title: The noradrenaline precursor L-DOPS reduces pathology in a mouse model of Alzheimer's disease.
abstract: Damage to noradrenergic neurons in the locus coeruleus (LC) is a hallmark of Alzheimer's disease (AD) and may contribute to disease progression. In 5xFAD transgenic mice, which accumulate amyloid burden at early ages, the LC undergoes stress as evidenced by increased astrocyte activation, neuronal hypertrophy, reduced levels of LC-enriched messenger RNAs (mRNAs), and increased inflammatory gene expression. Central nervous system (CNS) noradrenaline (NA) levels in 5-month-old male 5xFAD mice were increased using the NA precursor L-threo-3,4-dihydroxyphenylserine (L-DOPS). After 1 month, L-DOPS treatment improved learning in the Morris water maze test compared with vehicle-treated mice. L-DOPS increased CNS NA levels, and average latency times in the water maze test were inversely correlated to NA levels. L-DOPS reduced astrocyte activation and Thioflavin-S staining; increased mRNA levels of neprilysin and insulin degrading enzyme, and of several neurotrophins; and increased brain-derived neurotrophic factor protein levels. These data demonstrate the presence of LC stress in a robust mouse model of AD, and suggest that raising CNS NA levels could provide benefit in AD.
authors.affiliation: Department of Anesthesiology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Kalinin
authors.forename: Paul E
authors.initials: PE
authors.lastname: Polak
authors.forename: Shao Xia
authors.initials: SX
authors.lastname: Lin
authors.forename: Amul J
authors.initials: AJ
authors.lastname: Sakharkar
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Pandey
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
mesh_terms: D059331:Adrenergic Neurons / Q000187:drug effects* / Q000473:pathology; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage; D015103:Droxidopa / Q000008:administration & dosage*; D008125:Locus Coeruleus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009638:Norepinephrine / Q000378:metabolism / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000978:Antiparkinson Agents; D015103:Droxidopa; D009638:Norepinephrine