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AD-Related N-Terminal Truncated Tau Is Sufficient to Recapitulate In Vivo the Early Perturbations of Human Neuropathology: Implications for Immunotherapy

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Abstract

The NH2tau 26–44 aa (i.e., NH2htau) is the minimal biologically active moiety of longer 20–22-kDa NH2-truncated form of human tau—a neurotoxic fragment mapping between 26 and 230 amino acids of full-length protein (htau40)—which is detectable in presynaptic terminals and peripheral CSF from patients suffering from AD and other non-AD neurodegenerative diseases. Nevertheless, whether its exogenous administration in healthy nontransgenic mice is able to elicit a neuropathological phenotype resembling human tauopathies has not been yet investigated. We explored the in vivo effects evoked by subchronic intracerebroventricular (i.c.v.) infusion of NH2htau or its reverse counterpart into two lines of young (2-month-old) wild-type mice (C57BL/6 and B6SJL). Six days after its accumulation into hippocampal parenchyma, significant impairment in memory/learning performance was detected in NH2htau-treated group in association with reduced synaptic connectivity and neuroinflammatory response. Compromised short-term plasticity in paired-pulse facilitation paradigm (PPF) was detected in the CA3/CA1 synapses from NH2htau-impaired animals along with downregulation in calcineurin (CaN)-stimulated pCREB/c-Fos pathway(s). Importantly, these behavioral, synaptotoxic, and neuropathological effects were independent from the genetic background, occurred prior to frank neuronal loss, and were specific because no alterations were detected in the control group infused with its reverse counterpart. Finally, a 2.0-kDa peptide which biochemically and immunologically resembles the injected NH2htau was endogenously detected in vivo, being present in hippocampal synaptosomal preparations from AD subjects. Given that the identification of the neurotoxic tau species is mandatory to develop a more effective tau-based immunological approach, our evidence can have important translational implications for cure of human tauopathies.

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Abbreviations

CSF:

Cerebrospinal fluid

AD:

Alzheimer’s disease

APP:

Amyloid precursor protein

i.c.v.:

Intracerebroventricular

mAb:

Monoclonal antibody

NO:

Novel object

FO:

Familiar object

NOR:

Novel object recognition

vGlut1:

Vesicular glutamate transporter 1

SNAP-25:

Synaptosomal-associated protein 25

αSyn:

α-Synuclein

NMDA:

N-methyl-D-aspartate

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

GFAP:

Glial fibrillary acidic protein

PPR:

Paired-pulse ratio

HFS:

High-frequency stimulation

CaN:

Calcineurin

CaMKII:

Ca2+-calmodulin-dependent kinase II

CREB:

cAMP response element-binding protein

FTDP-17:

Frontotemporal dementia with parkinsonism-17

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

fEPSPs:

Field excitatory postsynaptic potentials

LTP:

Long-term potentiation

SOD1:

Superoxide dismutase 1

NeuN:

Neuron-specific neuronal nuclei

WB:

Western blot

ND:

Nondiseased

DSG:

Disuccinimidyl glutarate

RT:

Room temperature

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Acknowledgements

We wish to thank Dott.ssa Francesca Malerba and Dott. Bruno Bruni Ercole for their technical help in 12A12 antibody purification. We are also grateful to Dott. Francesco Valeri and Dott. Francesco Marrocco for their technical help in morphological studies. We finally thank Dott.ssa Antonella Gentile for providing us several antibodies against synaptic and inflammatory markers.

Ethics Approvals

All protocols involving animals were performed in accordance with the guidelines established by the European Communities Council (Directive 2010/63/EU of 22 September 2010). Experiments involving animals were performed in accordance with the relevant approved guidelines and regulations accepted by the Italian Ministry of Health and approved by the Ethical Committee on Animal Experiments of Rome, Italy.

Human brain material was provided via the rapid autopsy program of the Netherlands Brain Bank (NBB), which provides postmortem specimens from clinically well documented and neuropathologically confirmed cases. All research involving them was conducted according to the ethical declaration of the NBB. Ethical approval and written informed consent from the donors or the next of kin were obtained in all cases. For details (ethics statement declarations and subjects’ demographics), see [25, 56].

