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Tau oligomers impair memory and synaptic plasticity through the cellular prion protein

Acta Neuropathologica Communications volume 13, Article number: 17 (2025) Cite this article

Abstract

Deposition of abnormally phosphorylated tau aggregates is a central event leading to neuronal dysfunction and death in Alzheimer’s disease (AD) and other tauopathies. Among tau aggregates, oligomers (TauOs) are considered the most toxic. AD brains show significant increase in TauOs compared to healthy controls, their concentration correlating with the severity of cognitive deficits and disease progression. In vitro and in vivo neuronal TauO exposure leads to synaptic and cognitive dysfunction, but their mechanisms of action are unclear. Evidence suggests that the cellular prion protein (PrPC) may act as a mediator of TauO neurotoxicity, as previously proposed for β-amyloid and α-synuclein oligomers. To investigate whether PrPC mediates TauO detrimental activities, we compared their effects on memory and synaptic plasticity in wild type (WT) and PrPC knockout (Prnp0/0) mice. Intracerebroventricular injection of TauOs significantly impaired recognition memory in WT but not in Prnp0/0 mice. Similarly, TauOs inhibited long-term potentiation in acute hippocampal slices from WT but not Prnp0/0 mice. Surface plasmon resonance indicated a high-affinity binding between TauOs and PrPC with a KD of 20–50 nM. Immunofluorescence analysis of naïve and PrPC-overexpressing HEK293 cells exposed to TauOs showed a PrPC dose-dependent association of TauOs with cells over time, and their co-localization with PrPC on the plasma membrane and in intracellular compartments, suggesting PrPC-may play a role in TauO internalization. These findings support the concept that PrPC mediates the detrimental activities of TauOs through a direct interaction, suggesting that targeting this interaction might be a promising therapeutic strategy for AD and other tauopathies.

Introduction

The term tauopathies refers to neurodegenerative diseases involving the accumulation of insoluble toxic aggregates of the abnormally phosphorylated tau protein in the brain, mainly in neurons and glia, but also in the extracellular compartment [1]. These diseases are classified as primary tauopathies when the predominant pathological feature is the deposition of tau protein. Secondary tauopathies refer to neurodegenerative disorders where other proteins play a central role in driving the disease.

Alzheimer's disease (AD) is considered a secondary tauopathy, and is the most prevalent form of dementia, affecting over 30 million people worldwide. In AD toxic aggregates of β-amyloid (Aβ) coexist with tau aggregates, and act synergistically to induce synaptic dysfunction, cognitive impairment and neurodegeneration [2]. Similar to Aβ, emerging evidence suggests that small oligomeric species (TauOs) play a central role in the pathology [3, 4]. TauOs are implicated in impairing memory, synaptic plasticity, neuronal networking and glial cell activity. In addition, the presence of both Aβ and TauOs causes abnormal increases in glial cell phagocytic activity, leading to the excessive engulfment of synapses, particularly those enriched in TauOs [3, 5, 6].

TauOs levels are high in AD patient brains even in the early stages of disease [7], before the onset of clinical symptoms. TauOs have also been identified in other neurodegenerative diseases, such as progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, dementia with Lewy bodies, and Huntington’s disease [8, 9].

The TauO concentration correlates better with disease progression and cognitive deficits than the number of neurofibrillary tangles [10, 11]. TauOs may exert detrimental effects at various levels: within the nucleus they influence the expression of genes related to synaptic damage; at synapses they disrupt the expression of synaptic proteins and glutamatergic receptors, compromising synaptic plasticity and memory; within the axon, they disrupt axonal transport [3, 12,13,14]. However, the precise mechanisms underlying TauO-mediated detrimental actions require further investigation.

Several observations have indicated a possible role of the cellular prion protein (PrPC) in tau toxicity. Initially an interaction between tau and PrPC was proposed, based on neuropathological examination of Gerstmann-Sträussler-Scheinker (GSS) syndrome patients, where abnormally phosphorylated tau deposits were often found close to PrPSc, the prion isoform of PrPC pathognomonic of this disease [15,16,17,18,19]. Subsequent studies found that PrPC co-immunoprecipitated with phosphorylated tau and Aβ in 60% of symptomatic AD-derived human samples [20]. Full-length recombinant tau was then reported to bind to recombinant PrPC in vitro, with the N-terminal PrPC region mediating the interaction [21].

The first evidence suggesting PrPC was involved in tau toxicity emerged from investigations into the neurotoxic effect of secretomes collected from induced pluripotent stem cells (iPSC) derived from AD patients with a trisomy of chromosome 21 (Ts21secretome), which were highly enriched in extracellular tau species. Intracerebral injection of Ts21 secretomes into the rat brain inhibited long-term potentiation (LTP), a measure of synaptic plasticity. This effect was prevented by immunodepleting the secretomes with an anti-tau antibody or by pre-injecting the rat brain with the 6D11 antibody against the mid region of PrPC [22]. Furthermore, LTP inhibition induced by intracerebroventricular (ICV) injection of both recombinant and AD brain-derived soluble tau in rats was prevented by anti-PrPC antibodies 6D11 and MI-0131 targeting the PrPC N-terminal domain [23]. More recently, it was seen that soluble recombinant tau aggregates interacted with recombinant PrPC via the N-terminal region of PrPC [24]. This form of tau disrupted the neuritic integrity of primary mouse or human iPSC-derived cortical neurons, and impaired LTP in mouse hippocampal slices. These effects were prevented by genetic ablation of PrPC or pre-treatment with anti-PrPC antibodies [24].

