Human P301L-mutant tau expression in mouse entorhinal-hippocampal network causes tau aggregation and presynaptic pathology but no cognitive deficits

Accumulation of hyperphosphorylated tau in the entorhinal cortex (EC) is one of the earliest pathological hallmarks in patients with Alzheimer's disease (AD). It can occur before significant Aβ deposition and appears to "spread" into anatomically connected brain regions. To determine...

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Bibliographic Details
Published in:PloS one 2012-09, Vol.7 (9), p.e45881-e45881
Main Authors: Harris, Julie A, Koyama, Akihiko, Maeda, Sumihiro, Ho, Kaitlyn, Devidze, Nino, Dubal, Dena B, Yu, Gui-Qiu, Masliah, Eliezer, Mucke, Lennart
Format: Article
Language:English
Subjects:
Accumulation
Age
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Alzheimer's disease
Analysis
Animal behavior
Animal memory
Animal models
Animals
Biology
Brain
Brain research
Cognitive ability
Cognitive disorders
Cognitive Dysfunction - genetics
Cognitive Dysfunction - metabolism
Cognitive Dysfunction - pathology
Cortex (entorhinal)
Dentate Gyrus
Entorhinal Cortex - metabolism
Entorhinal Cortex - pathology
Entorhinal Cortex - physiopathology
Female
Gene Expression
Hippocampus
Hippocampus - metabolism
Hippocampus - pathology
Hippocampus - physiopathology
Humans
Male
Maze Learning
Medicine
Memory
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Mutation, Missense
Neurodegenerative diseases
Neurons
Neuroplasticity
Pathology
Pattern Recognition, Visual
Perforant Pathway - metabolism
Perforant Pathway - pathology
Perforant Pathway - physiopathology
Presynapse
Recognition, Psychology
Rodents
Synapses
Synapses - metabolism
Synapses - pathology
Tau protein
Tau proteins
tau Proteins - genetics
tau Proteins - metabolism
Terminals
Citations: Items that cite this one
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Description
Summary:Accumulation of hyperphosphorylated tau in the entorhinal cortex (EC) is one of the earliest pathological hallmarks in patients with Alzheimer's disease (AD). It can occur before significant Aβ deposition and appears to "spread" into anatomically connected brain regions. To determine whether this early-stage pathology is sufficient to cause disease progression and cognitive decline in experimental models, we overexpressed mutant human tau (hTauP301L) predominantly in layer II/III neurons of the mouse EC. Cognitive functions remained normal in mice at 4, 8, 12 and 16 months of age, despite early and extensive tau accumulation in the EC. Perforant path (PP) axon terminals within the dentate gyrus (DG) contained abnormal conformations of tau even in young EC-hTau mice, and phosphorylated tau increased with age in both the EC and PP. In old mice, ultrastructural alterations in presynaptic terminals were observed at PP-to-granule cell synapses. Phosphorylated tau was more abundant in presynaptic than postsynaptic elements. Human and pathological tau was also detected within hippocampal neurons of this mouse model. Thus, hTauP301L accumulation predominantly in the EC and related presynaptic pathology in hippocampal circuits was not sufficient to cause robust cognitive deficits within the age range analyzed here.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0045881