Funding

This research was supported by Magnetic Diagnostic Assay for neurodegenerative diseases H2020-ICT-2016-2017 “SSI-Smart System Integration” Proposal 732678 SEP 210349930. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Author notes

  1. A. Borreca, V. Latina and V. Corsetti contributed equally to this work.

Authors and Affiliations

  1. Institute of Cellular Biology and Neurobiology (IBCN)–CNR, Via del Fosso di Fiorano 64-65, 00143, Rome, Italy

    A. Borreca, S. Middei & M. Ammassari-Teule

  2. IRCSS Santa Lucia Foundation, Via del Fosso di Fiorano 64-65, 00143, Rome, Italy

    A. Borreca, S. Middei, F. Della Valle & M. Ammassari-Teule

  3. European Brain Research Institute (EBRI), Viale Regina Elena 295, 00161, Rome, Italy

    V. Latina, V. Corsetti, S. Piccinin, R. Nisticò, P. Calissano & G. Amadoro

  4. UCO Pathological Anatomy and Histopathology Unit, Cattinara Hospital, Strada di Fiume 447, 34149, Trieste, Italy

    R. Bussani

  5. Department of Biology, University of Rome Tor Vergata, 00133, Rome, Italy

    R. Nisticò

  6. Institute of Translational Pharmacology (IFT) – National Research Council CNR, Via Fosso del Cavaliere 100, 00133, Rome, Italy

    G. Amadoro

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  1. A. Borreca
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Contributions

A.B., V.L., S.M., and S.P. performed morphological, biochemical, electrophysiological, and behavioral experiments; V.C. and F.D.V. performed crosslinking experiments on human brain tissue and carried out 12A12 production; M. A-T., R.N., and P.C. contributed through discussions; R.B. provided analytical tools; and G.A. designed the research, conceived and supervised all the experiments, and wrote the manuscript.

Corresponding author

Correspondence to G. Amadoro.

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Conflict of Interest

The authors declare that they have no conflicts of interest.

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All authors approve the study described in this report and give their consent for publication.

Electronic Supplementary Material

Suppl. Fig. 1

Biochemical characterization of the human NH2tau 26–44 (i.e. NH2htau) preparations. An aliquot of NH2htau preparation which was used for in vivo intracerebroventricular (i.c.v.) injection (20 μg) was checked prior to any administration via stereotaxic surgeries by Western blotting on Bis- Tris gel 4–12% resolution gels followed by electroblotting onto a high-performing PVDF transfer membrane. The filter was probed with specific 12A12 monoclonal antibody directed against the extreme N-terminal 26–36 aa of human tau protein. Note that the prevailing molecular form of NH2htau appears to be soluble and monomeric, being lowly-aggregated (dimeric/oligomeric) species migrating <35-50 kDa less abundant. (GIF 96 kb)

High resolution image (EPS 10154 kb)

Suppl. Fig. 2

In vivo analysis of neuronal distribution of injected NH2htau into hippocampus. Confocal microscopy analysis of double immunofluorescence with neuron-specific βIII tubulin (green channel) and human-specific NH2 21–36 tau- antibodies (red channel) carried out on CA1 hippocampal sections from B6SJL wild-type (2-month-old) NH2htau- and reverse-injected mice. Nuclei were stained with DAPI (blue channel). Note that the staining of exogenously-applied NH2htau within hippocampal structures is mainly distributed along the neuritic processes (yellow, arrow). Similar results were found from reverse- and NH2htau-injected wild-type C57BL/6 mice. Scale bar: 20 μm. (GIF 187 kb)

High resolution image (EPS 11291 kb)

Suppl. Fig. 3

Soluble NH2htau is toxic in vivo to synapses but not lethal to neurons. Western blotting analysis was carried out on equal amounts of total protein extract (50 μg) from hippocampal tissues of reverse- and NH2htau-injected wild-type B6SJL (2-month-old). Immunoblots were probed with antibodies against the active-(cleaved) form of caspase-3 (Asp175). SY5Y cells exposed to 1 μM staurosporine (STS) for 4 h were used as positive control. For normalization of the samples’ loading, β-actin was used. Similar results were found from reverse- and NH2htau-injected wild-type C57BL/6 mice. (GIF 115 kb)

