Air Pollution and Alzheimer’s Disease Risk Interact With Premature Aging of Neural Stem Cells and Apolipoprotein E Alleles

2021

Environmental factors in Alzheimer’s disease (AD) are poorly defined. Recent epidemiological studies strongly associate elevated air pollution (AirPoll) with increased risks for accelerated cognitive loss and AD. Moreover, carriers of APP mutations, which contribute to amyloidosis in familial AD, are more vulnerable to AirPoll. However, it remains unknown how AirPoll and APP risks interact. We propose studies on how neural stem cells (NSC) integrate AirPoll and APP risk in adult mouse brains. NSC proliferation declines during normal aging, but is greater in AD brains. Maintenance of NSC in older ages is hypothesized as critical for resistance to AD-related pathology and cognitive deficits. Our pilot data shows that AirPoll exposure of adult rodents impairs NSC replication. Because brain amyloid peptides increase during normal aging in rodents and humans, we examined possible benefits of BPN-15606, an anti-amyloid drug developed by CureAlz investigators and with CureAlz support. In a pilot study, BPN-15606 protected mouse NSC from loss during AirPoll exposure. We propose further studies with BPN-15606 to identify the relation of early NSC loss to brain amyloid increase during normal aging and the role of amyloid beta in NSC loss. Single-cell studies of NSC messenger RNA response to AirPoll will identify molecular pathways that damage NSC and could identify further targets to protect AD risk from AirPoll. These studies are the first to examine NSC aging at the single-cell level for modulation by AirPoll and environmental interactions with amyloid peptides. The findings could extend the benefits of anti-amyloid drugs and treatments to lowering environmental risks for AD.


Funding to Date

$257,679

Focus

Studies of APP and Abeta, Translational

Researchers

Caleb Finch, Ph.D.


Michael A. Bonaguidi, Ph.D.