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 GSK3ß 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.
Subject(s)
Axons/metabolism , Brain/metabolism , Nerve Fibers, Myelinated/metabolism , Synapses/metabolism , Tauopathies/genetics , tau Proteins/genetics , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Animals , Axons/pathology , Axons/ultrastructure , 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/pathology , Nerve Fibers, Myelinated/ultrastructure , Synapses/pathology , Synaptic Transmission/genetics , Synaptic Transmission/physiology , Tauopathies/metabolism , Tauopathies/physiopathology , tau Proteins/metabolismABSTRACT
Cell adhesion molecules are important structural substrates, required for synaptic plasticity and synaptogenesis. CAMs differ widely in their expression throughout different brain regions and their specific structural and functional roles in the brain remain to be elucidated. Here, we investigated selected cell adhesion molecules for alterations in expression levels and neuronal localization in validated mouse models for Alzheimer's disease that mimic the age-related progression of amyloid accumulation and tauopathy. Among the cell adhesion molecules analyzed, Nectin-3 expression was affected most and specifically in all mouse models with tauopathy. In particular was Nectin-3 depleted from the specific region of the hippocampus, known as the stratum lacunosum and moleculare, in mice that express wild-type or mutant human protein Tau, either chronically or sub-acutely. Tauopathy progresses from the entorhinal cortex to the hippocampus by unknown mechanisms that could involve transport by the myelinated axons of the temporoammonic and perforant pathways. The decreased expression of Nectin-3 in the stratum lacunosum moleculare is an early marker of impaired transport, and eventual synaptic problems, caused by beginning tauopathy.
Subject(s)
Brain/metabolism , Brain/pathology , Cell Adhesion Molecules/metabolism , Down-Regulation/genetics , Tauopathies/metabolism , Animals , Cell Adhesion Molecules/genetics , Dependovirus/metabolism , Disease Models, Animal , Humans , Mice , Mice, Transgenic , Nectins , RNA, Messenger/genetics , RNA, Messenger/metabolism , Synaptosomes/metabolism , Tauopathies/pathologyABSTRACT
Alzheimer's dementia is developing ever more as a complex syndrome with various unknown genetic and epigenetic contributions. These are compounded on and exacerbating the underlying amyloid and tau pathology that remain the basis of the pathological definition of Alzheimer's disease. Here, we present a selection of aspects of recent bigenic and virus-based mouse strains, developed as pre-clinical models for Alzheimer's disease. We discuss newer features in the context of the characteristics defined in previously validated transgenic models. We focus on specific aspects of single and multiple transgenic mouse models for Alzheimer's disease and for tauopathies, rather than providing an exhaustive list of all available models. We concentrate on the content of information related to neurodegeneration and disease mechanisms. We pay attention to aspects and defects that are predicted by the models and can be tested in humans. We discuss implications that help translate the fundamental knowledge into clinical, diagnostic and therapeutic applications. We elaborate on the increasing knowledge extracted from transgenic models and from newer adeno-associated viral models. We advocate this combination as a valuable strategy to study molecular, cellular and system-related pathogenic mechanisms in AD and tauopathies. We believe that innovative animal models remain needed to critically test current views, to identify and validate therapeutic targets, to allow testing of compounds, to help understand and eventually treat tauopathies, including Alzheimer's disease.
