Fragile X Syndrome (FXS) is a neurodevelopmental disorder that is highly comorbid with autism spectrum disorders and can cause abnormal social behaviors. The CA2 subregion of the hippocampus is essential for social memory processing and social recognition. A social interaction induces changes in CA2 neuronal firing; however, it is unknown whether these changes are impaired in FXS models. Here, we examined CA2 activity in a rat model of Fragile X Syndrome (Fmr1 knockout rats). In Fmr1 knockout rats, we observed impaired CA2 cell responses to social stimuli, despite similar social behaviors. Further, in CA2 of Fmr1 knockout rats, we found reduced expression of oxytocin receptors and impaired whole cell responses to oxytocin. Together, these results raise the possibility that abnormal CA2 activity contributes to impaired social behavior in FXS and may suggest novel treatment targets for FXS patients.

Hippocampal region CA2 is essential for social memory processing. Interaction with social stimuli induces changes in CA2 place cell firing during active exploration and sharp wave-ripples during rest following a social interaction. However, it is unknown whether these changes in firing patterns are caused by integration of multimodal social stimuli or by a specific sensory modality associated with a social interaction. Rodents rely heavily on chemosensory cues in the form of olfactory signals for social recognition processes. To determine the extent to which social olfactory signals contribute to CA2 place cell responses to social stimuli, we recorded CA2 place cells in rats freely exploring environments containing stimuli that included or lacked olfactory content. We found that CA2 place cell firing patterns significantly changed only when social odors were prominent. Also, place cells that increased their firing in the presence of social odors alone preferentially increased their firing during subsequent sharp wave-ripples. Our results suggest that social olfactory cues are essential for changing CA2 place cell firing patterns during and after social interactions. These results support prior work suggesting CA2 performs social functions and shed light on processes underlying CA2 responses to social stimuli.

CA1 place cells become more anticipatory with experience, an effect thought to be caused by NMDA receptor-dependent plasticity in the CA3-CA1 network. Theta (~5-12 Hz), slow gamma (~25-50 Hz), and fast gamma (~50-100 Hz) rhythms are thought to route spatial information in the hippocampal formation and to coordinate place cell ensembles. Yet, it is unknown whether these rhythms exhibit experience-dependent changes concurrent with those observed in place cells. Slow gamma rhythms are thought to indicate inputs from CA3 to CA1, and such inputs are thought to be strengthened with experience. Thus, we hypothesized that slow gamma rhythms would become more evident with experience. We tested this hypothesis using mice freely traversing a familiar circular track for three 10-min sessions per day. We found that slow gamma amplitude was reduced in the early minutes of the first session of each day, even though both theta and fast gamma amplitudes were elevated during this same period. However, in the first minutes of the second and third sessions of each day, all three rhythms were elevated. Interestingly, theta was elevated to a greater degree in the first minutes of the first session than in the first minutes of later sessions. Additionally, all three rhythms were strongly influenced by running speed in dynamic ways, with the influence of running speed on theta and slow gamma changing over time within and across sessions. These results raise the possibility that experience-dependent changes in hippocampal rhythms relate to changes in place cell activity that emerge with experience. NEW & NOTEWORTHY We show that CA1 theta, slow gamma, and fast gamma rhythms exhibit characteristic changes over time within sessions in familiar environments. These effects in familiar environments evolve across repeated sessions.

