The Synaptic Accumulation of Hyperphosphorylated Tau Oligomers in Alzheimer Disease Is Associated With Dysfunction of the Ubiquitin-Proteasome System

In Alzheimer disease (AD), deposition of neurofibrillary tangles and loss of synapses in the neocortex and limbic system each correlate strongly with cognitive impairment. Tangles are composed of misfolded hyperphosphorylated tau proteins; however, the link between tau abnormalities and synaptic dysfunction remains unclear. We examined the location of tau in control and AD cortices using biochemical and morphologic methods. We found that, in addition to its well-described axonal localization, normal tau is present at both presynaptic and postsynaptic terminals in control human brains. In AD, tau becomes hyperphosphorylated and misfolded at both presynaptic and postsynaptic terminals, and this abnormally posttranslationally modified tau is enriched in synaptoneurosomal fractions. Synaptic tau seems to be hyperphosphorylated and ubiquitinated, and forms stable oligomers resistant to SDS denaturation. The accumulation of hyperphosphorylated tau oligomers at human AD synapses is associated with increased ubiquitinated substrates and increased proteasome components, consistent with dysfunction of the ubiquitin-proteasome system. Our findings suggest that synaptic hyperphosphorylated tau oligomers may be an important mediator of the proteotoxicity that disrupts synapses in AD. In Alzheimer disease (AD), deposition of neurofibrillary tangles and loss of synapses in the neocortex and limbic system each correlate strongly with cognitive impairment. Tangles are composed of misfolded hyperphosphorylated tau proteins; however, the link between tau abnormalities and synaptic dysfunction remains unclear. We examined the location of tau in control and AD cortices using biochemical and morphologic methods. We found that, in addition to its well-described axonal localization, normal tau is present at both presynaptic and postsynaptic terminals in control human brains. In AD, tau becomes hyperphosphorylated and misfolded at both presynaptic and postsynaptic terminals, and this abnormally posttranslationally modified tau is enriched in synaptoneurosomal fractions. Synaptic tau seems to be hyperphosphorylated and ubiquitinated, and forms stable oligomers resistant to SDS denaturation. The accumulation of hyperphosphorylated tau oligomers at human AD synapses is associated with increased ubiquitinated substrates and increased proteasome components, consistent with dysfunction of the ubiquitin-proteasome system. Our findings suggest that synaptic hyperphosphorylated tau oligomers may be an important mediator of the proteotoxicity that disrupts synapses in AD. Alzheimer disease (AD) is the most common neurodegenerative disorder in the elderly, and affects primarily the neocortex and the limbic system, with complex pathophysiologic features that include tau inclusions (neurofibrillary tangles, neuropil threads, and dystrophic neurites), β-amyloid inclusions (plaques and cerebral amyloid angiopathy), loss of neurons and synapses, astrogliosis, microglial activation, and inflammation.1Serrano-Pozo A. Frosch M.P. Masliah E. Hyman B.T. Neuropathological alterations in Alzheimer disease.Cold Spring Harb Perspect Med. 2011; 1: a006189Crossref PubMed Scopus (2195) Google Scholar, 2Braak E. Griffing K. Arai K. Bohl J. Bratzke H. Braak H. Neuropathology of Alzheimer's disease: what is new since A. Alzheimer?.Eur Arch Psychiatry Clin Neurosci. 1999; 249: 14-22Crossref PubMed Google Scholar Among these features, synaptic loss3Terry R.D. Masliah E. Salmon D.P. Butters N. DeTeresa R. Hill R. Hansen L.A. Katzman R. 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Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models.Cell. 2010; 142: 387-397Abstract Full Text Full Text PDF PubMed Scopus (1418) Google Scholar We hypothesized that tau may pathologically accumulate at synaptic sites in AD because it has been recently suggested that tau can be present in postsynaptic locales in normal mice,13Ittner L.M. Ke Y.D. Delerue F. Bi M. Gladbach A. van Eersel J. Wolfing H. Chieng B.C. Christie M.J. Napier I.A. Eckert A. Staufenbiel M. Hardeman E. Gotz J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models.Cell. 2010; 142: 387-397Abstract Full Text Full Text PDF PubMed Scopus (1418) Google Scholar ubiquitinated tau accumulates in the brain in AD,14Cripps D. Thomas S.N. Jeng Y. Yang F. Davies P. Yang A.J. 