# Pathogenesis of Postoperative Cognitive Dysfunction

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $636,424

## Abstract

Project Summary/Abstract.
 Postoperative cognitive dysfunction (POCD), the most common postoperative complication among geriatric
patients and an important research area in the field of Geriatrics and Aging, is associated with substantially
increased Alzheimer’s disease (AD) dementia, morbidity, and mortality as well as cost of care. However, the
pathogenesis of POCD is still largely unknown, which impede the further studies into POCD. Consistent with
the notion that blood CX3CR1+ monocytes and the mitochondria permeability transition pore component
Cyclophilin D (CypD) in the brain regulate neuroinflammation and mitochondrial function, our published work
and preliminary studies in mice showed that CypD and CX3CR1+ monocytes mediated anesthesia/surgery-
and infection-induced cognitive impairment. In addition, CypD levels are higher in brain tissues of AD
transgenic (Tg) and aged mice. Thus, the proposed research will assess the effects of anesthesia/surgery on
toxicity, including the AD neuropathogenesis-associated changes (e.g., increased CypD levels,
neuroinflammation, mitochondrial dysfunction, and neuronal dysfunction). Moreover, we will define a
multifactorial model of POCD pathogenesis where the interaction of blood (anesthesia/surgery-induced
increases in CX3CR1+ monocytes, the precipitating factor and insulting action) and brain [aging- or AD gene
mutation-associated elevation of Cyclophilin D (CypD), the predisposing factor and gating regulation] is needed
to cause POCD. The hypothesis of the proposed study is that anesthesia/surgery-induced increases in blood
CX3CR1+ monocytes functionally interact with aging- and AD gene mutation-associated enhancement of brain
CypD, leading to neuronal dysfunction and POCD-like behavior in mice. We will employ chemical and genetic
tools through both neuroimmunology and behavioral approaches to accomplish three Specific Aims: (1) we will
assess the effects of anesthesia/surgery on levels of blood CX3CR1+ monocytes and cytokines; brain-
infiltrating CX3CR1+ monocytes, neuroinflammation, mitochondrial dysfunction, neuronal dysfunction, and
behavior; (2) we will use Cx3cr1CreER/+;R26iDTR/+ and CypD knockout chimeric mice in which CX3CR1+
monocytes, microglia and CypD are depleted so we can assess the roles of blood CX3CR1+ monocytes and
brain CypD on the anesthesia/surgery-induced changes; (3) we will determine the effects of a monoclonal
antibody for the CX3CR1 ligand CX3CL1; and the protectors of mitochondria (WS635 and Vitamin K2) on the
anesthesia/surgery-induced changes. We will include wild-type and adult (4 month-old) mice versus age
matched AD Tg and aged (18 month-old) mice (with higher levels of CypD) while employing in vivo cell
depletion, in vivo two-photon calcium imaging, Western blot, ELISA, immunohistochemistry, flow cytometry,
and behavioral tests. This proposal aims to investigate an understudied topic in innovative systems by testing
novel hypotheses, which would ultimately provide bett...

## Key facts

- **NIH application ID:** 10432058
- **Project number:** 5R01AG041274-09
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Zhongcong Xie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $636,424
- **Award type:** 5
- **Project period:** 2012-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10432058

## Citation

> US National Institutes of Health, RePORTER application 10432058, Pathogenesis of Postoperative Cognitive Dysfunction (5R01AG041274-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10432058. Licensed CC0.

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