Early structural and functional defects in synapses and myelinated axons in stratum lacunosum moleculare in two preclinical models for tauopathy

PLoS One. 2014 Feb 3;9(2):e87605. doi: 10.1371/journal.pone.0087605. eCollection 2014.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / physiopathology
  • Animals
  • Axons / metabolism*
  • Axons / pathology
  • Axons / ultrastructure
  • Brain / metabolism*
  • Brain / pathology
  • Brain / physiopathology
  • Cognition Disorders / genetics
  • Cognition Disorders / physiopathology
  • Dendritic Spines / metabolism
  • Dendritic Spines / pathology
  • Disease Models, Animal
  • Entorhinal Cortex / metabolism
  • Entorhinal Cortex / pathology
  • Entorhinal Cortex / physiopathology
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Hippocampus / physiopathology
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron
  • Motor Activity / physiology
  • Mutation
  • Nerve Fibers, Myelinated / metabolism*
  • Nerve Fibers, Myelinated / pathology
  • Nerve Fibers, Myelinated / ultrastructure
  • Synapses / metabolism*
  • Synapses / pathology
  • Synaptic Transmission / genetics
  • Synaptic Transmission / physiology
  • Tauopathies / genetics*
  • Tauopathies / metabolism
  • Tauopathies / physiopathology
  • tau Proteins / genetics*
  • tau Proteins / metabolism

Substances

  • tau Proteins
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Glycogen Synthase Kinase 3

Grant support

The investigations were funded and supported by Fonds Wetenschappelijk Onderzoek-Vlaanderen (FWO-Vlaanderen); Instituut Wetenschap & Techniek (IWT); EEC 6th & 7th Framework Programs: MEMStick, neuroGSK3, EURON, NEURAD; KULeuven-Research Fund; KULeuven-Research&Development. HM acknowledges Marie Curie fellowship MEST CT 2005/020013 NEURAD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.