Tau Causes Synapse Loss without Disrupting Calcium Homeostasis in the rTg4510 Model of Tauopathy

Katherine J Kopeikina,Bradley T Hyman,Susanne Wegmann,Rose Pitstick,Rebecca A Betensky,George A Carlson,Tara L Spires-Jones,Brian J Bacskai,Chad A Dickey

doi:10.1371/journal.pone.0080834

Abstract

Neurofibrillary tangles (NFTs) of tau are one of the defining hallmarks of Alzheimer’s disease (AD), and are closely associated with neuronal degeneration. Although it has been suggested that calcium dysregulation is important to AD pathogenesis, few studies have probed the link between calcium homeostasis, synapse loss and pathological changes in tau. Here we test the hypothesis that pathological changes in tau are associated with changes in calcium by utilizing in vivo calcium imaging in adult rTg4510 mice that exhibit severe tau pathology due to over-expression of human mutant P301L tau. We observe prominent dendritic spine loss without disruptions in calcium homeostasis, indicating that tangles do not disrupt this fundamental feature of neuronal health, and that tau likely induces spine loss in a calcium-independent manner.

Highlights

The Alzheimer Disease (AD) brain accumulates intracellular neurofibrillary tangles, composed primarily of the microtubule associated protein tau and extracellular amyloid-β plaques
Pathological increases in intracellular calcium levels have been demonstrated to increase levels of tau hyperphosphorylation [15,16], and tau accumulation in dendrites has been associated with local calcium elevations after application of Aβ to primary neurons in culture [12], leading to the supposition that tau alterations are downstream of calcium elevations
Using in vivo multi-photon imaging of the ratiometric calcium indicator yellow cameleon (YC3.6) we quantified the resting calcium levels in neuronal processes of living 8-month old rTg4510 and control mouse brains. rTg4510 mice express human P301L tau in most cortical neurons and at this age exhibit abnormal accumulation of tau in the soma of a subset of neurons (Figure S1)

Summary

Introduction

The Alzheimer Disease (AD) brain accumulates intracellular neurofibrillary tangles, composed primarily of the microtubule associated protein tau and extracellular amyloid-β plaques. Calcium is critical for inter-neuronal signaling, which underlies the processes involved in learning and memory [13,14]. At non-synaptic sites, calcium is critical for intra-neuronal signaling cascades, which when altered can lead to initiation of apoptotic cell death. Pathological increases in intracellular calcium levels have been demonstrated to increase levels of tau hyperphosphorylation [15,16], and tau accumulation in dendrites has been associated with local calcium elevations after application of Aβ to primary neurons in culture [12], leading to the supposition that tau alterations are downstream of calcium elevations. There are no data to our knowledge that test whether tau alterations are upstream of calcium dysregulation in the intact brain

Methods

Results

Conclusion