High resolution image (EPS 1188 kb)

Suppl. Fig. 4

Neuronal connectivity is severely disrupted in NH2htau-injected mice from wild-type B6SJL genetic background without any significant change in the cell number. A-B): Representative microphotographs (n = 3) of double immunofluorescence and confocal microscopy analysis for presynaptic marker synaptophysin (red channel) and the postsynaptic marker PSD95 (green channel) carried out on CA1 hippocampal sections from wild-type (2-month-old) B6SJL NH2htau- and reverse-injected mice. Nuclei were stained with DAPI (blue channel) (A). The number of intact synaptic boutons (Syn/PSD95-positive puncta, arrow) from the three experimental groups (reverse, NH2htau-injected and age-matched home-cage controls) was also shown (B). Statistically significant differences were calculated by a one-way ANOVA analysis followed by Fisher post hoc test (one-way ANOVA analysis (2,23) = 27.5 Fisher post hoc test home-cage vs NH2htau-injected: **p < 0.01; reverse-injected vs NH2htau-injected: ***p < 0.001). Scale bar: 10 μm. C-D): Representative confocal microscopy images (n = 3) of CA1 hippocampal region from NH2htau- and reverse-injected from wild-type (2-month-old) B6SJL stained for neuron-specific nuclear marker NeuN (C). No statistically difference in the number of NeuN positive neurons (one-way ANOVA analysis, F(2, 23) = 1.62 p = 0.22 Fisher post hoc test reverse- vs NH2htau-injected p = 0.22; home-cage vs NH2htau-injected p = 0.74; reverse-injected vs home-cage 푝=0.08) was calculated among the three analyzed experimental groups (reverse, NH2htau-injected and age-matched home-cage controls) (D). Scale bar: 10 μm. E-F): Representative blots (n = 3) of Western blotting analysis on isolated synaptosomal preparations from hippocampal region of NH2htau- and reverse-injected wild-type B6SJL mice (2-month-old) to assess the content of presynaptic (α-synuclein, syntaxin, synaptosomal-associated protein 25 (SNAP-25), synaptophysin) and postsynaptic proteins (N-Methyl-D-aspartate (NMDA) Receptor subunit NR1, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) metabotropic Receptor subunit mGluR2 and mGluR5). β-actin and GAPDH (glyceraldehyde 3-phosphate dehydrogenase) were used as loading controls (E) and densitometric quantification was shown (F). Values are means of at least three independent experiments and statistically significant differences were calculated by unpaired two-tailed t-Student’s test (*p < 0.05). G-H): Representative examples (G) of Golgi-stained hippocampal CA1 pyramidal neurons showing dendritic segments at low magnification (4X) and high (100X) magnifications to display spines in NH2htau- and reverse-injected wild-type B6SJL mice (2-month-old). Quantification (H) of dendritic spine density was also shown. Values are means of at least three independent experiments and statistically significant differences were calculated by one-way ANOVA analysis followed by Fisher post hoc test (F(2, 23) = 7.4 p = 0.003; reverse- vs NH2htau-injected **p < 0.01; home-cage vs NH2htau-injected: **p < 0.01; home-cage vs reverse p = 0.77). (GIF 487 kb)

High resolution image (EPS 137862 kb)

