权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Air Pollution, Elevated Brain Iron and Alzheimer's Disease

空气污染、脑铁含量升高和阿尔茨海默病

基本信息

批准号：
10285494
负责人：
Deborah A Cory-Slechta
金额：
$ 38.08万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-18 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10285494
关键词：
Adult Affect Aging Air Pollution Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Amygdaloid structure Amyloid Amyloid beta-Protein Amyloid deposition Area Behavioral Biological Biological Models Birth Blood Blood - brain barrier anatomy Brain Brain region Bypass Cell Count Cerebrum Cognitive Copper DNA Sequence Alteration Data Dementia Disease Environmental Risk Factor Epidemiology Etiology Exposure to Female Funding Geography Grant Health protection Hippocampus (Brain)Histologic Homeostasis Human Impaired cognition Impairment Inductively Coupled Plasma Mass Spectrometry Inflammation Inhalation Inhalation Exposure Iron Lead levels Link Maps Mediating Memory Meta-Analysis Metals Modeling Mus Nerve Degeneration Neurodegenerative Disorders Neurodevelopmental Disorder Neurofibrillary Tangles Neurons Nose Nucleus Accumbens Olfactory Nerve Olfactory dysfunction Olfactory tract Outcome Measure Oxidation-Reduction Oxidative Stress Particulate Matter Pathologic Pathway interactions Peripheral Public Health Regulation Reporting Risk Factors Role Schizophrenia Senile Plaques Sensorimotor functions Sex Differences Site Stream Suggestion Synapses Third Pregnancy Trimester Time Trigeminal nerve structure abeta accumulation air contaminant air filter behavior measurement behavior test disease phenotype economic cost epidemiology study executive function experimental study fetal geographic difference high efficiency particulate air filter in utero macrophage male mortality myelination nanoparticle nanoparticle exposure neural network neurodegenerative dementia olfactory bulb piriform cortex postnatal postnatal period pre-clinical sex social tau Proteins ultrafine particle uptake virtual young adult

项目摘要

ABSTRACT Numerous epidemiological studies have now linked air pollution (AP) with Alzheimer’s Disease (AD) and cognitive decline. Idiopathic AD, the most common form of dementia in the US, is a female-biased neurodegenerative disease of unknown etiology. In addition to the accumulation of plaques and tangles, AD is also characterized by marked elevations in brain levels of the redox active metal, iron (Fe), giving rise to a brain metal dyshomeostasis hypothesis for AD. The basis for the elevated Fe is not clear, but this supplement hypothesizes that exposures to Fe contamination from the ultrafine particle (UFP) component of AP, considered the most reactive component of AP, to which exposures can begin in utero and be lifelong following birth, contributes to the AD phenotype. Indeed, post-birth, such UFPs and associated contaminants move directly into blood stream, bypassing macrophages to each brain; UFPs can also be directly taken up into brain via olfactory and trigeminal nerves, bypassing the blood brain barrier. Our data from mice exposed via inhalation to concentrated ambient UFPs confirms significant elevation of brain Fe and alterations in other essential brain metals as well. Like most neurodegenerative diseases, AD is heterogeneous in expression which could reflect the geographical differences in the extent of Fe contamination. Interestingly, in that regard, the levels of highest Fe emissions in the U.S. overlap with areas of highest Alzheimer’s disease mortality. In preliminary data obtained from early postnatal exposures of both male and female mice, numerous female-specific features of AD have been seen: increased olfactory bulb microglial activation, consistent with nasal olfactory uptake, decreased trajectory of neuronal cell counts in nucleus accumbens, and increased levels of total hippocampal amyloids and tau at PND90. Ventriculomegaly, another feature seen in AD, was found in both sexes. The aim of this proposed supplement is to extend our current studies of AP-induced brain metal contamination, which to date has focused on neurodevelopmental disorders, to examine the effects of a 6 week exposure of adult mice to Fe UFPs at multiple time-points post exposure. Outcome measures will include neuropathological features of AD, specifically hyperphosphyorylated tau, beta amyloids, ventriculomegaly, myelination, and oxidative stress and ferroptosis, with behavioral measures of executive function. This supplement should establish a model that could be critical to defining mechanisms of AD and sex-related differences in vulnerability, as well as to provide data that is important to regulation of AP, and consequently to public health protection.

摘要