TrkB reduction exacerbates Alzheimer's disease-like signaling aberrations and memory deficits without affecting β-amyloidosis in 5XFAD mice.
Accumulating evidence shows that brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) significantly decrease early in Alzheimer's disease (AD). However, it remains unclear whether BDNF/TrkB reductions may be mechanistically involved in the pathogenesis of AD. To address this question, we generated 5XFAD transgenic mice with heterozygous TrkB knockout (TrkB(+/-)·5XFAD), and tested the effects of TrkB reduction on AD-like features in this mouse model during an incipient stage that shows only modest amyloid-β (Aβ) pathology and retains normal mnemonic function. TrkB(+/-) reduction exacerbated memory declines in 5XFAD mice at 4-5 months of age as assessed by the hippocampus-dependent spontaneous alternation Y-maze task, while the memory performance was not affected in TrkB(+/-) mice. Meanwhile, TrkB(+/-)·5XFAD mice were normal in nest building, a widely used measure for social behavior, suggesting the memory-specific aggravation of AD-associated behavioral impairments. We found no difference between TrkB(+/-)·5XFAD and 5XFAD control mice in cerebral plaque loads, Aβ concentrations including total Aβ42 and soluble oligomers and β-amyloidogenic processing of amyloid precursor protein. Interestingly, reductions in hippocampal expression of AMPA/NMDA glutamate receptor subunits as well as impaired signaling pathways downstream to TrkB such as CREB (cAMP response element-binding protein) and Akt/GSK-3β (glycogen synthase kinase-3β) were observed in TrkB(+/-)·5XFAD mice but not in 5XFAD mice. Among these signaling aberrations, only Akt/GSK-3β dysfunction occurred in TrkB(+/-) mice, while others were synergistic consequences between TrkB reduction and subthreshold levels of Aβ in TrkB(+/-)·5XFAD mice. Collectively, our results indicate that reduced TrkB does not affect β-amyloidosis but exacerbates the manifestation of hippocampal mnemonic and signaling dysfunctions in early AD.
Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA.
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1] Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA [2] Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA.
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D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006579:Heterozygote; D008562:Membrane Glycoproteins / Q000235:genetics*; D008568:Memory; D008569:Memory Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000235:genetics* / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction; D020813:Receptor, trkB
D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C075222:amyloid beta-protein (1-42); C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB; C000605507:Gsk3b protein, mouse