Building on this evidence, the present study aimed to elucidate the involvement of PrPC in mediating the effects of TauOs on memory. Specifically, we used an acute mouse model of TauO toxicity, [25, 26] where a single ICV injection of well-characterized TauOs permitted the evaluation of their specific impact on memory in wild type (WT) or Prnp0/0 mice, assessed using the novel object recognition test (NORT).

We also employed electrophysiology to examine the effects of TauOs on synaptic plasticity in brain slices from WT or Prnp0/0 mice. Surface plasmon resonance (SPR) was used to investigate the direct interaction between TauOs and PrPC and to determine their binding affinity. We also analyzed the dependence of the TauO association with the cell membrane on PrPC, using HEK293 cells expressing varying levels of PrPC.

Material and methods

Expression and purification of recombinant human tau.

Full-length human tau (2N4R) was expressed in T7 Express Competent E. coli cells (New England Biosciences, Ipswich, MA, C2566) and purified using a series of chromatography steps as previously described [27]. Briefly, protein expression was induced by culturing bacteria in 6 L of LB medium containing 1 mM isopropil-β-D-1-tiogalattopiranoside (IPTG, Sigma) for 2 h at 37 °C. The whole culture was pelleted by centrifugation at 8,000 × g at 4 °C for 10 min in a Sorvall S3000 Rotor. Cells were lysed in a French press and centrifuged in a Type 70 Ti rotor at 76,765 × g (ave; 38,200 RPM) for 45 min at 4 °C. The supernatant was injected into a 50 mL super loop using GE ÄKTA FPLC and tau protein was purified using the metal affinity GE HiTrap Talon Crude column (28-9537-67) then eluted with 100 mM imidazole buffer + PMSF. Fractions containing tau were combined and loaded onto an equilibrated Hiprep 16/60 Sephacryl S-500 column HR (28-9356-06) using a 5-mL capillary loop. Tau was eluted from the column using 1.25 column volumes, and concentrated using Amicon Ultra-15 Centrifugal Filters (10 kDa MW). Finally, tau was further cleaned using anion exchange chromatography (GE HiTrap Q HP column, 17-1154-01) to help remove DnaK (a bacterial heat shock protein), fractions containing tau without DnaK were pooled and concentrated as above. Dithiothreitol (DTT) was added to a final concentration of 1 mM to reduce disulfide bonds. Purified tau was then aliquoted and stored at − 80 °C. The protein concentration was determined using a Sodium Dodecyl Sulphate (SDS)-Lowry assay (Sigma, 1003499321). The monomeric tau samples used in this study were made by diluting this stock of tau protein in PBS at the same concentration and pH used to dilute the oligomeric tau (5 mM PBS at pH 7.4 for behavioral and electrophysiological experiments and 10 mM PBS with 0.005% Tween-20, pH 7.4 for surface plasmon resonance analysis).

Tau oligomerization

Purified tau was diluted to a final concentration of 10 µM in oligomerization buffer (NaCl 100 mM, Hepes pH 7.6 10 mM, EDTA 0.1 mM and arachidonic acid 375 µM), and incubated for 6 h at RT (Combs et al. 2017).

Expression and purification of recombinant PrP

Human PrP23-231 (rhPrP) was expressed in E. coli BL21(DE3) cells and purified from the inclusion bodies on a Ni–NTA column as described [28]. Briefly, protein expression was induced by culturing bacteria in M9 minimal medium containing 1 mM isopropil-β-D-1-tiogalattopiranoside (IPTG, Giotto Biotech) overnight at 37 °C. Bacteria were lysed by sonication, and the inclusion bodies containing the recombinant protein were collected by centrifugation at 18,000xg for 45 min at 4 °C, and washed twice with milli-Q water. The recombinant protein was solubilized from the inclusion bodies by incubation in 6 M guanidine-HCl pH 8 overnight at 37 °C, and sonication. The solubilized protein was purified using a histidine affinity column (Ni–NTA agarose, Quiagen), taking advantage of the natural histidines in the PrP protein, and buffers containing 2 M guanidine-HCl pH 8. The purified protein was refolded through three dialysis steps (4 h, overnight, 4 h) at 4 °C against 20 mM sodium acetate pH 5. Correct folding was verified by circular dichroism and NMR spectra (data not shown). The protein concentration was determined from the A280 values and molar extinction coefficients.