Gereke BJ, Mably AJ, Colgin LL. Experience-dependent trends in CA1 theta and slow gamma rhythms in freely behaving mice. J Neurophysiol 119: 476–489, 2018. First published October 25, 2017; doi:10.1152/jn.00472.2017.—CA1 place cells become more anticipatory with experience, an effect thought to be caused by NMDA receptor-dependent plasticity in the CA3–CA1 network. Theta (~5–12 Hz), slow gamma (~25–50 Hz), and fast gamma (~50–100 Hz) rhythms are thought to route spatial information in the hippocampal formation and to coordinate place cell ensembles. Yet, it is unknown whether these rhythms exhibit experience-dependent changes concurrent with those observed in place cells. Slow gamma rhythms are thought to indicate inputs from CA3 to CA1, and such inputs are thought to be strengthened with experience. Thus, we hypothesized that slow gamma rhythms would become more evident with experience. We tested this hypothesis using mice freely traversing a familiar circular track for three 10-min sessions per day. We found that slow gamma amplitude was reduced in the early minutes of the first session of each day, even though both theta and fast gamma amplitudes were elevated during this same period. However, in the first minutes of the second and third sessions of each day, all three rhythms were elevated. Interestingly, theta was elevated to a greater degree in the first minutes of the first session than in the first minutes of later sessions. Additionally, all three rhythms were strongly influenced by running speed in dynamic ways, with the influence of running speed on theta and slow gamma changing over time within and across sessions. These results raise the possibility that experience-dependent changes in hippocampal rhythms relate to changes in place cell activity that emerge with experience.

Gamma oscillations (similar to 25-100 Hz) are believed to play a role in cognition. Accordingly, aberrant gamma oscillations have been observed in several cognitive disorders, including Alzheimer's disease and Fragile X syndrome. Here, we review how recent results showing abnormal gamma rhythms in Alzheimer's disease and Fragile X syndrome help reveal links between cellular disturbances and cognitive impairments. We also discuss how gamma results from rodent models of Alzheimer's disease and Fragile X syndrome may provide insights about unique functions of distinct slow (similar to 25-50 Hz) and fast gamma (similar to 55-100 Hz) subtypes. Finally, we consider studies employing brain stimulation paradigms in Alzheimer's disease and discuss how such studies may reveal causal relationships between gamma impairments and memory disturbances.

Intracellular neurofibrillary tangles (NFTs) composed of tau protein are a neuropathological hallmark of several neurodegenerative diseases, the most common of which is Alzheimer's disease (AD). For some time NFTs were considered the primary cause of synaptic dysfunction and neuronal death, however, more recent evidence suggests that soluble aggregates of tau are key drivers of disease. Here we investigated the effect of different tau species on synaptic plasticity in the male rat hippocampus in vivo Intracerebroventricular injection of soluble aggregates formed from either wild-type or P301S human recombinant tau potently inhibited hippocampal long-term potentiation (LTP) at CA3-to-CA1 synapses. In contrast, tau monomers and fibrils appeared inactive. Neither baseline synaptic transmission, paired-pulse facilitation nor burst response during high-frequency conditioning stimulation was affected by the soluble tau aggregates. Similarly, certain AD brain soluble extracts inhibited LTP in a tau-dependent manner that was abrogated by either immunodepletion with, or coinjection of, a mid-region anti-tau monoclonal antibody (mAb), Tau5. Importantly, this tau-mediated block of LTP was prevented by administration of mAbs selective for the prion protein (PrP). Specifically, mAbs to both the mid-region (6D11) and N-terminus (MI-0131) of PrP prevented inhibition of LTP by both recombinant and brain-derived tau. These findings indicate that PrP is a mediator of tau-induced synaptic dysfunction.SIGNIFICANCE STATEMENT Here we report that certain soluble forms of tau selectively disrupt synaptic plasticity in the live rat hippocampus. Further, we show that monoclonal antibodies to cellular prion protein abrogate the impairment of long-term potentiation caused both by recombinant and Alzheimer's disease brain-derived soluble tau. These findings support a critical role for cellular prion protein in the deleterious synaptic actions of extracellular soluble tau in tauopathies, including Alzheimer's disease. Thus, approaches targeting cellular prion protein, or downstream pathways, might provide an effective strategy for developing therapeutics.

