Human P301L-Mutant Tau Expression in Mouse Entorhinal-Hippocampal Network Causes Tau Aggregation and Presynaptic Pathology but No Cognitive Deficits

Julie A. Harris, Akihiko Koyama, Sumihiro Maeda, Kaitlyn Ho, Nino Devidze, Dena B. Dubal, Gui Qiu Yu, Eliezer Masliah, Lennart Mucke

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere45881
JournalPLoS One
Volume7
Issue number9
DOIs
Publication statusPublished - 2012 Sep 24
Externally publishedYes

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Entorhinal Cortex
Pathology
Neurons
cortex
Agglomeration
Perforant Pathway
mutants
mice
Conformations
Brain
Presynaptic Terminals
Networks (circuits)
neurons
Dentate Gyrus
Alzheimer disease
synapse
disease course
cognition
axons
Synapses

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Human P301L-Mutant Tau Expression in Mouse Entorhinal-Hippocampal Network Causes Tau Aggregation and Presynaptic Pathology but No Cognitive Deficits. / Harris, Julie A.; Koyama, Akihiko; Maeda, Sumihiro; Ho, Kaitlyn; Devidze, Nino; Dubal, Dena B.; Yu, Gui Qiu; Masliah, Eliezer; Mucke, Lennart.

In: PLoS One, Vol. 7, No. 9, e45881, 24.09.2012.

Research output: Contribution to journalArticle

Harris, Julie A. ; Koyama, Akihiko ; Maeda, Sumihiro ; Ho, Kaitlyn ; Devidze, Nino ; Dubal, Dena B. ; Yu, Gui Qiu ; Masliah, Eliezer ; Mucke, Lennart. / Human P301L-Mutant Tau Expression in Mouse Entorhinal-Hippocampal Network Causes Tau Aggregation and Presynaptic Pathology but No Cognitive Deficits. In: PLoS One. 2012 ; Vol. 7, No. 9.
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