Atomic force microscopy

The TauO preparation was diluted to 2 µM in PBS 10 mM (pH 7.5) and spotted (30 µl) onto freshly cleaved mica (Bruker AFM probes) at RT for 5 min. After washing with 5 mL of milliQ water the mica was dried under a gentle nitrogen flow. AFM were measured on a MultiMode 8HR AFM with a Nanoscope V system operating in tapping mode, using standard antimony-doped silicon probes (T: 3.75 µm, L: 125 µm, W: 35 µm, k: 40 N/m, f0: 300 kHz, Bruker AFM probes) with a scan rate in the 0.5–1.2 Hz range, proportional to the area scanned. To exclude any interfering artifacts, freshly cleaved mica and freshly cleaved mica soaked with 30 µL of PBS 10 mM, were also analyzed as controls. All the topographic patterns were confirmed in a minimum of five different well-separated areas.

Western blot

Two μg of human Tau 2N4R were loaded into NuPAGE™ 3–8% Tris–Acetate gel (EA0375BOX, Invitrogen). Samples were diluted in a 4X loading buffer composed of 500 mM Tris solution pH 6.8 containing 40% glycerol, 0.04% bromophenol blue, and 8% SDS. At the end of electrophoresis proteins were transferred onto nitrocellulose membrane, blocked in 3% bovine serum albumin (BSA), and incubated overnight with the anti-tau chicken polyclonal antibody (1:3000, PA5-95,648) followed by Dylight 488 anti-chicken secondary antibody. The image was acquired using a ChemiDoc MP Imager (Bio-Rad).

Animals

Male C57BL/6 J mice were obtained from Charles River-Italy. Zürich I Prnp0/0 mice (55), maintained on a pure C57BL/6 J background, were obtained from the European Mouse Mutant Archive (strain EM01723). Mice were between 7–8 weeks of age. All behavioral tests were conducted during the light cycle. Animals were housed in a specific pathogen free facility in standard mouse cages containing sawdust with food (2018S Envigo diet) and water ad libitum, under conventional laboratory conditions (room temperature: 20 ± 2 °C; humidity: 60%) and a 12/12-h light/dark cycle (7:00 am–7:00 pm). The Mario Negri Institute for Pharmacological Research adheres to the principles set out in the following laws, regulation, and policies governing the Care and Use of Laboratory Animals: Italian Governing Law (D.lgs 26/2014; Authorization N°19/2008-A issued March 6, 2008 by Ministry of Health); Mario Negri Institutional Regulations and Policies providing internal authorization for persons conducting animal experiments (Quality Management System Certificate – UNI EN ISO 9001:2015–Reg. N° 6121); the NIH Guide for the Care and Use of Laboratory Animals (2011 edition) and EU directives and guidelines (EEC Council Directive 2010/63/UE). The statement of Compliance (Assurance) with the Public Health Service (PHS) Policy on Human Care and Use of Laboratory Animals was reviewed on 9/9/2014 (Animal Welfare Assurance #A5023-01). All animals were managed in accordance with European directive 2010/63/UE and with Italian law D.l. 26/2014. The procedures were approved by the local animal-health and ethical committee and were authorized by the national authority (Istituto Superiore di Sanità; authorization numbers 370/2016-PR and 532/2021-PR). All efforts were made to reduce the number of animals by following the 3R’s rule.

Intracerebroventricular cannulation

Mice were anesthetized with Forane (Abbott) and a 7 mm-long guide cannula was implanted into the cerebral lateral ventricle (L ± 1.0 and DV-3.0 from dura with incisor bar at 0°) using a stereotaxic apparatus (model 900, David Kopf, CA), and secured to the skull with two stainless steel screws and dental cement. Mice were allowed 10–15 days to recover from surgery before the experiment and were monitored daily for their health.

TauO treatment

Tau preparations, checked by AFM, were infused into the lateral cerebral ventricle using an injection unit inserted into the guide cannula. TauO solutions were diluted to 1 µM in 5 mM PBS, pH 7.4, and 7.5 µL were infused using a Hamilton syringe in a total time of 5 min. The injection unit was left in place for 2 more min to allow the solution to diffuse. The vehicle consisted of tau oligomerization buffer diluted 1:10 in 5 mM PBS, pH 7.4.

Novel object recognition test (NORT)

Two hours after TauO injection mice entered the familiarization phase of the NORT. Mice were tested in their home cage (30 × 13 cm) to reduce stress related to the exposure to a new environment. The following objects were used: a black plastic cylinder (4 × 5 cm), a glass vial with a white cup filled with water (3 × 6 cm) and a metal cube (3 × 5 cm). The task started with a 10 min familiarization trial during which exploration was recorded by an investigator blind to strain and treatment. Sniffing, touching and stretching the head toward the object within a distance of 2 cm were scored as object investigation. Twenty-four hours later (test trial) mice were exposed for 10 min to two objects: one familiar and a new, different one (novel object), and the time spent exploring the objects was recorded. Memory was expressed as a discrimination index, i.e. (seconds on novel − seconds on familiar)/(total time on objects) [25, 26].