Alzheimer's disease (AD) is an irreversible and highly progressive neurodegenerative disease. Clinically, patients with AD display impairments in episodic and spatial memory. However, the underlying neuronal dysfunctions that result in these impairments remain poorly understood. The hippocampus is crucial for spatial and episodic memory, and thus we tested the hypothesis that abnormal neuronal representations of space in the hippocampus contribute to memory deficits in AD. To test this hypothesis, we recorded spikes from place cells in hippocampal subfield CA1, together with corresponding rhythmic activity in local field potentials, in the 3xTg AD mouse model. We observed disturbances in place cell firing patterns, many of which were consistent with place cell disturbances reported in other rodent models of AD. We found place cell representations of space to be unstable in 3xTg mice compared to control mice. Furthermore, coordination of place cell firing by hippocampal rhythms was disrupted in 3xTg mice. Specifically, a smaller proportion of place cells from 3xTg mice were significantly phase-locked to theta and slow gamma rhythms, and the theta and slow gamma phases at which spikes occurred were also altered. Remarkably, these disturbances were observed at an age before detectable Aβ pathology had developed. Consistencies between these findings in 3xTg mice and previous findings from other AD models suggest that disturbances in place cell firing and hippocampal rhythms are related to AD rather than reflecting peculiarities inherent to a particular transgenic model. Thus, disturbed rhythmic organization of place cell activity may contribute to unstable spatial representations, and related spatial memory deficits, in AD. © 2017 Wiley Periodicals, Inc.

Dysregulation of glutamate homeostasis in the interstitial fluid of the brain is strongly implicated in causing synaptic dysfunction in many neurological and psychiatric illnesses. In the case of Alzheimer's disease (AD), amyloid β (Aβ)-mediated disruption of synaptic plasticity and memory can be alleviated by interventions that directly remove glutamate or block certain glutamate receptors. An alternative strategy is to facilitate the removal of excess glutamate from the nervous system by activating peripheral glutamate clearance systems. One such blood-based system, glutamate oxaloacetate transaminase (GOT), is activated by oxaloacetate, which acts as a co-substrate. We report here that synthetic and AD brain-derived Aβ-mediated inhibition of synaptic long-term potentiation in the hippocampus is alleviated by oxaloacetate. Moreover the effect of oxaloacetate was GOT-dependent. The disruptive effects of a general inhibitor of excitatory amino acid transport or TNFα, a pro-inflammatory mediator of Aβ action, were also reversed by oxaloacetate. Furthermore, another intervention that increases peripheral glutamate clearance, peritoneal dialysis, mimicked the beneficial effect of oxaloacetate. These findings lend support to the promotion of the peripheral clearance of glutamate as a means to alleviate synaptic dysfunction that is caused by impaired glutamate homeostasis in the brain.

Dysregulation of glutamate homeostasis in the interstitial fluid of the brain is strongly implicated in causing synaptic dysfunction in many neurological and psychiatric illnesses. In the case of Alzheimer's disease (AD), amyloid β (Aβ)-mediated disruption of synaptic plasticity and memory can be alleviated by interventions that directly remove glutamate or block certain glutamate receptors. An alternative strategy is to facilitate the removal of excess glutamate from the nervous system by activating peripheral glutamate clearance systems. One such blood-based system, glutamate oxaloacetate transaminase (GOT), is activated by oxaloacetate, which acts as a co-substrate. We report here that synthetic and AD brain-derived Aβ-mediated inhibition of synaptic long-term potentiation in the hippocampus is alleviated by oxaloacetate. Moreover the effect of oxaloacetate was GOT-dependent. The disruptive effects of a general inhibitor of excitatory amino acid transport or TNFα, a pro-inflammatory mediator of Aβ action, were also reversed by oxaloacetate. Furthermore, another intervention that increases peripheral glutamate clearance, peritoneal dialysis, mimicked the beneficial effect of oxaloacetate. These findings lend support to the promotion of the peripheral clearance of glutamate as a means to alleviate synaptic dysfunction that is caused by impaired glutamate homeostasis in the brain.

Introduction: Much knowledge about amyloid b (Ab) aggregation and toxicity has been acquired using synthetic peptides and mouse models, whereas less is known about soluble Ab in human brain. Methods: We analyzed aqueous extracts from multiple AD brains using an array of techniques. Results: Brains can contain at least four different Ab assembly forms including: (i) monomers, (ii) a w7kDa Ab species, and larger species (iii) from w30-150 kDa, and (iv) .160 kDa. High molecular weight species are by far the most prevalent and appear to be built from w7 kDa Ab species. The w7 kDa Ab species resist denaturation by chaotropic agents and have a higher Ab42/Ab40 ratio than monomers, and are unreactive with antibodies to Asp1 of Ab or APP residues N-terminal of Asp1. Discussion: Further analysis of brain-derived w7 kDa Ab species, the mechanism by which they assemble and the structures they form should reveal therapeutic and diagnostic opportunities. 2015 The Alzheimer’s Association. Published by Elsevier Inc. All rights reserved.

