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The center of olfactory bulb-seeded α-synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice.
Brain Pathol. 2019 11; 29(6):741-770.BP

Abstract

At early disease stages, Lewy body disorders are characterized by limbic vs. brainstem α-synucleinopathy, but most preclinical studies have focused solely on the nigrostriatal pathway. Furthermore, male gender and advanced age are two major risk factors for this family of conditions, but their influence on the topographical extents of α-synucleinopathy and the degree of cell loss are uncertain. To fill these gaps, we infused α-synuclein fibrils in the olfactory bulb/anterior olfactory nucleus complex-one of the earliest and most frequently affected brain regions in Lewy body disorders-in 3-month-old female and male mice and in 11-month-old male mice. After 6 months, we observed that α-synucleinopathy did not expand significantly beyond the limbic connectome in the 9-month-old male and female mice or in the 17-month-old male mice. However, the 9-month-old male mice had developed greater α-synucleinopathy, smell impairment and cell loss than age-matched females. By 10.5 months post-infusion, fibril treatment hastened mortality in the 21.5-month-old males, but the inclusions remained centered in the limbic system in the survivors. Although fibril infusions reduced the number of cells expressing tyrosine hydroxylase in the substantia nigra of young males at 6 months post-infusion, this was not attributable to true cell death. Furthermore, mesencephalic α-synucleinopathy, if present, was centered in mesolimbic circuits (ventral tegmental area/accumbens) rather than within strict boundaries of the nigral pars compacta, which were defined here by tyrosine hydroxylase immunolabel. Nonprimate models cannot be expected to faithfully recapitulate human Lewy body disorders, but our murine model seems reasonably suited to (i) capture some aspects of Stage IIb of Lewy body disorders, which displays a heavier limbic than brainstem component compared to incipient Parkinson's disease; and (ii) leverage sex differences and the acceleration of mortality following induction of olfactory α-synucleinopathy.

Authors+Show Affiliations

Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA.Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA.Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA.Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA.Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA.Department of Biological Sciences, Duquesne University, Pittsburgh, PA.Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

30854742

Citation

Mason, Daniel M., et al. "The Center of Olfactory Bulb-seeded Α-synucleinopathy Is the Limbic System and the Ensuing Pathology Is Higher in Male Than in Female Mice." Brain Pathology (Zurich, Switzerland), vol. 29, no. 6, 2019, pp. 741-770.
Mason DM, Wang Y, Bhatia TN, et al. The center of olfactory bulb-seeded α-synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice. Brain Pathol. 2019;29(6):741-770.
Mason, D. M., Wang, Y., Bhatia, T. N., Miner, K. M., Trbojevic, S. A., Stolz, J. F., Luk, K. C., & Leak, R. K. (2019). The center of olfactory bulb-seeded α-synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice. Brain Pathology (Zurich, Switzerland), 29(6), 741-770. https://doi.org/10.1111/bpa.12718
Mason DM, et al. The Center of Olfactory Bulb-seeded Α-synucleinopathy Is the Limbic System and the Ensuing Pathology Is Higher in Male Than in Female Mice. Brain Pathol. 2019;29(6):741-770. PubMed PMID: 30854742.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The center of olfactory bulb-seeded α-synucleinopathy is the limbic system and the ensuing pathology is higher in male than in female mice. AU - Mason,Daniel M, AU - Wang,Yaqin, AU - Bhatia,Tarun N, AU - Miner,Kristin M, AU - Trbojevic,Sara A, AU - Stolz,John F, AU - Luk,Kelvin C, AU - Leak,Rehana K, Y1 - 2019/04/10/ PY - 2018/11/09/received PY - 2019/03/03/accepted PY - 2019/3/12/pubmed PY - 2020/4/9/medline PY - 2019/3/12/entrez KW - Lewy body KW - Lewy body disorder KW - Parkinson’s disease KW - limbic KW - olfactory KW - synuclein SP - 741 EP - 770 JF - Brain pathology (Zurich, Switzerland) JO - Brain Pathol VL - 29 IS - 6 N2 - At early disease stages, Lewy body disorders are characterized by limbic vs. brainstem α-synucleinopathy, but most preclinical studies have focused solely on the nigrostriatal pathway. Furthermore, male gender and advanced age are two major risk factors for this family of conditions, but their influence on the topographical extents of α-synucleinopathy and the degree of cell loss are uncertain. To fill these gaps, we infused α-synuclein fibrils in the olfactory bulb/anterior olfactory nucleus complex-one of the earliest and most frequently affected brain regions in Lewy body disorders-in 3-month-old female and male mice and in 11-month-old male mice. After 6 months, we observed that α-synucleinopathy did not expand significantly beyond the limbic connectome in the 9-month-old male and female mice or in the 17-month-old male mice. However, the 9-month-old male mice had developed greater α-synucleinopathy, smell impairment and cell loss than age-matched females. By 10.5 months post-infusion, fibril treatment hastened mortality in the 21.5-month-old males, but the inclusions remained centered in the limbic system in the survivors. Although fibril infusions reduced the number of cells expressing tyrosine hydroxylase in the substantia nigra of young males at 6 months post-infusion, this was not attributable to true cell death. Furthermore, mesencephalic α-synucleinopathy, if present, was centered in mesolimbic circuits (ventral tegmental area/accumbens) rather than within strict boundaries of the nigral pars compacta, which were defined here by tyrosine hydroxylase immunolabel. Nonprimate models cannot be expected to faithfully recapitulate human Lewy body disorders, but our murine model seems reasonably suited to (i) capture some aspects of Stage IIb of Lewy body disorders, which displays a heavier limbic than brainstem component compared to incipient Parkinson's disease; and (ii) leverage sex differences and the acceleration of mortality following induction of olfactory α-synucleinopathy. SN - 1750-3639 UR - https://www.unboundmedicine.com/medline/citation/30854742/The_center_of_olfactory_bulb_seeded_α_synucleinopathy_is_the_limbic_system_and_the_ensuing_pathology_is_higher_in_male_than_in_female_mice_ L2 - https://doi.org/10.1111/bpa.12718 DB - PRIME DP - Unbound Medicine ER -