Extracellular field recordings

Three-month-old C57BL6/J mice were killed by cervical dislocation and the brains were rapidly removed and transferred to oxygenated ice-cold modified artificial cerebrospinal fluid (aCSF) containing 87 mM NaCl, 2.5 mM KCl, 1 mM NaH2PO4, 75 mM sucrose, 7 mM MgCl2, 24 mM NaHCO3, 11 mM D-glucose, and 0.5 mM CaCl2. The same solution was used when sectioning 350 µm thick coronal brain slices with a Leica (VT 1000S) vibratome. The slices were then transferred to the incubation chamber and immersed in aCSF containing 130 mM NaCl, 3.5 mM KCl, 1.2 mM NaH2PO4, 1.3 mM MgCl2, 25 mM NaHCO3, 11 mM D-glucose, 2 mM CaCl2, and continuously aerated with 95% O2 and 5% CO2 at room temperature (RT). The slices remained in this condition for at least 1 h before being pre-incubated with TauOs, tau monomers (TauM) or the vehicle consisting of tau oligomerization buffer diluted 1:100 in aCSF. Preincubation lasted 60–90 min and was done in a chamber containing 3 ml aCSF. Recordings were made in a submerged recording chamber perfused with oxygenated aCSF at a constant rate of 2–3 mL/min at RT. Stimuli were delivered via a Constant Voltage Isolated Stimulator (Digitimer Ltd, Welwyn Garden City, UK) with a bipolar twisted Ni/Cr stimulating electrode. LTP was elicited by a 4-theta burst tetanus stimulation protocol (each burst consisted of four 100 Hz pulses with 200 ms between bursts). Signals were amplified and filtered (10 Hz-3 kHz) using a DAM 80 AC differential amplifier (World Precision Instruments, Sarasota, FL) and digitized at 10 kHz using a Digidata 1322 (Molecular Devices, Foster City, CA). LTP recordings in which the amplitude of the presynaptic fiber volley changed by more than 20% were discarded.

Surface plasmon resonance (SPR)

The in vitro interaction between recombinant human PrP23-231 (rhPrP) or PrPC extracted from the mouse brain (bPrPC) and tau (monomers or oligomers) was characterized using SPR. SPR analysis was carried out with a ProteOn XPR36 system (BioRad), which allows immobilising up to six ligands on parallel channels of the same sensor surface [29]. rhPrP, the anti-PrP antibody 94B4 [30] and the anti-TauOs antibody TOC1 (RRID: AB_2832939) [31, 32] were immobilized in parallel channels of a GLM CMD 50L sensor chip (XanTec bioanalytics) through an amine-coupling process [33]. The final levels of immobilization were approximately 5300 RU for the 94B4 antibody, 5000 RU for TOC1, and 3350 RU for rhPrP (RU = resonance units, where 1000 RU = 1 ng protein/mm2). An empty (activated and deactivated) parallel lane was used as reference. 94B4 was immobilized on two separate channels, one kept as such (reference) and the other used to immunocapture bPrPC (0.5 mg protein/mL prepared in PBS containing 0.5% Nonidet P-40 and 0.5% Na-deoxycholate), obtained from Tg(WT-E1)/Prnp0/0 mice overexpressing 3F4-tagged mouse PrPC [25, 34, 35]. The brain homogenate was flowed for 10 min at 30 µL/min over the immobilized 94B4 antibody, resulting in stable binding of about 2000 RU; we had previously established that this binding accounts for the capture of bPrPC only [33]. The flow channels can be rotated 90° so that up to six analyte solutions can be flowed in parallel on all immobilized ligands and reference surfaces. After chip rotation, TauM or TauOs, diluted in SPR running buffer (Dulbecco’s Phosphate Buffered Saline with 0.005% Tween-20, pH 7.4) at different concentrations, or the vehicle alone, were injected over immobilised ligands for 2 min at 30 μL/min. Dissociation was measured in the next 11 min. The SPR signals on the sensorgrams (expressed as Resonance Units, RU) were corrected by subtracting the nonspecific response in the respective reference channel. The kinetic parameters, association and dissociation rate constants (kon and koff), and the equilibrium dissociation constant (KD) were obtained using the heterogeneous ligand model.

Cell lines

HEK293 were cultured in high-glucose Dulbecco’s modified Eagle’s medium (DMEM, D5671, Sigma-Aldrich) supplemented with 10% fetal bovine serum (FBS, F7524, Sigma-Aldrich), 100 U/mL penicillin/streptomycin (Pen/Strep, P4333, Sigma-Aldrich) and 1% L-glutamine (G7513, Sigma-Aldrich), at 37 °C in 5% CO2/95% air. HEK293 cells stably expressing PrPC (HEK293-PrP) at the same level as primary mouse neurons [36] were cultured with 200 µg/mL hygromycin (10,687,010, Invitrogen).

Immunofluorescence

HEK293 and HEK293-PrP cells were incubated with TauOs at 0.5 µM for 15, 30, or 60 min, then fixed with paraformaldehyde 4% in PBS (pH 7.5) for 10 min at RT. Cells were rinsed three times with PBS, permeabilized with 0.2% Triton X-100 for 5 min, and incubated with blocking solution (5% BSA) for 1 h at RT. After blocking, cells were incubated with mouse monoclonal anti-Tau antibody TAU-5 (1:250, AHB0042 Invitrogen) and rabbit polyclonal anti-PrP antibody P45-66 (1:250, kindly provided by D.A. Harris) overnight at 4 °C, rinsed three times in PBS, and incubated with anti-mouse 488 and anti-rabbit 594 DyLight secondary antibodies (1:500, Invitrogen) for 1 h at RT. Nuclei were stained with DAPI (2 μg/mL).

