Impaired plasticity of cortical dendritic spines in P301S tau transgenic mice

Nadine A Hoffmann,Sonja Blumenstock,Michel Goedert,Jochen Herms,Mario M Dorostkar

doi:10.1186/2051-5960-1-82

Abstract

BackgroundIlluminating the role of the microtubule-associated protein tau in neurodegenerative diseases is of increasing importance, supported by recent studies establishing novel functions of tau in synaptic signalling and cytoskeletal organization. In severe dementias like Alzheimer’s disease (AD), synaptic failure and cognitive decline correlate best with the grade of tau-pathology. To address synaptic alterations in tauopathies, we analyzed the effects of mutant tau expression on excitatory postsynapses in vivo.ResultsHere we followed the fate of single dendritic spines in the neocortex of a tauopathy mouse model, expressing human P301S mutated tau, for a period of two weeks. We observed a continuous decrease in spine density during disease progression, which we could ascribe to a diminished fraction of gained spines. Remaining spines were enlarged and elongated, thus providing evidence for morphological reorganization in compensation for synaptic dysfunction. Remarkably, loss of dendritic spines in cortical pyramidal neurons occurred in the absence of neurofibrillary tangles (NFTs). Therefore, we consider prefibrillar tau species as causative for the observed impairment in spine plasticity.ConclusionsDendritic spine plasticity and morphology are altered in layer V cortical neurons of P301S tau transgenic mice in vivo. This does not coincide with the detection of hyperphosphorylated tau in dendritic spines.

Highlights

Illuminating the role of the microtubule-associated protein tau in neurodegenerative diseases is of increasing importance, supported by recent studies establishing novel functions of tau in synaptic signalling and cytoskeletal organization
Dendritic spines and synaptic pathology in tauopathy mouse models have been analyzed by other groups, obtaining divergent results: rTg4510 mice, transgenic for human tau with the FTDP-17 mutation P301L, show reduced spine density and impaired dendritic complexity of pyramidal neurons in the cortex, both in the absence and presence of neurofibrillary tangles (NFTs) [8,9]
In order to analyze the effects of cortical tau-pathology on dendritic spines, we performed long-term twophoton in vivo imaging of P301S Tau mice (Figure 1a)

Summary

Introduction

Illuminating the role of the microtubule-associated protein tau in neurodegenerative diseases is of increasing importance, supported by recent studies establishing novel functions of tau in synaptic signalling and cytoskeletal organization. Intracellular aggregates of the microtubule-associated protein tau are found in a large number of neurodegenerative diseases, including AD and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) [1,2] In these so-called tauopathies, hyperphosphorylation of tau promotes its detachment from microtubules, resulting in tau mislocalization to the somatodendritic compartment, where it forms oligomers, neuropil threads and NFTs. The pathological mechanisms triggered by abnormal tau remain largely unknown, especially with regard to synaptic failure. In cortical layer III pyramidal neurons of mice expressing all six human tau isoforms instead of murine tau, the spine volume decreases with advancing age, while spine density stays unaffected [13] Since these studies were based on fixed brain tissue, so far, dendritic spine plasticity has not been analyzed in a tauopathy mouse model in vivo. Alterations in the total number of spines could not be attributed to changes in spine kinetics

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