Short Research Article
Rapid doubling of Alzheimer’s amyloid-β40 and 42 levels in brains of mice exposed to a nickel nanoparticle model of air pollution [v1; ref status: indexed, http://f1000r.es/T5Rxeo]
Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Department of Environmental Sciences, New York University, Tuxedo Park, New York, NY 10987, USA
Department of Psychiatry and Alzheimer’s Disease Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
James J. Peters Veterans Affairs Medical Center, Bronx, New York, NY 10468, USA
This work was supported by the Cure Alzheimer's Fund (S.G.), VA MERIT Review Award I01BX000348 (S.G.), and the American Health Assistance Foundation A2012625 (S.H.K.). This work was also supported by National Institutes of Health Grant U01ES020126 and P30ES00260 (L.C.C.).
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
How to cite: Kim SH, Knight EM, Saunders EL et al. Rapid doubling of Alzheimer’s amyloid-β40 and 42 levels in brains of mice exposed to a nickel nanoparticle model of air pollution [v1; ref status: indexed, http://f1000r.es/T5Rxeo] F1000Research 2012, 1:70 (doi: 10.12688/f1000research.1-70.v1)
© 2012 Kim SH et al.
This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).
S.G. holds research grant support from Amicus Pharmaceuticals and Baxter Pharmaceuticals; he is a consultant to Balance Pharmaceuticals and Diagenic; and he is a member of the Data and Safety Monitoring Board for the Pfizer-Janssen Alzheimer's Immunotherapy Alliance.
First published: 21 Dec 2012, 1:70 (doi: 10.12688/f1000research.1-70.v1)
First indexed: 23 Jan 2013, 1:70 (doi: 10.12688/f1000research.1-70.v1)
Latest published: 21 Dec 2012, 1:70 (doi: 10.12688/f1000research.1-70.v1)
One common neurodegenerative disease, Parkinson’s disease, has been linked to exposure to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and to inhaled manganese1,2. Similarly, inhaled aluminum dust has been associated with neurotoxic effects and pre-clinical cognitive impairment3. Certain inhalation anesthetics have also been implicated in elevating AD risk, possibly by exacerbating the neurotoxic oligomerization of the amyloid-β (Aβ) peptide4. The early involvement of the olfactory cortex in AD has caused longtime speculation that some inhaled agent might play a role in AD risk5.
Recently, AD pathology was identified in young people living in areas with high levels of air pollution6,7. Furthermore, impaired cognition has been recently attributed to air pollution exposure in some populations8. These converging lines of evidence led us to analyze brain levels of Aβ40 and Aβ42 in mice exposed to an inhaled particulate matter (nickel nanoparticle; Ni NP) model of air pollution.
All procedures involving animals were conducted in compliance with guidelines for ethical animal research and approved by the New York University School of Medicine Animal Care and Use Committee. Two-month-old male and female FVBN mice (Taconic Farm, Hudson, NY) were randomly assigned to Ni NP inhalation (count median diameter 54 nm, at 1 mg/m3, which is the current Occupational Safety and Health Administration’s Permissible Exposure Limit for nickel hydroxide [http://www.osha.gov/pls/oshaweb/owadisp.show_document?p_table=standards&p_id=9992]) (n = 16 per group) or control filtered air (n = 5 per group) for 3 hours in a nose-only exposure chamber. This protocol has been established as a model for air pollution toxicity in pulmonary disease9, atherosclerosis10, and insulin resistance11. Twenty-four hours post exposure, mice were given pentobarbital, bled out via the vena cava, and then their brains were harvested, snap frozen and stored at -80ºC until assay. For measurement of endogenous mouse brain Aβ40 and Aβ42, we employed the Schmidt method12 and human/rat Aβ 1–40/1–42 ELISA kits (Wako, Richmond, VA). Statistical analysis was performed via Mann-Whitney test. #8 Ni NP is excluded from the analysis due to being more than 2 SD's away from mean or closest value.
Both endogenous Aβ40 and Aβ42 were elevated in the brains of mice following Ni NP exposure (Figure 1). Aβ40 was increased by 1.72-fold (P = 0.0011, Mann-Whitney test), and Aβ42 was increased by 2.29-fold (P = 0.0005, Mann-Whitney test). Aβ42/40 ratio was also increased in the Ni NP-exposed group compared to the filtered air control group (0.27 ± 0.01 and 0.21 ± 0.007, respectively; P = 0.0093, Mann-Whitney test). Both male and female mice responded similarly to Ni NP exposure (male vs. female for Aβ40 and Aβ42 levels; P > 0.1, Mann-Whitney test).
Figure 1. Exposure to air pollution increases amyloid-β (Aβ) levels in the mouse brain.
Elevated endogenous mouse brain Aβ40 and Aβ42 in mice exposed to nickel nanoparticles (count median diameter 54 nm, at 1 mg/m3) (n = 16 per group) versus filtered air (n = 5 per group) for 3 hours in a nose-only exposure chamber. Data presented as mean + SEM. **P < 0.01, ***P < 0.001 (Mann-Whitney test).
Raw data of endogenous mouse brain Aβ40 and Aβ42 levels (pmol/L) in mice exposed to nickel nanoparticles (count median diameter 54 nm, at 1 mg/m3) (n = 16 per group) versus filtered air (n = 5 per group) for 3 hours in a nose-only exposure chamber. *Mouse 8 was excluded from the data analysis as these results were 2 SD's away from mean or closest value.
These data add credence to the proposal4 that one or more inhaled neurotoxin(s) might increase the risk for AD by elevating levels of brain Aβ. We have not identified whether this accumulation occurs at the level(s) of transcription, translation, or post-translational processing. It is tempting to speculate that the well-known links between inhaled toxins and brain inflammation, and other links between brain inflammation and AD established by Griffin and colleagues13 may underlie these phenomena.
The changes that we observed were dramatic, rapid, and unexpected. Human Aβ is more aggregatable than murine Aβ, making it conceivable that the effect on Aβ levels in human brain could be even greater. While elucidating the genesis and molecular underpinnings will be an important next step, an even more important step will be a rigorous application of environmental toxicology and epidemiology to determine whether the elevated brain Aβ caused in mice by this air pollution model corresponds to any situation of authentic human inhalation exposure that is linked to an increased risk for AD.