Air Pollution and Alzheimer’s Disease
Project Collaborators:
- Uschi Graham (Bioinnovations Institute)
- Rashad Hussain
- Maiken Nedergaard
- Dr. Günter Oberdörster
Exposure to airborne hazards is associated with increased incidence and severity of neurological disorders. More specifically, population-based studies point to combustion-derived particulates and metals as being associated with neurodegenerative diseases. We have two projects underway in the Elder lab that are focused on Alzheimer’s and related dementias and that aim to gain a better mechanistic understanding of how inhaled particles can affect brain health. One focuses on ambient air pollution ultrafine particles and the other on simulated burn pit aerosols in the context of exposures in the military population.
Emerging studies document that exposure to ambient particulate matter (PM) air pollution increases the risk of developing Alzheimer's Disease (AD) and AD-Related Dementias (ADRD). Our understanding of the mechanisms by which PM exposure augments the progression of ADRD-related pathology and cognitive impairment in humans and animal models is very limited. Airborne ultrafine particles (UFP, <100 nm diameter) could be causally related to the development and/or progression of AD/ADRD due to their ability to distribute throughout the body – including the brain – after inhalation exposures and to enhance tissue oxidative stress. The glymphatic pathway is emerging as a key to maintaining brain health and its dysfunction is broadly implicated in neurological disorders. It is dedicated to draining soluble waste proteins from the interstitial fluid to maintain brain health. In a project funded via the NIH, we are testing the hypothesis that airborne UFP are transported to the brain and cause inflammation that, either directly or indirectly, impairs glymphatic fluid flow and contributes to onset or acceleration of AD/ADRD-like pathology and behavioral deficits in a mouse model of AD, namely transgenic APP/PS1 mice, which over-express a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9) and develop Aβ deposits by six months of age. These mice also manifest AD-like cognitive deficits. The work includes short and repeated exposure to laboratory-generated model and concentrated ambient UFPs to test for changes in glymphatic fluid transport, cognitive performance, progression of Aβ deposition, accumulation and bioprocessing of particles that translocate to the brain, and sleep disturbances. We will also test interventions that improve sleep quality and adrenergic signaling to determine if glymphatic function and pathology progression can be mitigated.
While exposure to combustion-derived UFPs is a global public health concern, military personnel experience higher exposures, including to emissions from ‘burn pits’. Veterans returning from deployment have increased respiratory complaints and neurological disorders. In a study that is funded by the DOD, we are conducting a detailed study of the impact of simulated burn-pit aerosols on perivascular spaces and CSF circulation within the brain. We hypothesize that structural and anatomical abnormalities in the vasculature have a profound impact on CSF flow within the brain; reduced CSF flow impedes the clearance of burn pit airborne PM from the brain and leads to its accumulation along perivascular spaces and brain interstitium. Compromised clearance starts a vicious cycle of neuroinflammation, disturbed homeostasis, and neuronal/glial dysfunction, leading to more complex neurological disorders. We are pursuing aims to study how burn pit PM exposures contribute to the accumulation of particles in lung and secondary tissues, structural remodeling of periarterial spaces and glymphatic dysfunction, white matter integrity, AD pathology, and how physiological co-morbidities (hypertension, sleep disturbance) affect outcomes related to burn pit PM exposures.