title: Dendritic degeneration, neurovascular defects, and inflammation precede neuronal loss in a mouse model for tau-mediated neurodegeneration.
abstract: Adeno-associated virus (AAV)-mediated expression of wild-type or mutant P301L protein tau produces massive degeneration of pyramidal neurons without protein tau aggregation. We probed this novel model for genetic and structural factors and early parameters of pyramidal neurodegeneration. In yellow fluorescent protein-expressing transgenic mice, intracerebral injection of AAV-tauP301L revealed early damage to apical dendrites of CA1 pyramidal neurons, whereas their somata remained normal. Ultrastructurally, more and enlarged autophagic vacuoles were contained in degenerating dendrites and manifested as dark, discontinuous, vacuolated processes surrounded by activated astrocytes. Dendritic spines were lost in AAV-tauP301L-injected yellow fluorescent protein-expressing transgenic mice, and ultrastructurally, spines appeared dark and degenerating. In CX3CR1(EGFP/EGFP)-deficient mice, microglia were recruited early to neurons expressing human tau. The inflammatory response was accompanied by extravasation of plasma immunoglobulins. α2-Macroglobulin, but neither albumin nor transferrin, became lodged in the brain parenchyma. Large proteins, but not Evans blue, entered the brain of mice injected with AAV-tauP301L. Ultrastructurally, brain capillaries were constricted and surrounded by swollen astrocytes with extensions that contacted degenerating dendrites and axons. Together, these data corroborate the hypothesis that neuroinflammation participates essentially in tau-mediated neurodegeneration, and the model recapitulates early dendritic defects reminiscent of "dendritic amputation" in Alzheimer's disease.
authors.affiliation: Laboratory of Experimental Genetics and Transgenesis/Experimental Genetics Group (LEGTEGG), Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Jaworski
authors.forename: Benoit
authors.initials: B
authors.lastname: Lechat
authors.forename: David
authors.initials: D
authors.lastname: Demedts
authors.forename: Lies
authors.initials: L
authors.lastname: Gielis
authors.forename: Herman
authors.initials: H
authors.lastname: Devijver
authors.forename: Peter
authors.initials: P
authors.lastname: Borghgraef
authors.forename: Hans
authors.initials: H
authors.lastname: Duimel
authors.forename: Fons
authors.initials: F
authors.lastname: Verheyen
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kügler
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology / Q000648:ultrastructure; D015415:Biomarkers / Q000378:metabolism; D001808:Blood Vessels / Q000473:pathology / Q000648:ultrastructure; D001812:Blood-Brain Barrier / Q000473:pathology; D056547:CA1 Region, Hippocampal / Q000473:pathology / Q000648:ultrastructure; D003712:Dendrites / Q000473:pathology* / Q000648:ultrastructure; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000150:complications / Q000473:pathology*; D009420:Nervous System / Q000098:blood supply* / Q000473:pathology*; D018384:Oxidative Stress; D010539:Permeability; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D013569:Synapses / Q000473:pathology / Q000648:ultrastructure; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D016875:tau Proteins