title: Protein homeostasis gene dysregulation in pretangle-bearing nucleus basalis neurons during the progression of Alzheimer's disease.
abstract: Conformational phosphorylation and cleavage events drive the tau protein from a soluble, monomeric state to a relatively insoluble, polymeric state that precipitates the formation of neurofibrillary tangles (NFTs) in projection neurons in Alzheimer's disease (AD), including the magnocellular perikarya located in the nucleus basalis of Meynert (NBM) complex of the basal forebrain. Whether these structural changes in the tau protein are associated with pathogenic changes at the molecular and cellular level remains undetermined during the onset of AD. Here, we examined alterations in gene expression within individual NBM neurons immunostained for pS422, an early tau phosphorylation event, or dual labeled for pS422 and TauC3, a later stage tau neoepitope, from tissue obtained postmortem from subjects who died with an antemortem clinical diagnosis of no cognitive impairment, mild cognitive impairment, or mild/moderate AD. Specifically, pS422-positive pretangles displayed an upregulation of select gene transcripts subserving protein quality control. On the other hand, late-stage TauC3-positive NFTs exhibited upregulation of messenger RNAs involved in protein degradation but also cell survival. Taken together, these results suggest that molecular pathways regulating protein homeostasis are altered during the evolution of NFT pathology in the NBM. These changes likely contribute to the disruption of protein turnover and neuronal survival of these vulnerable NBM neurons during the progression of AD.
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Chelsea T
authors.initials: CT
authors.lastname: Tiernan
authors.affiliation: Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA; Department of Psychiatry, NYU Langone Medical Center, New York, NY, USA; Department of Neuroscience & Physiology, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Ginsberg
authors.affiliation: Allen Institute for Brain Science, Seattle, WA, USA.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Guillozet-Bongaarts
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Ward
authors.affiliation: Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Hauenstein Neurosciences Center, Mercy Health Saint Mary's Hospital, Grand Rapids, MI, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Kanaan
authors.affiliation: Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ, USA.
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Mufson
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Lester I
authors.initials: LI
authors.lastname: Binder
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA; Hauenstein Neurosciences Center, Mercy Health Saint Mary's Hospital, Grand Rapids, MI, USA; Department of Family Medicine, Michigan State University, Grand Rapids, MI, USA. Electronic address: scott.counts@hc.msu.edu.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Counts
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D020532:Basal Nucleus of Meynert / Q000378:metabolism* / Q000473:pathology*; D002470:Cell Survival / Q000235:genetics; D060825:Cognitive Dysfunction / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D059748:Proteolysis; D015854:Up-Regulation; D016875:tau Proteins / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins; D016875:tau Proteins
keywords: Alzheimer's disease; Cholinergic basal forebrain; Mild cognitive impairment; Protein homeostasis; Tau