Alzheimer's disease (AD) and familial Danish dementia (FDD) are degenerative neurological diseases characterized by amyloid pathology. Normal human sera contain IgG antibodies that specifically bind diverse preamyloid and amyloid proteins and have shown therapeutic potential in vitro and in vivo. We cloned one of these antibodies, 3H3, from memory B cells of a healthy individual using a hybridoma method. 3H3 is an affinity-matured IgG that binds a pan-amyloid epitope, recognizing both Aβ and λ Ig light chain (LC) amyloids, which are associated with AD and primary amyloidosis, respectively. The pan-amyloid-binding properties of 3H3 were demonstrated using ELISA, immunohistochemical studies, and competition binding assays. Functional studies showed that 3H3 inhibits both Aβ and LC amyloid formation in vitro and abrogates disruption of hippocampal synaptic plasticity by AD-patient-derived soluble Aβ in vivo. A 3H3 single-chain variable fragment (scFv) retained the binding specificity of the 3H3 IgG and, when expressed in the brains of transgenic mice using an adeno-associated virus (AAV) vector, decreased parenchymal Aβ amyloid deposition in TgCRND8 mice and ADan (Danish Amyloid) cerebral amyloid angiopathy in the mouse model of FDD. These data indicate that naturally occurring human IgGs can recognize a conformational, amyloid-specific epitope and have potent anti-amyloid activities, providing a rationale to test their potential as antibody therapeutics for diverse neurological and other amyloid diseases.

The amyloid β (Aβ)-protein and microtubule-associated protein, tau, are the major components of the amyloid plaques and neurofibrillary tangles that typify Alzheimer's disease (AD) pathology. As such both Aβ and tau have long been proposed as therapeutic targets. Immunotherapy, particularly targeting Aβ, is currently the most advanced clinical strategy for treating AD. However, several Aβ-directed clinical trials have failed, and there is concern that targeting this protein may not be useful. In contrast, there is a growing optimism that tau immunotherapy may prove more efficacious. Here, for the first time, we studied the effects of chronic administration of an anti-tau monoclonal antibody (5E2) in amyloid precursor protein transgenic mice. For our animal model, we chose the J20 mouse line because prior studies had shown that the cognitive deficits in these mice require expression of tau. Despite the fact that 5E2 was present and active in the brains of immunized mice and that this antibody appeared to engage with extracellular tau, 5E2-treatment did not recover age-dependent spatial reference memory deficits. These results indicate that the memory impairment evident in J20 mice is unlikely to be mediated by a form of extracellular tau recognized by 5E2. In addition to the lack of positive effect of anti-tau immunotherapy, we also documented a significant increase in mortality among J20 mice that received 5E2. Because both the J20 mice used here and tau transgenic mice used in prior tau immunotherapy trials are imperfect models of AD our results recommend extensive preclinical testing of anti-tau antibody-based therapies using multiple mouse models and a variety of different anti-tau antibodies.

