title: ApoE and TDP-43 neuropathology in two siblings with familial FTLD-motor neuron disease.
abstract: Frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) is characterized by neuronal cytoplasmic inclusions containing TDP-43. Apolipoprotein E4 (apoE4), derived from the apoE ϵ4 allele, enhances brain atrophy in FTLD through unknown mechanisms. Here, we studied two siblings with C9ORF72-linked familial FTLD-MND, an apoE ϵ4 homozygote and an apoE ϵ3 homozygote. The apoE ϵ4 homozygote had more cognitive-behavioral symptoms, fronto-insulo-temporal atrophy, and apoE fragments and aggregates in the anterior cingulate cortex. ApoE formed complexes with TDP-43 that were more abundant in the apoE ϵ4 homozygote. Although differences seen in a sibling pair could arise due to chance, these findings raise the possibility that apoE4 exacerbates brain pathology in FTLD through formation of neurotoxic apoE fragments and interactions with TDP-43.
authors.affiliation: Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Vossel
authors.forename: Nga
authors.initials: N
authors.lastname: Bien-Ly
authors.forename: Aubrey
authors.initials: A
authors.lastname: Bernardo
authors.forename: Katya
authors.initials: K
authors.lastname: Rascovsky
authors.forename: Anna
authors.initials: A
authors.lastname: Karydas
authors.forename: Gil D
authors.initials: GD
authors.lastname: Rabinovici
authors.forename: Manu
authors.initials: M
authors.lastname: Sidhu
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.forename: Yadong
authors.initials: Y
authors.lastname: Huang
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
mesh_terms: D001057:Apolipoproteins E / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000150:complications / Q000175:diagnosis / Q000235:genetics*; D009483:Neuropsychological Tests; D011569:Psychiatric Status Rating Scales; D035781:Siblings
chemical_list: D001057:Apolipoproteins E; D004268:DNA-Binding Proteins