Image acquisitions

An A1 Nikon confocal microscope managed by NIS elements software was used in a sequential scanning mode to avoid bleed-through effects, with excitation 488 nm for Tau and 594 nm for PrP signals. Images in supplementary Fig. 3 were acquired with a 40X objective, with a pixel size of 0.31 μm. Three-dimensional and higher magnification images were acquired using a 100X oil immersion objective with a pixel size of 0.12 μm, over a 10–13-μm z axis with a 0.125-μm step size and processed by using Imaris software (Bitplane). Three-dimensional acquisitions were displayed as volumes or as x,y single plane image with z-projections in supplementary Fig. 4.

Statistical analysis

Data were expressed as mean ± standard error of the mean (SEM) and analyzed using GraphPad Prism 10 software. Normality of the data distribution was ascertained so as to select either parametric or non- parametric analyses. Where there was a significant effect of treatment or a significant interaction the appropriate post-hoc tests were employed. A p-value < 0.05 was considered significant.

Results

Characterization of TauOs

To obtain TauOs, full-length 2N4R wild-type tau protein aggregation was induced using arachidonic acid for 6 h, as depicted in Fig. 1a and as previously described [27]. To investigate the morphology of the structures formed, the samples were analysed using atomic force microscopy (AFM) imaging, which confirmed the presence of oligomers and excluded that of fibrils or protofibrils (Fig. 1b). Western blot analysis of tau preparations under non-reducing conditions demonstrated the predominance of dimers, trimers, and tetramers with small amounts of residual monomers (Fig. 1c).

Fig. 1
figure 1

Biochemical features of human 2N4R wild-type TauOs. a Scheme of the tau oligomerization procedure. b Representative atomic force microscopy (AFM) image. c Western blot analysis of TauOs. Samples were run on 3–8% tris–acetate gel and incubated with anti-total tau antibody. Both techniques show the oligomeric nature of the preparation

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TauOs impair recognition memory in WT but not in Prnp 0/0 mice

C57BL/6 J (WT) mice received a single ICV injection of vehicle (Veh), TauM or TauOs both at 1 µM concentration (nominal tau solution), and were then tested in the NORT. As shown in Fig. 2a, TauO-injected mice showed an impaired recognition memory as indicated by the significantly lower discrimination index (DI) compared to Veh- or TauM-treated mice. TauM was inactive as shown by a DI comparable to that of Veh-treated mice. TauOs had no effect on recognition memory in Prnp0/0 mice (Fig. 2b).

Fig. 2
figure 2

TauOs, but not the monomer (TauM), impair memory and synaptic plasticity in WT but not in Prnp0/0 mice. a Scatter plots ± standard error mean (SEM) of the DI of WT mice receiving a single ICV injection of Veh (n = 10), TauM (n = 9) or TauOs (n = 9) and then tested in the NORT; (One-Way ANOVA: F(2,25) = 16.28, P < 0.001); *** P < 0.001, ****P < 0.0001 Tukey’s post-hoc test. b Scatter plot ± SEM of the DI of WT or Prnp0/0 mice treated with Veh (WT: n = 6; Prnp0/0 n = 9) or TauOs (WT: n = 6; Prnp0/0 n = 10) and tested in the NORT. Two-way ANOVA found an effect of: Tg F(1, 27) = 3,481, P = 0.073, Treatment F(1, 27) = 8.32, P = 0.0076 and a significant Interaction F(1, 27) = 11.01, P = 0.0026; * P < 0.05, **P < 0.01, Tukey’s post-hoc test. c Time course of LTP in the CA1 hippocampal area in slices from WT mice pre-incubated for 60–90 min with either Veh (n = 7), 100 nM monomers (n = 7) or 100 nM TauOs (n = 7). Two-way ANOVA for repeated measures found: VEH vs. TauM F(1,12) = 0.18, P = 0.68; VEH vs. TauOs F(1,12) = 14.62, P = 0.002; TauOs versus TauM F(1,12) = 11.45, P = 0.005; (n = 7/group). d Data are scatter plots ± SEM of residual potentiation calculated by averaging the slopes of the field excitatory postsynaptic potentials (fEPSP) in the last 10 min of LTP recorded in WT slices. One-way ANOVA for treatment factor found: F(2,18) = 26.39, P < 0.0001; VEH vs. TauOs P < 0.0001; TauM vs VEH P = 0.51; TauOs vs. TauM P < 0.0001. ***P < 0.001, ****P < 0.0001; Tukey’s post-hoc test). e Time course of LTP in the CA1 hippocampal area in slices from Prnp0/0 mice preincubated with Veh or TauOs. f Scatter plot ± SEM of residual potentiation calculated by averaging the fEPSP slopes in the last 10 min of LTP in Prnp0/0 slices (t9 = 2.26, P = 0.985)

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TauOs inhibit long-term potentiation in WT but not Prnp 0/0 mice

Next, we investigated the impact of TauOs on LTP, a form of synaptic plasticity considered to be the neuronal basis of memory formation. In accordance with behavioral experiments, TauOs significantly inhibited LTP in brain slices from WT mice, whereas TauM did not (Fig. 2c, d). As for memory, when TauOs were applied to Prnp0/0 brain slices LTP was preserved (Fig. 2e, f).

