Soluble forms of tau are toxic in Alzheimer's disease

Abstract

Accumulation of neurofibrillary tangles (NFT), intracellular inclusions of fibrillar forms of tau, is a hallmark of Alzheimer Disease. NFT have been considered causative of neuronal death, however, recent evidence challenges this idea. Other species of tau, such as soluble misfolded, hyperphosphorylated, and mislocalized forms, are now being implicated as toxic. Here we review the data supporting soluble tau as toxic to neurons and synapses in the brain and the implications of these data for development of therapeutic strategies for Alzheimer's disease and other tauopathies.

Figures

Figure 1

Mechanisms of tau toxicity. Strong evidence supports a role of soluble pathological forms of tau in several mechanistic pathways leading to synapse and neuronal death. Tau is normally largely bound to axonal microtubules and plas a role in dendritic spine plasticity. During Alzheimer’s disease and other tauopathies, tau becomes hyperphosphorylated and misfolded. It detaches from microtubules and accumulates in the somatodendritic compartment. Accumulation of soluble tau in the soma is associated with caspase activation and disruptions of membrane integrity, which resolve after the soluble tau coalesces into a neurofibrillary tangle. Removal of tau from microtubules causes them to degenerate, and pathological tau may also directly interfere with microtubule based transport mechanisms. Disturbances in microtubule transport affect mitochondrial trafficking to distal parts of the neuron resulting in perinuclear clumping. Synapses become dysfunctional and dendritic spines are lost, and calcium levels increase in dendrites with accumulations of soluble tau. Synapse loss and the inability to energetically maintain axons are thought to contribute to the dying back of processes and cell death.

Figure 2

Cell death in tauopathy model mice. In vivo multiphoton imaging of neurons in mice expressing yellow fluorescent protein and P301L mutant tau (YFPxrTg4510 line) in pyramidal neurons undergo cell death (asterisk indicates a cell that died between one day and the next). Postmortem staining (bottom) confirms that YFP expressing neurons also express human tau in this model. Neuronal death is halted by transgene suppression in rTg4510 mice without removing existing tangles [54], and caspase activation, which occurs in neurons before NFT form, is turned off after tangle formation [113], both implicating soluble tau in cell death. However, the forms of tau present in dying neurons have not yet been elucidated. Scale bars 50 µm. Thanks to Rose Pitstick and George Carlson for mouse breeding and genotyping.