Cigarette Smoke Exposure Induces Neurocognitive Impairments and Neuropathological Changes in the Hippocampus

Abstract

Background and ObjectiveNeurocognitive dysfunction is present in up to ∼61% of people with chronic obstructive pulmonary disease (COPD), with symptoms including learning and memory deficiencies, negatively impacting the quality of life of these individuals. As the mechanisms responsible for neurocognitive deficits in COPD remain unknown, we explored whether chronic cigarette smoke (CS) exposure causes neurocognitive dysfunction in mice and whether this is associated with neuroinflammation and an altered neuropathology.MethodsMale BALB/c mice were exposed to room air (sham) or CS (9 cigarettes/day, 5 days/week) for 24 weeks. After 23 weeks, mice underwent neurocognitive tests to assess working and spatial memory retention. At 24 weeks, mice were culled and lungs were collected and assessed for hallmark features of COPD. Serum was assessed for systemic inflammation and the hippocampus was collected for neuroinflammatory and structural analysis.ResultsChronic CS exposure impaired lung function as well as driving pulmonary inflammation, emphysema, and systemic inflammation. CS exposure impaired working memory retention, which was associated with a suppression in hippocampal microglial number, however, these microglia displayed a more activated morphology. CS-exposed mice showed changes in astrocyte density as well as a reduction in synaptophysin and dendritic spines in the hippocampus.ConclusionWe have developed an experimental model of COPD in mice that recapitulates the hallmark features of the human disease. The altered microglial/astrocytic profiles and alterations in the neuropathology within the hippocampus may explain the neurocognitive dysfunction observed during COPD.

Targeting accelerated pulmonary ageing to treat chronic obstructive pulmonary disease‐induced neuropathological comorbidities

“…We have also shown that chronic cigarette smoke exposure induces a reactive astrocyte profile within the hippocampus (Dobric et al, 2022) and hypothalamus (De Luca et al, 2023). This reactive astrocyte profile was associated with endothelial cell tight junction protein impairment (reduction in ZO-1), thus reducing BBB integrity, compared to sham mice, leading to working memory impairments (Dobric et al, 2022).…”

Inhibition of oxidative stress by apocynin attenuated chronic obstructive pulmonary disease progression and vascular injury by cigarette smoke exposure

“…The Sham mice were handled identically and exposed to room air. We have previously shown that this cigarette smoke exposure protocol in male BALB/c mice recapitulates key clinical traits of human COPD, including lung inflammation and pathology (airway inflammation, emphysema and impaired lung function), increased lung and systemic oxidative stress and co-morbidities including skeletal muscle dysfunction (Chan et al, 2020;Dobric et al, 2022). Hence, only male mice were included in the present study.…”

Inhibition of oxidative stress by apocynin attenuated COPD progression and vascular injury by cigarette smoke exposure

“…The Sham mice were handled identically and exposed to room air. We have previously shown that this CS exposure protocol in male BALB/c mice recapitulates key clinical traits of human COPD, including lung inflammation and pathology (airway inflammation, emphysema and impaired lung function), increased lung and systemic oxidative stress and comorbidities including skeletal muscle dysfunction (Chan et al, 2020;Dobric et al, 2022). Hence, only male mice were included in the present study.…”

“…Fat and lean contents were determined using an EchoMRI apparatus (Echo Medical Systems, Houston, TX, USA). To understand the systemic impact of CS exposure and apocynin treatment, whole blood was collected from the inferior vena cava at the end of the experiment and counted using a CELL-DYN Emerald hematology analyser (Abbott Core Laboratory, USA), as previously described (Dobric et al, 2022).…”

“…Deflation of the lungs were performed to generate inspiratory capacity (IC). Pressure-volume (PV) loops and negative pressure-driven forced expiratory (NPFE) were performed to obtain inspiratory capacity (IC), static compliance, forced vital capacity (FVC), the PV curve and the area enclosed by the PV loop area as previously performed (Dobric et al, 2022). Following lung function testing, mice were humanely killed by overdosing with sodium pentobarbitone (240 mg•kg −1 ; Virbac, NSW, Australia) via i.p.…”