Late onset loss of hippocampal 5-HT and NE is accompanied by increases in BDNF protein expression in mice co-expressing mutant APP and PS1.
Transgenic mice expressing both mutant amyloid precursor protein (APPswe) and presenilin-1 (PS1DeltaE9) develop amyloid deposits as early as 4 months of age and preliminary evidence suggests that this may be associated with degenerative changes in serotonin axons innervating the dentate gyrus of the hippocampus. In the present investigation, which focused on further delineating the effects of amyloid deposition on hippocampal neurochemistry, decreases in serotonin neurotransmitter levels (-25%) were discovered to be present at 18 months in APP+/PS1+ mice, while norepinephrine was reduced in the hippocampus of 12- (-30%) and 18-month-old (-45%) APP+/PS1+ double mutants. In addition, brain-derived neurotrophic factor (BDNF) protein levels were investigated since changes in BDNF are reported to occur in AD, and BDNF has been shown to have trophic effects on serotonin and norepinephrine neurons. In doubly, but not singly mutant mice, hippocampal BDNF levels were increased at 12 (+70%) and 18 months (+170%). Furthermore, in a different model of serotonergic and noradrenergic degeneration, BDNF protein levels were similarly increased in response to depletions in hippocampal serotonin and norepinephrine caused by the chemical neurotoxin 1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP). These findings show that early amyloid deposition in mice expressing mutant human APP and PS-1 is associated with a progressive loss of serotonin and norepinephrine neurotransmitter levels in the hippocampus later in life. Furthermore, BDNF protein levels are increased in APP+/PS1+ and 2'-NH2-MPTP-treated mice, possibly as a compensatory response to serotonergic and noradrenergic neurodegeneration in a brain region important for learning and memory.
Szapacs
Matthew E
ME
Department of Chemistry and the Huck Institute for Life Sciences, The Pennsylvania State University, University Park, PA 16802-4615, USA.
Numis
Adam L
AL
Andrews
Anne M
AM
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000367:Age Factors; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009638:Norepinephrine / Q000378:metabolism*; D053764:Presenilin-1; D012701:Serotonin / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; C079794:1-methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine; D012701:Serotonin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine; D009638:Norepinephrine