TauOs bind to PrPC with high affinity

We employed SPR to determine whether there was a direct physical interaction between TauOs and PrPC. Figure 3 shows the sensorgrams obtained injecting different concentrations of TauOs over bPrPC immunocaptured with the 94B4 antibody or rhPrP protein. Sensor chips coated with the anti-PrP antibody 94B4 or the anti-TauOs antibody TOC1 served as negative and positive controls, respectively. All sensorgrams were subtracted of the non-specific signal measured in the empty sensor chip (reference surface); raw sensorgrams are provided in Suppl. Figure 1.

Fig. 3
figure 3

SPR sensorgrams of TauO-PrPC binding. Sensorgrams were obtained flowing two different concentrations of TauOs (expressed in monomer equivalents) over immobilized 94B4 PrP antibody (a) or TOC1 anti-TauO antibody (b), PrP captured by 94B4 antibody (c) or rhPrP protein (d). TauOs were flowed for 2 min as indicated by the dashed lines. The sensorgrams were obtained after correction for the signal obtained in a reference (empty) surface and are shown in red. For each immobilized protein the sensorgrams with both TauOs concentrations were globally fitted using a two-sites model, and the fitting is shown in black

Full size image

No TauO binding was observed on the sensor chip coated with the anti-PrP 94B4 antibody (Fig. 3a). In contrast, a concentration-dependent binding of TauOs with immobilized TOC1, the anti-TauOs antibody was observed (Fig. 3b) [32]. Fitting the sensorgrams with a simple 1:1 interaction model was inadequate, quite likely due to the heterogeneous nature of TauOs. Therefore, we employed a two-binding site model, revealing a high-affinity component with a KD of 67 nM towards the TOC1 antibody, which accounted for > 80% of the TauO binding signal. The second, less prominent component showed considerably lower affinity, with KD 11 µM.

SPR also indicated a concentration-dependent binding of TauOs to immobilized bPrPC (Fig. 3c) and rhPrP proteins (Fig. 3d). Similar to TauO binding to the TOC1 antibody, fitting of TauO binding to PrP proteins required a two-site model. The high-affinity components of the binding, accounting for the majority of the signals (~ 80%), had KD values of 51 and 20 nM for bPrPC and rhPrP proteins, respectively. There was a larger binding signal of TauOs towards bPrPC than rhPrP (compare panels C and D in Fig. 3). This may be attributed to the fact that bPrPC was immunocaptured on the sensor chip with the 94B4 antibody, which recognizes a C-terminal epitope (aa 186–193), potentially exposing the PrP N-terminal region where TauOs bind [24]. In contrast, rhPrP was immobilized on the sensor chip by amine coupling, which results in random orientation of the immobilized protein, so that only a fraction of them exposes the N-terminal domain.

TauO affinity for PrPC was determined based on the equivalent TauM concentration (i.e., the concentration of monomers used to originally generate TauOs), rather than the actual oligomer concentration, which varies depending on the degree of oligomerization. Therefore, the actual KD may be even lower; the larger the oligomeric species, the lower the concentration of these species and the lower the KD. The binding for the TauO samples was not due to the residual TauM, which showed a completely different binding pattern, with a significant binding signal even on the empty cell (Suppl. Figure 2). The fact that TauOs did not bind to the empty cell (Suppl. Figure 1) indicates that the negligible amount of TauM seen by WB did not contribute to TauO binding (Fig. 1).

PrPC mediates the TauO association with the cell surface and their internalization.

To determine whether PrPC facilitates the association of TauOs with the plasma membrane and their subsequent internalization, we exposed naïve HEK293 cells, which express minimal PrPC levels, or HEK293 cells overexpressing PrPC (HEK293-PrP) to 0.5 µM TauOs for 15, 30, or 60 min. After incubation, cells were fixed, permeabilized and immunostained with the anti-tau antibody Tau5. A distinct fluorescent signal was seen on the cell surface of HEK293-PrP cells as early as 15 min post-incubation, whereas no signal was detectable in naïve HEK293 cells at this time (Fig. 4a). Furthermore, the fluorescence intensity of TauOs increased over time in HEK293-PrP cells (Fig. 4a, lower panels). Some staining was also visible in naïve cells (Fig. 4a, upper panels), perhaps reflecting the association of TauOs with small amounts of PrPC expressed on the surface of these cells, or a PrPC-independent interaction of TauOs with the plasma membrane. Single channel images of TauO staining clearly show the intracellular accumulation of TauOs in a time- and PrPC-dependent manner (Suppl. Figure 3a). We also observed a change in the PrPC cellular distribution in the presence of TauOs over time (Suppl. Figure 3b). The merge of all channels is shown in Suppl. Figure 3c.

