title: Opposing effects of APP/PS1 and TrkB.T1 genotypes on midbrain dopamine neurons and stimulated dopamine release in vivo.
abstract: Brain derived neurotrophic factor (BDNF) signaling disturbances in Alzheimer׳s disease (AD) have been demonstrated. BDNF levels fall in AD, but the ratio between truncated and full-length BDNF receptors TrkB.T1 and TrkB.TK, respectively, increases in brains of AD patients and APPswe/PS1dE9 (APP/PS1) AD model mice. Dopaminergic (DAergic) system disturbances in AD and detrimental effects of BDNF signaling deficits on DAergic system functions have also been indicated. Against this, we investigated changes in nigrostriatal dopamine (DA) system in mice carrying APP/PS1 and/or TrkB.T1 transgenes, the latter line modeling the TrkB.T1/TK ratio change in AD. Employing in vivo voltammetry, we found normal short-term DA release in caudate-putamen of mice carrying APP/PS1 or TrkB.T1 transgenes but impaired capacity to recruit more DA upon prolonged stimulation. However, mice carrying both transgenes did not differ from wild-type controls. Immunohistochemistry revealed normal density of tyrosine hydroxylase positive axon terminals in caudate-putamen in all genotypes and intact presynaptic machinery for DA release and reuptake, as shown by unchanged levels of SNAP-25, α-synuclein and DA transporter. However, we observed increased DAergic neurons in substantia nigra of TrkB.T1 mice resulting in decreased tyrosine hydroxylase per neuron in TrkB.T1 mice. The finding of unchanged nigral DAergic neurons in APP/PS1 mice largely confirms earlier reports, but the unexpected increase in midbrain DA neurons in TrkB.T1 mice is a novel finding. We suggest that both APP/PS1 and TrkB.T1 genotypes disrupt DAergic signaling, but via separate mechanisms.
authors.affiliation: A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland. Electronic address: elisa.karkkainen@fimnet.fi.
authors.forename: E
authors.initials: E
authors.lastname: Kärkkäinen
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland; Invilog Research Ltd, Kuopio, Finland.
authors.forename: L
authors.initials: L
authors.lastname: Yavich
authors.affiliation: A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: P O
authors.initials: PO
authors.lastname: Miettinen
authors.affiliation: A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Tanila
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; D050483:Dopamine Plasma Membrane Transport Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; C494209:Snap25 protein, mouse; C497605:Snca protein, mouse; D050825:Synaptosomal-Associated Protein 25; D051844:alpha-Synuclein; D014446:Tyrosine 3-Monooxygenase; D020813:Receptor, trkB; D004298:Dopamine
keywords: Alzheimer׳s disease; Amyloid protein precursor; BDNF; Dopamine; Presenilin-1; Transgenic mice