Introduction: Much knowledge about amyloid beta (A beta) aggregation and toxicity has been acquired using synthetic peptides and mouse models, whereas less is known about soluble Ab in human brain.Methods: We analyzed aqueous extracts from multiple A beta brains using an array of techniques.Results: Brains can contain at least four different A beta assembly forms including: (i) monomers, (ii) a similar to 7kDa Ab species, and larger species (iii) from similar to 30-150 kDa, and (iv)>160 kDa. High molecular weight species are by far the most prevalent and appear to be built from similar to 7 kDa A beta species. The similar to 7 kDa A beta species resist denaturation by chaotropic agents and have a higher A beta 42/A beta 40 ratio than monomers, and are unreactive with antibodies to Asp1 of Ab or APP residues N-terminal of Asp1.Discussion: Further analysis of brain-derived similar to 7 kDa Ab species, the mechanism by which they assemble and the structures they form should reveal therapeutic and diagnostic opportunities. (C) 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Compelling genetic evidence links the amyloid precursor protein (APP) to Alzheimer's disease (AD). A leading hypothesis proposes that a small amphipathic fragment of APP, the amyloid β-protein (Aβ), self-associates to form soluble assemblies loosely referred to as “oligomers” and that these are primary mediators of synaptic dysfunction. As such, Aβ, and specifically Aβ oligomers, are targets for disease modifying therapies. Currently, the most advanced experimental treatment for AD relies on the use of anti-Aβ antibodies. In this study, we tested the ability of the monomer-preferring antibody, m266 and a novel aggregate-preferring antibody, 1C22, to attenuate spatial reference memory impairments in J20 mice. Chronic treatment with m266 resulted in a ~70-fold increase in Aβ detected in the bloodstream, and a ~50% increase in water-soluble brain Aβ — and in both cases Aβ was bound to m266. In contrast, 1C22 increased the levels of free Aβ in the bloodstream, and bound to amyloid deposits in J20 brain. However, neither 1C22 nor m266 attenuated the cognitive deficits evident in 12 month old J20 mice. Moreover, both antibodies failed to alter the levels of soluble Aβ oligomers in J20 brain. These results suggest that Aβ oligomers may mediate the behavioral deficits seen in J20 mice and highlight the need for the development of aggregate-preferring antibodies that can reach the brain in sufficient levels to neutralize bioactive Aβ oligomers.Aside from the lack of positive effect of m266 and 1C22 on cognition, a substantial number of deaths occurred in m266- and 1C22-immunized J20 mice. These fatalities were specific to anti-Aβ antibodies and to the J20 mouse line since treatment of wild type or PDAPP mice with these antibodies did not cause any deaths. These and other recent results indicate that J20 mice are particularly susceptible to targeting of the APP/Aβ/tau axis. Notwithstanding the specificity of fatalities for J20 mice, it is worrying that the murine precursor (m266) of a lead experimental therapeutic, Solanezumab, did not engage with putatively pathogenic Aβ oligomers.

Epidemiological evidence suggests that chronic treatment with simvastatin may protect against the development of Alzheimer's disease (AD), but as yet it is unclear how this effect is mediated. Extensive data also indicates that the amyloid β-protein (Aβ) plays a central role in the disease process, and it has been suggested that the protective effects of simvastatin may be mediated by reducing Aβ production or by counteracting the toxic effects of Aβ. Accordingly, using the AβPPswe/PS1dE9 mouse model of AD, we investigated the effects of simvastatin on long-term potentiation (LTP), amyloid biology, and two key kinases involved in Aβ-mediated toxicity. Since burgeoning data indicate that both fibrillar and non-fibrillar forms of Aβ play a prominent role in AD pathogenesis, we were careful to investigate the effects of simvastatin on three biochemically distinct pools of Aβ. In untreated AβPPswe/PS1dE9 mice, there was a dramatic and significant increase in the levels of water-soluble Aβ between 6 and 8 months, but this remained constant between 8 and 18 months. In contrast, the concentrations of detergent-soluble and formic acid (FA)-soluble Aβ species increased across all ages examined, thus demonstrating that while amyloid deposition continued, the levels of water-soluble Aβ remained relatively constant. LTP was normal at 6 months, but was significantly impaired at 8 and 18 months. Importantly, a diet supplemented with 0.04% simvastatin for one month (at 7 months) positively affected synaptic plasticity in AβPPswe/PS1dE9 mice and did not significantly alter levels of water-soluble, detergent-soluble, or FA-soluble Aβ, but did increase phosphorylation of both Akt and GSK-3, while tau and tau phosphorylation were unaltered. These results indicate that the protective effects of simvastatin may be mediated by maintaining signaling pathways that help to protect and rescue LTP.

