title: Conditional Depletion of Hippocampal Brain-Derived Neurotrophic Factor Exacerbates Neuropathology in a Mouse Model of Alzheimer's Disease.
abstract: Damage occurring to noradrenergic neurons in the locus coeruleus (LC) contributes to the evolution of neuroinflammation and neurodegeneration in a variety of conditions and diseases. One cause of LC damage may be loss of neurotrophic support from LC target regions. We tested this hypothesis by conditional unilateral knockout of brain-derived neurotrophic factor (BDNF) in adult mice. To evaluate the consequences of BDNF loss in the context of neurodegeneration, the mice harbored familial mutations for human amyloid precursor protein and presenilin-1. In these mice, BDNF depletion reduced tyrosine hydroxylase staining, a marker of noradrenergic neurons, in the rostral LC. BDNF depletion also reduced noradrenergic innervation in the hippocampus, the frontal cortex, and molecular layer of the cerebellum, assessed by staining for dopamine beta hydroxylase. BDNF depletion led to an increase in cortical amyloid plaque numbers and size but was without effect on plaque numbers in the striatum, a site with minimal innervation from the LC. Interestingly, cortical Iba1 staining for microglia was reduced by BDNF depletion and was correlated with reduced dopamine beta hydroxylase staining. These data demonstrate that reduction of BDNF levels in an LC target region can cause retrograde damage to LC neurons, leading to exacerbation of neuropathology in distinct LC target areas. Methods to reduce BDNF loss or supplement BDNF levels may be of value to reduce neurodegenerative processes normally limited by LC noradrenergic activities.
authors.affiliation: 1 Department of Anesthesiology, University of Illinois, Chicago, IL, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Braun
authors.affiliation: 1 Department of Anesthesiology, University of Illinois, Chicago, IL, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Kalinin
authors.affiliation: 2 Jesse Brown VA Medical Center, Chicago, IL, USA.
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Feinstein
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency* / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008125:Locus Coeruleus / Q000378:metabolism / Q000473:pathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C545487:APP protein, human; C491049:Aif1 protein, mouse; D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1
keywords: Alzheimer’s disease; adeno-associated virus; amyloid; brain-derived neurotrophic factor; locus coeruleus; neuroinflammation; neurotrophin; noradrenaline; tyrosine hydroxylase