Fig. 4
figure 4

Time course of TauO binding and internalization in naïve and PrPC-overexpressing HEK293 cells. a Representative images of TauOs (green) in naïve (HEK293, upper panels) or PrP-overexpressing (HEK293-PrP, lower panels) cells after 15, 30 and 60 min of incubation (0.5 µM). TauOs immunofluorescence is detectable at early time points only in HEK293-PrP cells, indicating that PrPC facilitates the association of TauOs to cells. Scale bar 50 µm. b Higher magnification confocal images of TauOs (green) and PrPC (red) acquired after 60 min of incubation, showing TauOs—PrPC co-localization in naïve (b1) or PrP-overexpressing (b2) HEK293 cells. The co-localization channels (yellow) together with TauOs and PrP was reconstructed as 3D rendering and shown in (b3) and (b4) for both naïve and HEK293-PrP cells respectively. Major thick 10 µm

Full size image

Higher-magnification images and 3D renderings of acquired confocal volumes (Fig. 4b) clearly show TauO-PrPC intracellular co-localization in HEK293-PrP cells (b2, b4), which was only weakly detectable in naïve cells (b1, b3), suggesting a potential role of PrPC in mediating TauO internalization. Supplementary Fig. 4 shows z-projections of co-localized TauO-PrPC in perinuclear regions in HEK293-PrP cells exposed to TauOs for 60 min (lower panels), but not in naïve cells (upper panel).

Discussion

In addition to Aβ as a primary pathological agent in AD, soluble TauOs are increasingly acknowledged as critical mediators of AD pathogenesis and other tauopathies [37]. Emerging evidence suggests that tau and Aβ oligomers, in concert, may mutually potentiate their toxic effects, with sub-toxic doses of the two species leading to LTP and memory impairment when administered together [28]. This raises questions regarding potential shared receptors and mediators, or second messengers driving their detrimental actions, with far-reaching implications for therapeutic interventions. PrPC was proposed as a receptor and mediator of Aβ, α-synuclein, and, more recently, TauO toxicities, [24, 38] through an interaction involving its N-terminal domain.

PrPC is a cell surface glycoprotein which physiological functions are emerging [39], but best known for its role in prion diseases, such as Creutzfeldt-Jakob disease, GSS, and fatal familial insomnia [40]. In these diseases, PrPC undergoes a conformational change into PrPSc, a misfolded, aggregation-prone isoform that propagates through misfolding native PrPC, leading to neuronal dysfunction and death. However, while the involvement of PrPC in Aβ and α-synuclein toxicity remains controversial [25, 35, 41,42,43,44], its interaction with tau is still in its infancy.

The interaction between PrPC and tau has been mainly discussed in relation to the pathological PrPSc form and the increased phosphorylation of tau, as evidenced by the frequent occurrence of tau pathology in inherited prion diseases [45,46,47]. In support of a pathogenic link between PrPC and tau there are also evidence of elevated PrPC levels in the early stages of AD correlating with lower tau and p-tau levels, whereas reduced PrPC levels have been found in later stages associated with higher tau pathology [48].

In the present study, we specifically focused our attention on the role of PrPC in mediating TauO detrimental actions on memory and synaptic functions. We found that TauOs, but not monomers, impaired memory and synaptic plasticity and these effects were PrPC-dependent. Our findings agree with previous data indicating that TauOs from different sources, including AD brain or iPSC, or recombinant TauOs obtained with different procedures, impair LTP and memory, with these effects mitigated by anti-PrPC antibodies or genetic PrPC depletion [3, 4, 12, 49,50,51].

PrPKO mice have been reported to develop LTP and cognitive impairments [52, 53]. However, the detection of electrophysiological and behavioral phenotypes in PrPKO mice appears to depend on various factors, including the specific mouse line used, the methodology employed by investigators, and the age of mice [54, 55]. In our study, based on both electrophysiological and behavioral data, as well as previously published evidence by Bertani et al. [56], we confidently conclude that at the ages tested, our PrPKO mice of the Zürich I line do not differ from WT mice in terms of LTP or memory abilities.

SPR experiments found high-affinity binding between TauOs and PrPC, in either post-translationally modified protein from the mouse brain or recombinant human PrP. This corroborates previous findings by ELISA, showing specific binding between TauOs and recombinant mouse PrP23–231, mediated by the N-terminal region [24]. PrPC binding affinity for TauOs was higher than for Aβ and α-synuclein oligomers, indeed much lower concentrations of TauOs were required to inhibit LTP in acute hippocampal slices [24].

It was previously reported that cultured cells engulf extracellular tau aggregates, promoting intracellular fibrillization of endogenous tau. The newly formed aggregates are then released and taken up by neighboring cells, spreading tau aggregation in the culture [57]. Internalized TauOs can impair mitochondrial function [49] and their nuclear localization may alter gene expression [58].

