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.
Highlights
Deteriorating intellectual and mental faculties are all but the most feared in the elderly in our ageing society
We demonstrated that neuronal expression of human protein Tau, either wild-type or mutant, engendered pronounced and specific reduction of Nectin-3, the major synaptic cell adhesion molecule (CAM) [25]
The defect was most pronounced in the stratum lacunosum moleculare (SLM), the connection hub between entorhinal cortex (ERC) and hippocampus proper, two brain regions at the center of attention in clinical and experimental studies in Alzheimer’s Disease (AD)
Summary
Deteriorating intellectual and mental faculties are all but the most feared in the elderly in our ageing society. Besides the well-known defects in gray matter, problems with white matter are recognized in AD. These include structural defects in, with partial to extensive loss of myelin sheaths, inflicting axons with microstructural changes that remain largely to be defined [2,3,4,5,6,7,8,9]. ERC and hippocampus are intimately involved in various forms of learning and memory that are affected in AD, which make entorhinal-hippocampal projections of prime interest, both functionally and in relation to the proposed ‘spreading’ or sub-regional progression of tauopathy [13,14,15,16,17]
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