There is growing evidence that non-smokers who were exposed to second-hand smoke (SHS) are at an increased risk of mild cognitive impairment (MCI), often a preclinical form of dementia. Patients with MCI have a significantly higher rate of exposure to SHS than dementia patients and most MCI patients eventually develop dementia. Environmental factors ranging from previous head trauma to educational level to one's early life experiences (e.g., altered brain growth and development), including exposure to toxins through the diet (e.g., nitrosamines) or by inhalation (e.g., cigarette smoke), are major risk factors for the sporadic forms of dementia. It is becoming increasingly clear that environmental factors play an important role in the etiology of dementia, but which of them is poorly understood. SHS might be an important environmental trigger of MCI and dementia. Studies that focus on exploring the influence of SHS on cognitive function and the underlying metabolic processes could advance understanding of the etiopathogenesis of MCI and sporadic dementia and possibly reveal novel approaches for their effective treatment. MCI is characterized by a dysfunction in brain glucose metabolism as well as the accumulation of pathological proteins (e.g., tau, amyloid), biomarkers that correlate with disease severity. Tau misregulation is an important underlying mechanism of the progressive cognitive and neuropathological changes that develop in patients with MCI or dementia. Smoke inhaled through a cigarette (active or mainstream smoking) is an important risk factor for MCI and dementia. SHS doubles the risk for dementia among individuals who never smoked and it is 2-6 times more toxic and tumorigenic to humans than mainstream smoke. Thus, SHS might have a greater effect on brain metabolism and cognitive function than mainstream smoking. Studies strongly suggest that SHS increases the risk of MCI or dementia by perturbing brain metabolism (i.e., insulin signaling, oxidative stress) and the accumulation of pathological proteins (i.e, tau, amyloid). We hypothesize that chronic exposure to SHS induces changes in brain metabolism that lead to tau misregulation, amyloid accumulation and cognitive injury. We also hypothesize that these SHS-induced cognitive and pathological changes will be accelerated in susceptible individuals (i.e., those with misregulated tau such as htau mice). These hypotheses will be tested by comparing the effect of chronic (12-month) SHS exposure on cognitive function of wild-type and htau mice. Following behavioral and cognitive testing, brain areas pertinent to the behavioral and cognitive changes will be assessed for metabolic changes, tau and amyloid pathology, and neuronal loss. These studies will provide important information about the role of SHS in the cognitive injury and early metabolic changes in MCI. Importantly, this animal model may be especially useful for developing therapeutic agents to counteract the metabolic, pathological and cognitive changes following human exposure to SHS.

Public Health Relevance

This exploratory proposal is submitted by the Department of Behavioral Neuroscience at the Oregon Health & Science University (OHSU) with the goal of determining whether chronic exposure to second-hand smoke (SHS) induces tau misregulation and changes in brain metabolism that are associated with cognitive deficits and tau pathology. The results of the proposed study will determine if SHS induces cognitive impairment and pathological changes that are pertinent to MCI and dementia, and whether they are associated with insulin resistance, oxidative stress, DNA damage and perturbations in brain metabolic pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21ES027943-02
Application #
9608741
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Tyson, Frederick L
Project Start
2017-12-15
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239