title: Human Striatal Dopaminergic and Regional Serotonergic Synaptic Degeneration with Lewy Body Disease and Inheritance of APOE ε4.
abstract: Cognitive impairment in older individuals is a complex trait that in population-based studies most commonly derives from an individually varying mixture of Alzheimer disease, Lewy body disease, and vascular brain injury. We investigated the molecular composition of synaptic particles from three sources: consecutive rapid autopsy brains from the Adult Changes in Thought Study, a population-based cohort; four aged nonhuman primate brains optimally processed for molecular investigation; and targeted replacement transgenic mice homozygous for APOE ε4. Our major goal was to characterize the molecular composition of human synaptic particles in regions of striatum and prefrontal cortex. We performed flow cytometry to measure six markers of synaptic subtypes, as well as amyloid β 42 and paired helical filament tau. Our results showed selective degeneration of dopaminergic terminals throughout the striatum in individuals with Lewy body disease, and serotonergic degeneration in human ventromedial caudate nucleus from individuals with an APOE ε4 allele. Similar results were seen in mouse caudate nucleus homozygous for APOE ε4 via targeted replacement. Together, extension of these clinical, pathologic, and genetic associations from tissue to the synaptic compartment of cerebral cortex and striatum strongly supports our approach for accurately observing the molecular composition of human synapses by flow cytometry.
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Nadia
authors.initials: N
authors.lastname: Postupna
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Caitlin S
authors.initials: CS
authors.lastname: Latimer
authors.affiliation: Group Health Research Institute, Seattle, Washington.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Larson
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Emily
authors.initials: E
authors.lastname: Sherfield
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Julie
authors.initials: J
authors.lastname: Paladin
authors.affiliation: Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Shively
authors.affiliation: Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Jorgensen
authors.affiliation: Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Rachel N
authors.initials: RN
authors.lastname: Andrews
authors.affiliation: Department of Pathology, Section on Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Jay R
authors.initials: JR
authors.lastname: Kaplan
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Crane
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Kathleen S
authors.initials: KS
authors.lastname: Montine
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Craft
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: C Dirk
authors.initials: CD
authors.lastname: Keene
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington. Electronic address: tmontine@stanford.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
mesh_terms: D000369:Aged, 80 and over; D000483:Alleles; D000818:Animals; D053327:Apolipoprotein E4 / Q000378:metabolism*; D001344:Autopsy; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000473:pathology; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006720:Homozygote; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics*; D020961:Lewy Body Disease / Q000150:complications / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000473:pathology*; D009410:Nerve Degeneration / Q000150:complications / Q000473:pathology*; D011323:Primates; D013569:Synapses / Q000378:metabolism / Q000473:pathology*
chemical_list: D053327:Apolipoprotein E4; D015415:Biomarkers