Different internalization pathways and receptors seem to be implicated in Tau internalization depending on the conformation of the aggregates [59]. Our results add new evidence in HEK293 cells, indicating that PrPC is involved in TauO internalization by promoting their association with the plasma membrane. This is consistent with previous findings that PrPC mediates the internalization of tau K18 (a truncated form of human tau containing only the four microtubule binding repeats) in N2a cells [60]. PrPC constitutively cycles between the plasma membrane and the endocytic compartment, with a portion of internalized PrPC re-exposed on the cell surface. This suggests that PrPC may also contribute to TauO exocytosis, and this warrants further investigation.

Our data support the notion that PrPC is needed for the detrimental effects of TauOs on synaptic plasticity and memory, very likely through direct interaction. These findings also implicate PrPC in TauO internalization. Once internalized TauOs may disrupt various cellular processes, including mitochondrial function, axonal functionality, synaptic activity and gene expression, ultimately leading to synaptic and cognitive dysfunction [3, 4, 13, 14, 61].

While the detrimental effects of TauOs on memory and LTP described here parallel those observed with Aβ or α-synuclein oligomers, we confirmed the dependency on PrPC only for TauOs [25, 35].

The multifactorial nature of AD calls for a multi-target therapeutic approach, in view of the importance of identifying substrates specific to or shared by Aβ or tau. Further clarification of the precise relationship between PrPC and Aβ or Tau oligomer actions will shed light on the therapeutic potential of targeting PrPC in the treatment of AD.

Availability of data and materials

No datasets were generated or analysed during the current study.

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Acknowledgements

We thank to Judith Baggott for English editing.

Funding

This research was funded by the Italian Ministry of Health grant RF-2021-12372337, Alzheimer’s Association Research Fellowship (AARF-22-928286), Fondazione Telethon (TCP15011) and by the NIH grants R01, NS082730.

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Author notes

  1. Claudia Balducci and Franca Orsini equally contributed to this work

Authors and Affiliations

  1. Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy

    Claudia Balducci, Franca Orsini, Milica Cerovic, Letizia Dacomo, Antonio Masone, Eleonora Busani, Ilaria Raimondi, Giada Lavigna, Susanna Leva, Roberto Chiesa, Luana Fioriti & Gianluigi Forloni

  2. Department of Biochemistry and Molecular Pharmacology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy

    Marten Beeg, Beatrice Rocutto, Laura Colombo & Marco Gobbi

  3. Department of Neuroscience, Zuckerman Institute, Columbia University, New York, NY, 10027, USA

    Po-Tao Chen & Luana Fioriti

  4. Biomolecular NMR Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, 20132, Milan, Italy

    Chiara Zucchelli & Giovanna Musco

  5. Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA

    Nicholas M. Kanaan

  6. Neuroscience Program, Michigan State University, East Lansing, MI, 48824, USA

    Nicholas M. Kanaan

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  1. Claudia Balducci
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Contributions

CB with the contribution of LD and SL, did all the in vivo experiments; analysed data and wrote the manuscript. FO prepared and characterized Tau oligomers; conducted in vitro experiments with the contribution of AM and EB, acquired and reconstructed confocal images. MC carried out all the electrophysiological experiments. MB, BR did the SPR experiments and analysis. IR and GL managed PrPKO mouse colonies. NMK, P-TC and LF produced and purified recombinant tau protein. LC did AFM analysis. NMK provided antibodies. CZ and GM provided recombinant prion protein for SPR experiments and revised the manuscript. MG coordinated SPR experiments. RC and LF coordinated in vitro studies; RC also provided PrPKO mice. GF directed the study. FO, MC, MG, RC, LF, GF, NMK edited the manuscript.

Corresponding authors

Correspondence to Roberto Chiesa, Luana Fioriti or Gianluigi Forloni.

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Ethics approval and consent to participate

The Mario Negri Institute for Pharmacological Research adheres to the principles set out in the following laws, regulation, and policies governing the Care and Use of Laboratory Animals: Italian Governing Law (D.lgs 26/2014; Authorization N°19/2008-A issued March 6, 2008 by Ministry of Health); Mario Negri Institutional Regulations and Policies providing internal authorization for persons conducting animal experiments (Quality Management System Certificate – UNI EN ISO 9001:2015 – Reg. N° 6121); the NIH Guide for the Care and Use of Laboratory Animals (2011 edition) and EU directives and guidelines (EEC Council Directive 2010/63/UE). The statement of Compliance (Assurance) with the Public Health Service (PHS) Policy on Human Care and Use of Laboratory Animals was reviewed on 9/9/2014 (Animal Welfare Assurance #A5023-01). All animals were managed in accordance with European directive 2010/63/UE and with Italian law D.l. 26/2014. The procedures were approved by the local animal-health and ethical committee and were authorized by the national authority (Istituto Superiore di Sanità; authorization numbers 370/2016-PR and 532/2021-PR). All efforts were made to reduce the number of animals by following the 3R’s rule.

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The authors declare no competing interests.

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Balducci, C., Orsini, F., Cerovic, M. et al. Tau oligomers impair memory and synaptic plasticity through the cellular prion protein. acta neuropathol commun 13, 17 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40478-025-01930-3

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Acta Neuropathologica Communications

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