# Cellular mechanisms for age-related cognitive dysfunction and its pharmacological reversal: a strategy towards prevention and treatment of postoperative cognitive deficits in elderly patients

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2022 · $388,547

## Abstract

PROJECT SUMMARY / ABSTRACT
A relatively frequent complication after major surgery in elderly patients is the development of postoperative
cognitive dysfunction (POCD), which can persist for several days to weeks, and in rare instances even months
postoperatively. In patients >60 years of age, 26% display signs of POCD after 1 week, and 10% after 3
months, compared to 3% in controls at both time points. POCD was found to be associated with increased
dependency on social transfer payments, increased risk of leaving the labor market prematurely and increased
mortality. The molecular and cellular mechanisms underlying POCD are unknown, as is the reason why
POCD occurs more frequently in elderly patients than in younger patients. As POCD increases with age, age-
related cognitive dysfunction likely represents a risk factor. It has been shown in rodents that loss of
somatostatin-positive interneurons in the dentate gyrus (DG) hilus results in hyperexcitability of DG and CA3
and is associated with age-related cognitive dysfunction. However, a cause-effect relationship between loss of
somatostatin-positive interneurons in the DG hilus and cognitive dysfunction has not been demonstrated so far.
We therefore want to chemogenetically inhibit and genetically ablate these neurons to demonstrate that these
changes are sufficient to elicit cognitive dysfunction. Moreover, we want to pharmacologically reverse these
deficits and identify the molecular and cellular basis for this reversal. It has been reported that in aged rats but
not in young rats a GABAA receptor α5-positive allosteric modulator (α5-PAM) improves cognitive function,
which is in line with an α5-PAM reducing the hyperexcitability of DG and CA3 of the hippocampus in aged rats.
It has also been reported that chronic intermittent propofol improves age-related cognitive dysfunction, but the
molecular and cellular substrates of this action have not been identified. We want to test the hypothesis that
this action of propofol is mediated by a sustained increase in expression of α5-containing GABAA receptors on
the cell surface. We also want to identify the neuronal cell population expressing the α5-containing GABAA
receptors that mediate this improvement of cognition. Furthermore, we want to test whether chemogenetic
inhibition of somatostatin-positive interneurons in the DG hilus of young adult mice is sufficient to elicit the
cognitive-enhancing effect of chronic intermittent propofol. Finally, we will study whether postoperative (i.e.,
post laparotomy) impairment of cognitive function can be prevented or reduced by chronic intermittent propofol
or a GABAA receptor α5-PAM. In summary, we will study molecular and cellular mechanisms underlying age-
related postoperative cognitive dysfunction and its reversal. The proposed studies are expected to provide an
avenue for the development of strategies to prevent and/or treat POCD in elderly patients. Future clinical trials
could use chronic intermittent pro...

## Key facts

- **NIH application ID:** 10407460
- **Project number:** 5R01GM128183-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Uwe Rudolph
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $388,547
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407460

## Citation

> US National Institutes of Health, RePORTER application 10407460, Cellular mechanisms for age-related cognitive dysfunction and its pharmacological reversal: a strategy towards prevention and treatment of postoperative cognitive deficits in elderly patients (5R01GM128183-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10407460. Licensed CC0.

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