals, the IRβ construct was associated with enhanced performance on the Morris water maze task, suggesting that this receptor was able to improve memory recall. Additionally, in both age-groups, a reduced stride length was noted in IRβ-treated animals along with elevated hippocampal insulin receptor levels. These results provide new insights into the potential impact of increasing neuronal insulin signaling in the hippocampus of aged animals and support the efficacy of molecularly elevating insulin receptor activity in vivo in the absence of the ligand to directly study this process.

Link: https://doi.org/10.1111/acel.13220

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