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Ehlers M.D. Emerging roles for ubiquitin and protein degradation in neuronal function.Pharmacol Rev. 2007; 59: 14-39Crossref PubMed Scopus (177) Google Scholar By isolating synaptic terminals, we observed that, in control brains, tau is present at both presynaptic and postsynaptic terminals. In contrast, in synaptoneurosomes isolated from brains in AD, p-tau can form stable SDS-resistant oligomers that accumulate on both sides of the synapse, showing synaptic enrichment when compared with the cytoplasm. The accumulation of p-tau at the synapse mirrors the accumulation of ubiquitinated proteins in the same fraction, as well as the accumulation of proteasomes and related chaperones, which suggests that tau aggregates are associated with impaired proteolysis mediated by the ubiquitin-proteasome system (UPS).18Keck S. Nitsch R. Grune T. Ullrich O. Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer's disease.J Neurochem. 2003; 85: 115-122Crossref PubMed Scopus (405) Google Scholar Protease inhibitor (cOmplete tablet) was purchased from Roche Applied Science (Roche Diagnostics Corp., Indianapolis, IN). Phosphatase inhibitor cocktails 2 and 3 were purchased from Sigma-Aldrich Corp. (St. Louis, MO) and used in a 1:1 combination. Mouse monoclonal antibodies PHF1 (pS396/pS404 tau), CP13 (pS202 tau), and DA9 (total tau) were gifts of Peter Davies (Albert Einstein College of Medicine, Bronx, NY). Rabbit anti–total tau (A20024) was purchased from Dako Denmark A/S (Glostrup, Denmark); rabbit anti-PSD95 (No. 2507) from Cell Signaling mouse from mouse rabbit and mouse from mouse mouse and rabbit from mouse rabbit and rabbit from Corp. and rabbit mouse and mouse from NY). from human with a of AD or cognitive were through the Alzheimer's and Neuropathology was in with and of and with AD used for are in of and in AD Alzheimer not or not in a new AD Alzheimer not or not to from human brains was in a with and 2 with 2 and The was through of to and a was The was with and through a and for to the synaptoneurosomes as described by E.T. of a from cerebral and Neurosci. PubMed Google Scholar the of the was through a Corp., to and and at for The was with and the from the was at for to the was by SDS and for were using and 2 and were for for isolating synaptic terminals was modified from D. and by isolated from rat brain by and PubMed Scopus Google Scholar of and were using The was in and to a and with and to form a at for 2 synaptic terminals were from the and from the and both were with to The was also in were at for and the were using and for The was in and of in a the was at for The was with SDS and for The was using and for protein were at for by to protein were for 3 and were using to Corp., and were to or for using an and antibodies were purchased from and were used to the were in and for and at for The was with an of and to The was using at for by with or protein at for 2 the was as the The was with and and for with to ubiquitinated In the was at with rabbit anti–total tau or by with protein for 2 at for 2 the was as the The was with and for with to of proteins were using or rabbit to from were in through and with an of in and in NY). of at synaptoneurosomes and to the and were using from this were using in with and were using normal and in for and with antibodies in with for 2 by antibodies in with were for by The was with a and Gold antibodies for 1: anti-PSD95 DA9 and PHF1 antibodies were purchased from and used at and and of synaptoneurosomes were using an with a were using the in Synaptic protein was on from were in and in at in and in were using a with an were using the function in of and were using Corp., from control and AD were using SDS and using In protein control brains tau to brains tau that were hyperphosphorylated p-tau antibodies K. H. L.M. S. M. B. M. J. M. K. Davies P. of in human and tau PubMed Scopus Google Scholar and Davies P. Binder L.I. tau proteins the same biochemical as normal Biol Chem. 1992; Full Text PDF PubMed Google and as a to to p-tau A. Takio K. Ihara Y. and formation in tau in paired helical of the of Biol Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar which were misfolded and resistant to SDS and the of tau proteins in AD, we and synaptic fractions. The fraction, when examined synaptic In both control and AD protein aggregates were of tau in control that tau was more enriched in the in consistent with its distribution in the axonal cytoplasm. In contrast, of AD that p-tau to in AD but in suggest that p-tau can form aggregates associated with the synaptoneurosomal SDS-resistant whether the p-tau oligomers observed in AD synaptoneurosomes were associated with synapses from such as tau we used to synaptic terminals was that tau aggregates have with synaptoneurosomes protein are more we a to synaptic terminals. synaptic terminals in such as and In control brains, but of a synaptic of tau and recent reports of a normal for tau at the L.M. Ke Y.D. Delerue F. Bi M. Gladbach A. van Eersel J. Wolfing H. Chieng B.C. Christie M.J. Napier I.A. Eckert A. Staufenbiel M. Hardeman E. Gotz J. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models.Cell. 2010; 142: 387-397Abstract Full Text Full Text PDF PubMed Scopus (1418) Google Scholar, K. J.J. F. T. H. Mucke L. tau amyloid in an Alzheimer's disease mouse 2007; PubMed Scopus Google Scholar In brains, of p-tau which suggested that and are to AD not whether tau and p-tau were localized to presynaptic or postsynaptic therefore, we a new to isolated synaptic terminals, we a of synaptoneurosomes a and it in and The synaptoneurosomes were for as a presynaptic and microtubule-associated protein 2 as a postsynaptic is a major protein in dendrites, but is also present at dendritic and at the M. E. Distribution of in dendritic and its with an PubMed Scopus Google Scholar, A. Binder L.I. P. L. O. of and the microtubule-associated protein in brain as by with monoclonal Neurosci. PubMed Google Scholar We the postsynaptic of by with and that and to be as to and most to be but therefore, to to postsynaptic sites to more of the presynaptic or postsynaptic of proteins an that both and forms of we tau in many presynaptic and also in most postsynaptic sites in control human brains. 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Yang F. of amyloid and tau in Alzheimer's disease Full Text Full Text PDF PubMed Scopus Google Scholar which is in with the accumulation of p-tau oligomers at AD are that tau is normally present at both presynaptic and postsynaptic and becomes ubiquitinated, and misfolded in situ where it or that posttranslationally modified tau is to synaptic where it We normal tau in most presynaptic and postsynaptic terminals in control brains We also found that synaptic p-tau aggregates are that to and to dendritic spines, misfolded p-tau with from axons or have to be to which seems we the that tau and in situ at both presynaptic and postsynaptic also in the degradation of We this because the has recently been to have a major in degradation of both neuronal M. J.H. C. G. S. G.A. C. C. M. L. of the ubiquitin to the but not the of both and tau Neurosci. 2006; PubMed Scopus Google Scholar, M. 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Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer's disease.J Neurochem. 2003; 85: 115-122Crossref PubMed Scopus (405) Google Scholar which in may the normal of to the formation of misfolded of brain it is to whether p-tau oligomers are to We however, that studies have that proteins are to neurons in M. Maeda S. Vossel K. Mucke L. The many faces of tau.Neuron. 2011; 70: 410-426Abstract Full Text Full Text PDF PubMed Scopus (674) Google Scholar, tau or PubMed Scopus Google Scholar, A. The toxicity of tau in Alzheimer disease: and Cell Med. 2011; PubMed Scopus Google Scholar The of misfolded proteins is both to the of on the misfolded protein and to the of protein control F. and human 2006; PubMed Scopus Google Scholar, what is the of protein in Cell 2005; PubMed Scopus Google Scholar Our present are consistent with both synaptic p-tau seems to be and is associated with and with the and in a and p-tau oligomers also correlate well with the accumulation of proteasome We found p-tau oligomers to be ubiquitinated and to directly with the of proteasomes site of ubiquitinated substrates on as substrates that the M. Hasegawa M. Takio K. Suzuki M. Titani K. Ihara Y. Ubiquitin is conjugated with amino-terminally processed tau in paired helical filaments.Neuron. 1993; 10: 1151-1160Abstract Full Text PDF PubMed Scopus (302) Google Scholar, S. Nitsch R. Grune T. Ullrich O. Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer's disease.J Neurochem. 2003; 85: 115-122Crossref PubMed Scopus (405) Google Scholar is also that SDS-resistant oligomers at synapses can as of and to or synapses, as in of L. M.P. C. K. of tau in PubMed Scopus Google Scholar, Calignon A. M. M. C. R. N. G.A. T.L. Hyman B.T. of tau in a of Alzheimer's Full Text Full Text PDF PubMed Scopus Google Scholar The that misfolded tau accumulates at the synapse is of the that also seems to accumulate at the T. A. D. S. K. Frosch M.P. Hyman B.T. T.L. in Alzheimer disease are mediated by PubMed Scopus Google Scholar, M. oligomers of the Alzheimer amyloid-beta protein synapse loss by an Neurosci. 2007; 27: PubMed Scopus Google Scholar We were to that and not correlate with p-tau accumulation or the correlated well pattern of correlation seems to to the of proteins and proteins such as tau are by M. 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Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain.Neurology. 2004; 62: 925-931Crossref PubMed Scopus (542) Google Scholar In in the present we to tau proteins at human synapses, to the that tau is a normal postsynaptic protein in addition to its as a presynaptic and axonal In AD, we p-tau oligomers as a that accumulates in both presynaptic and postsynaptic terminals. The accumulation of tau and of dysfunction at the of the of tau and may of the mechanisms of synaptic dysfunction and loss that are to cognitive in AD. We and the for to the for with brain and Peter Davies for antibodies and of the of in Cell with and Cell and of the issue of The of the The and have as PDF