Invited reviewA role for tau at the synapse in Alzheimer's disease pathogenesis
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.
References (120)
- et al.
Disease-related modifications in tau affect the interaction between fyn and tau
J. Biol. Chem.
(2005) - et al.
Abnormal tau phosphorylation at Ser396 in Alzheimer's disease recapitulates development and contributes to reduced microtubule binding
Neuron
(1993) - et al.
Synaptic mitochondria are more susceptible to Ca2+overload than nonsynaptic mitochondria
J. Biol. Chem.
(2006) - et al.
Tau protein isoforms, phosphorylation and role in neurodegenerative disorders
Brain Res. Brain Res. Rev.
(2000) - et al.
Neurons bearing neurofibrillary tangles are responsible for selected synaptic deficits in Alzheimer's disease
Neurobiol. Aging
(1995) - et al.
Constitutive secretion of tau protein by an unconventional mechanism
Neurobiol. Dis.
(2012) - et al.
Passive immunization with anti-Tau antibodies in two transgenic models: reduction of tau pathology and delay of disease progression
J. Biol. Chem.
(2011) - et al.
Synaptic slaughter in Alzheimer's disease
Neurobiol. Aging
(2003) - et al.
The intersection of amyloid beta and tau in glutamatergic synaptic dysfunction and collapse in Alzheimer's disease
Ageing Res. Rev.
(2013) - et al.
Propagation of tau pathology in a model of early Alzheimer's disease
Neuron
(2012)
Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau
J. Biol. Chem.
Why size matters – balancing mitochondrial dynamics in Alzheimer's disease
Trends Neurosci.
Tau promotes neurodegeneration via DRP1 mislocalization in vivo
Neuron
The beta-propensity of tau determines aggregation and synaptic loss in inducible mouse models of tauopathy
J. Biol. Chem.
Characteristics and consequences of muscarinic receptor activation by tau protein
Eur. Neuropsychopharmacol.
Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells
Mol. Cell Neurosci.
Fyn-tau-amyloid: a toxic triad
Cell
Tau phosphorylation: the therapeutic challenge for neurodegenerative disease
Trends Mol. Med.
Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis
J. Biol. Chem.
Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration
Neuron
Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice
Neurosci. Lett.
Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models
Cell
Neurofibrillary tangle-related synaptic alterations of spinal motor neurons of P301L tau transgenic mice
Neurosci. Lett.
Curcumin suppresses soluble tau dimers and corrects molecular chaperone, synaptic, and behavioral deficits in aged human tau transgenic mice
J. Biol. Chem.
The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of abeta oligomers through tau phosphorylation
Neuron
Tau domains, phosphorylation, and interactions with microtubules
Neurobiol. Aging
Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses
Neurobiol. Aging
Immunohistochemical quantification of the synapse-related protein synaptophysin in Alzheimer disease
Neurosci. Lett.
Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation
J. Biol. Chem.
Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimer's disease
Brain Res.
Phosphorylation regulates tau interactions with Src homology 3 domains of phosphatidylinositol 3-kinase, phospholipase Cgamma1, Grb2, and Src family kinases
J. Biol. Chem.
Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs
Exp. Neurol.
Tau phosphorylation affects its axonal transport and degradation
Neurobiol. Aging
Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease
J. Biol. Chem.
Synaptotagmin-syntaxin interaction: the C2 domain as a Ca2+-dependent electrostatic switch
Neuron
Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms
J. Neurochem.
Synaptic degeneration in Alzheimer's disease
Acta Neuropathol.
Semiquantitative proteomic analysis of human hippocampal tissues from Alzheimer's disease and age-matched control brains
Clin. Proteomics
Paradoxical upregulation of glutamatergic presynaptic boutons during mild cognitive impairment
J. Neurosci.
Accumulation of pathological tau species and memory loss in a conditional model of tauopathy
J. Neurosci.
Tau-targeted immunization impedes progression of neurofibrillary histopathology in aged P301L tau transgenic mice
PLoS One
The distribution of tau in the mammalian central nervous system
J. Cell Biol.
Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain
J. Neurochem.
Neuropathological stageing of Alzheimer-related changes
Acta Neuropathol.
Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain
J. Cell Biol.
Quantitative decrease in synaptophysin message expression and increase in cathepsin D message expression in Alzheimer disease neurons containing neurofibrillary tangles
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.
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