A role for tau at the synapse in Alzheimer's disease pathogenesis

doi:10.1016/j.neuropharm.2013.09.018

Neuropharmacology

Volume 76, Part A, January 2014, Pages 1-8

https://doi.org/10.1016/j.neuropharm.2013.09.018 Get rights and content

Highlights

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Synapse loss correlates with cognitive decline in Alzheimer's disease.
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Soluble, oligomeric tau may contribute to synapse degeneration.
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Tau is present in synapses, where it interacts with synaptic proteins.
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Tau may play a role in regulating synaptic function.

Abstract

Alzheimer's disease (AD) is characterized by brain deposition of amyloid plaques and tau neurofibrillary tangles along with steady cognitive decline. Although the mechanism by which AD pathogenesis occurs is unclear, accumulating evidence suggests that dysfunction and loss of synaptic connections may be an early event underlying disease progression. Profound synapse degeneration is observed in AD, and the density of these connections strongly correlates with cognitive ability. Initial investigations into AD-related synaptic changes focused on the toxic effects of amyloid. However, recent research suggests an emerging role for tau at the synapse. Even in the absence of tangles, mice overexpressing human tau display significant synaptic degeneration, suggesting that soluble, oligomeric tau is the synaptotoxic species. However, the localization of tau within synapses in both healthy and AD brains indicates that tau might play a role in normal synaptic function, which may be disrupted in disease. Tau is able to impact synaptic activity in several ways: studies show tau interacting directly with post-synaptic signaling complexes, regulating glutamatergic receptor content in dendritic spines, and influencing targeting and function of synaptic mitochondria. Early trials of tau-targeted immunotherapy reduce tau pathology and synapse loss, indicating that the toxic effects of tau may be reversible within a certain time frame. Understanding the role of tau in both normal and degenerating synapses is crucial for the development of therapeutic strategies designed to ameliorate synapse loss and prevent AD pathogenesis.

This article is part of the Special Issue entitled ‘The Synaptic Basis of Neurodegenerative Disorders’.

Section snippets

Synapse loss in Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and profound memory loss. Brains affected by AD display widespread neuronal loss and gross atrophy of the cortex and hippocampus. AD is characterized by lesions throughout the brain that are caused by deposition of amyloid beta peptide (Aβ) to form plaques, and aggregation of highly phosphorylated tau protein to form neurofibrillary tangles (Duyckaerts et al., 2009). These pathological

Tau in the synapse

Interestingly, depletion of tau in mice by knocking out the MAPT gene causes no overt disease phenotype (Ke et al., 2012), although muscle weakness (Ikegami et al., 2000) and decreased locomotion were observed in aged mice from one of the knockout strains (Lei et al., 2012). Indeed, loss of tau has been shown not to affect the number of dendritic spines (Tackenberg et al., 2013). However, removal of tau during development does appear to impair neuronal maturation. Knockdown of tau in developing

Involvement of tau in neuronal excitability

Synaptic tau may play a role in regulation of neuronal excitability. As described in more detail below, mouse models of tauopathy display abnormal electrophysiological changes in neuronal function (Fox et al., 2011). Further evidence for involvement of tau in regulating neuronal network activity comes from a study in which tau reduction reduced hyperexcitability in vivo in a mouse model of seizure (Holth et al., 2013). Changes in neuronal excitability have been reported in mouse models of

Conclusions

A progressive loss of synapses occurs in AD and is also observed in animal models of dementia. Initial research focused on amyloid-induced synaptotoxicity, but accumulating evidence indicates that tau may also be involved in synapse reduction in AD. Mouse models of tauopathy, in particular, have been useful for identifying toxic effects of tau on synapses, dendritic spines, and neuronal function. Data from these studies suggest that it is the soluble form of tau that is neurotoxic, rather than

Acknowledgments

Work in the authors' laboratories is supported by Alzheimer's Research UK, the Medical Research Council, the Wellcome Trust, and the Biotechnology and Biological Sciences Research Council.

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Invited reviewA role for tau at the synapse in Alzheimer's disease pathogenesis

Highlights

Abstract

Section snippets

Synapse loss in Alzheimer's disease

Tau in the synapse

Involvement of tau in neuronal excitability

Conclusions

Acknowledgments

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Synaptic degeneration in Alzheimer's disease

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Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain

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J. Neuropathol. Exp. Neurol.

The BCM theory of synapse modification at 30: interaction of theory with experiment

Nat. Rev. Neurosci.

Electrophysiological changes precede morphological changes to frontal cortical pyramidal neurons in the rTg4510 mouse model of progressive tauopathy

Acta Neuropathol.

Homeostatic responses by surviving cortical pyramidal cells in neurodegenerative tauopathy

Acta Neuropathol.

Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin

FASEB J.

Invited review
A role for tau at the synapse in Alzheimer's disease pathogenesis