title: Neuropathologic and biochemical changes during disease progression in liver X receptor beta-/- mice, a model of adult neuron disease.
abstract: In amyotrophic lateral sclerosis (ALS), there is selective degeneration of motor neurons that leads to paralysis and death. Although the etiology of ALS is unclear, its heterogeneity suggests that a combination of factors (endogenous and/or environmental) may induce progressive motor neuron stress that results in the activation of different cell death pathways. Alterations of brain cholesterol homeostasis have recently been considered as possible cofactors in many neurodegenerative disorders, including ALS. The liver X receptor beta (LXRbeta) receptor is involved in lipogenesis and cholesterol metabolism, and we previously found that adult-onset motor neuron pathology occurs in LXRbeta mice. Here, we investigated neuromuscular alterations of LXRbeta mice from ages 3 to 24 months. Increased cholesterol levels, gliosis, and inflammation preceded motor neuron loss and clinical disease onset; the mice showed progressivemotor neuron deficits starting from age 7 months. The numbers ofmotor neurons and neuromuscular junctions were decreased in 24-month-old mice, but neither paralysis nor reduced life span was observed. Moreover, other spinal neurons were also lost in these mice. These results suggest that LXRbeta may inhibit neuroinflammation and maintain cholesterol homeostasis, and that LXRbeta mice represent a potential model for investigating the role of cholesterol in ALS and other neurodegenerative disorders.
authors.affiliation: Department of Molecular Biochemistry and Pharmacology, Mario Negri Institute for Pharmacological Research, Milan, Italy. paolo.bigini@marionegri.it
authors.forename: Paolo
authors.initials: P
authors.lastname: Bigini
authors.forename: Knut R
authors.initials: KR
authors.lastname: Steffensen
authors.forename: Anna
authors.initials: A
authors.lastname: Ferrario
authors.forename: Luisa
authors.initials: L
authors.lastname: Diomede
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ferrara
authors.forename: Sara
authors.initials: S
authors.lastname: Barbera
authors.forename: Sonia
authors.initials: S
authors.lastname: Salzano
authors.forename: Elena
authors.initials: E
authors.lastname: Fumagalli
authors.forename: Pietro
authors.initials: P
authors.lastname: Ghezzi
authors.forename: Tiziana
authors.initials: T
authors.lastname: Mennini
authors.forename: Jan-Ake
authors.initials: JA
authors.lastname: Gustafsson
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001835:Body Weight / Q000502:physiology; D002452:Cell Count; D016923:Cell Death / Q000502:physiology; D002784:Cholesterol / Q000097:blood*; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005911:Gliosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045442:Rotarod Performance Test
chemical_list: D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D002784:Cholesterol