Suppl. Fig. 5

Prominent activation of astrocytes and microglia is also detected in NH2htau- injected wild-type B6SJL mice. A-B): Purified synaptosomal preparations from hippocampal region of NH2htau- and reverse-injected wild-type B6SJL mice (2-month-old) was subjected to SDS-PAGE electrophoresis and Western blotting analysis by filter probing with antibodies against to the phosphorylated (inactive) form of cofilin (Ser-3) and the total cofilin. β-actin and GAPDH (glyceraldehyde 3-phosphate dehydrogenase) were used as loading controls (H) and densitometric quantification was shown (I). Values are means of at least three independent experiments and statistically significant differences were calculated by unpaired two-tailed t-Student’s test (*p < 0.05). C-D): Immunofluorescence followed by confocal microscopy analysis of astrocytes and microglial markers -glial fibrillary acidic protein (GFAP) and Iba1, respectively (green channel)- was carried out on CA1 hippocampal sections from wild-type B6SJL mice (2-month-old) NH2htau- and reverse-injected mice to evaluate the magnitude of neuroinflammatory response. Nuclei were stained with DAPI (blue channel). Notice the extensive reactive gliosis (increased proliferation and morphological changes of astrocytes and microglia) in hippocampal region from NH2htau-infused animals. Scale bar: 50 μm. E-F-G-H): Neuroinflammation processes (activation of astrocytes and microglia) was assessed on hippocampal extracts from NH2htau- and reverse-injected wild-type B6SJL mice (2-month-old) by Western blotting analysis for inflammatory proteins (GFAP, Iba1, E-G respectively). Relative densitometric quantification of intensity signals (F-H) indicates increased levels of GFAP and Iba1 in NH2htau- compared to reverse-injected wild-type C57BL/6 mice (2-month-old). GAPDH serves as loading control. Data are mean +/− S.E.M and statistical significance was calculated by unpaired two-tailed t-Student’s test (***p < 0.001; *p < 0.05). (GIF 507 kb)

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NH2htau-injected mice from B6SJL strains show deficits in presynaptically mediated short-term enhancement of hippocampal neurotransmission. A): Input/output curves as plots of the fEPSP slopes against the corresponding presynaptic fiber volley amplitudes are shown from hippocampal slices of non-transgenic B6SJL (2-month-old) reverse- (n = 9) and NH2htau-injected mice (n = 10). No significant difference (unpaired two-tailed t-Student’s test p > 0.05) was detected between the treated experimental groups which were unaffected in all the analyzed conditions. B): Comparison of paired-pulse facilitation (PPF) in wild-type B6SJL (2-month-old) reverse- (n = 9) and NH2htau-injected mice (n = 10). PPF was induced by pairs of stimuli delivered at increasing interpulse intervals (20, 50, 100, 200, 500 msec). Data are presented as the mean (±SEM) facilitation ratio of the second response relative to the first response. Significant values were detected at 50 and 100 msec interval (unpaired two-tailed t-Student’s test *p < 0.05). C) Time plot of average fEPSP responses showed that no change in magnitude of CA1-LTP was found between 2-month-old wild-type B6SJL reverse- (n = 9) and NH2htau-injected mice (n = 10) (unpaired two-tailed t-Student’s test *p > 0.05). The magnitude of potentiation was measured 50–60 min after the conditioning train. For each condition fEPSP recordings from baseline and 60 min post-HFS were calculated. (GIF 207 kb)

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Suppl. Fig. 7

In vivo NH2htau accumulation induces calcineurin-mediated inactivation of the nuclear CaMKII/CREB/c-Fos signaling in hippocampus of B6SJL injected mice. A-B-C-D-E-F-G-H-I): Hippocampal tissues from a randomly selected subset of behaviourally-trained (1 h after the test acquisition) reverse- (n = 3) and NH2htau-injected (n = 3) wild-type B6SJL (2-month-old) mice were used for cytosol/nuclear protein fractionation from total lysates. Representative Western blotting analysis showing the expression profile of total CaMKII, pCaMKII (A), CN-A full length, CN-A active truncated form (C), total CREB, pCREB (E) and the three 62 kDa, 49 kDa and 41 kDa c-Fos (G) immunoreactive bands in enriched subcellular preparations and relative densitometric quantification (B-D-F-H) are shown. Superoxide dismutase 1 (SOD1) and neuron-specific Neuronal Nuclei (NeuN) proteins were used as cytosolic and nuclear markers, respectively (I). *p < 0.05(unpaired two-tailed t-Student’s test). (GIF 524 kb)

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ESM 1

Suppl. text Number of independent observations for experimental conditions analyzed in each assay. In the table is reported the number of observations (animals, image fields, protein samples) analyzed in each assay for experimental conditions from independent experiments. (DOCX 15 kb)

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Borreca, A., Latina, V., Corsetti, V. et al. AD-Related N-Terminal Truncated Tau Is Sufficient to Recapitulate In Vivo the Early Perturbations of Human Neuropathology: Implications for Immunotherapy. Mol Neurobiol 55, 8124–8153 (2018). https://doi.org/10.1007/s12035-018-0974-3

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  • DOI: https://doi.org/10.1007/s12035-018-0974-3

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