Early structural and functional defects in synapses and myelinated axons in stratum lacunosum moleculare in two preclinical models for tauopathy.
The stratum lacunosum moleculare (SLM) is the connection hub between entorhinal cortex and hippocampus, two brain regions that are most vulnerable in Alzheimer's disease. We recently identified a specific synaptic deficit of Nectin-3 in transgenic models for tauopathy. Here we defined cognitive impairment and electrophysiological problems in the SLM of Tau.P301L mice, which corroborated the structural defects in synapses and dendritic spines. Reduced diffusion of DiI from the ERC to the hippocampus indicated defective myelinated axonal pathways. Ultrastructurally, myelinated axons in the temporoammonic pathway (TA) that connects ERC to CA1 were damaged in Tau.P301L mice at young age. Unexpectedly, the myelin defects were even more severe in bigenic biGT mice that co-express GSK3β with Tau.P301L in neurons. Combined, our data demonstrate that neuronal expression of protein Tau profoundly affected the functional and structural organization of the entorhinal-hippocampal complex, in particular synapses and myelinated axons in the SLM. White matter pathology deserves further attention in patients suffering from tauopathy and Alzheimer's disease.
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, Leuven, Belgium.
Hervé
H
Maurin
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, Leuven, Belgium.
Seon-Ah
SA
Chong
Dept. Life Sciences, Open University, Milton Keynes, United Kingdom.
Igor
I
Kraev
Dept. Life Sciences, Open University, Milton Keynes, United Kingdom.
Heather
H
Davies
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, Leuven, Belgium.
Anna
A
Kremer
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, Leuven, Belgium.
Claire Marie
CM
Seymour
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, Leuven, Belgium.
Benoit
B
Lechat
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, Leuven, Belgium.
Tomasz
T
Jaworski
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, Leuven, Belgium.
Peter
P
Borghgraef
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, Leuven, Belgium.
Herman
H
Devijver
Research Group Neurodegeneration, KULAK, Kortrijk, Belgium.
Geert
G
Callewaert
Dept. Life Sciences, Open University, Milton Keynes, United Kingdom.
Michael G
MG
Stewart
Experimental Genetics Group - LEGTEGG, Dept. Human Genetics, Leuven, Belgium.
Fred
F
Van Leuven
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003072:Cognition Disorders / Q000235:genetics / Q000503:physiopathology; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018728:Entorhinal Cortex / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009043:Motor Activity / Q000502:physiology; D009154:Mutation; D009413:Nerve Fibers, Myelinated / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology; D024801:Tauopathies / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism
D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3