Alzheimer's disease (AD) is associated with pathological assembly states of amyloid-β protein (Aβ). Aβ-related synaptotoxicity can be blocked by anti-prion protein (PrP) antibodies, potentially allowing therapeutic targeting of this aspect of AD neuropathogenesis. Here, we show that intravascular administration of a high-affinity humanized anti-PrP antibody to rats can prevent the plasticity-disrupting effects induced by exposure to soluble AD brain extract. These results provide an in vivo proof of principle for such a therapeutic strategy.

NMDA-type glutamate receptors (NMDARs) are currently regarded as paramount in the potent and selective disruption of synaptic plasticity by Alzheimer’s disease amyloid β-protein (Aβ). Non-NMDAR mechanisms remain relatively unexplored. Here we describe how Aβ facilitates NMDAR-independent long-term depression of synaptic transmission in the hippocampus in vivo . Synthetic Aβ and Aβ in soluble extracts of Alzheimer’s disease brain usurp endogenous acetylcholine muscarinic receptor-dependent long-term depression, to enable long-term depression that required metabotropic glutamate-5 receptors (mGlu5Rs). We also find that mGlu5Rs are essential for Aβ-mediated inhibition of NMDAR-dependent long-term potentiation in vivo . Blocking Aβ binding to cellular prion protein with antibodies prevents the facilitation of long-term depression. Our findings uncover an overarching role for Aβ-PrP C -mGlu5R interplay in mediating both LTD facilitation and LTP inhibition, encompassing NMDAR-mediated processes that were previously considered primary.

Humanized anti-Abeta murine monoclonal IgGs (mAbs) generated against linear or conformational epitopes are investigational therapeutics that are being developed for Alzheimer's disease (AD). Such antibodies may have pan-Abeta conformer reactivity or preferential binding to a specific peptide conformer (aggregates or monomer) due to a unique exposed surface(s) and/or avidity effects (bivalent binding). To advance understanding on the Abeta conformer reactivity of clinically tested mAbs, we used a battery of solid- and solution-phase assays to compare the reactivities of murine forms of Bapineuzumab (3D6, N-terminal) and Solanezumab (266, mid-region) with our novel lead Abeta aggregate-preferring mAb, 1C22. Aggregate-preferring anti-Abeta IgGs were generated by immunizing mice with prefibrillar assemblies formed from disulfide cross-linked Abeta dimer (AbetaS26C)2. Hybridomas secreting anti-Abeta mAbs were produced by conventional fusion methods, and a lead aggregate-preferring mAb identified by solid phase. Sandwich and competition ELISAs; surface Plasmon resonance (SPR); microscale thermophoresis, and in vitro and ex vivo immunohistochemistry were used to compare forms of Abeta recognized by mAbs 3D6, 266, and our lead mAb 1C22. Our initial screen of 19 novel, in-house generated anti-Abeta mAbs utilized plate-immobilized Abeta conformers to identify antibodies that preferentially bound to protofibrils. MAb 1C22 was identified as a lead antibody candidate with nM binding to protofibrils and uM reactivity with Abeta monomer. In all other assays 1C22 showed a strong preference for protofibrils and fibrils - a preference that was largely driven by bivalent binding (avidity effects). Although less pronounced, 3D6, 6E10, and 4G8 also preferentially bound protofibrils, whereas mAb 266 bound strongest to Abeta monomer. Indeed, mAb 266 only bound to surface-immobilized Abeta aggregates under certain conditions. The pros and cons of these mAbs as therapeutic and diagnostic tools, and the methods used to assess their properties will be discussed.

Many endogenous factors influence the time course and extent of the detrimental effects of amyloid β-protein (Aβ) on synaptic function. Here, we assessed the impact of varying endogenous glutamatergic and cholinergic transmission by pharmacological means on the disruption of plasticity at hippocampal CA3-to-CA1 synapses in the anaesthetized rat. NMDA receptors (NMDARs) are considered critical in mediating Aβ-induced inhibition of long-term potentiation (LTP). However, intracerebroventricular injection of Aβ1–42 inhibited not only NMDAR-dependent LTP but also voltage-activated Ca2+-dependent LTP induced by strong conditioning stimulation during NMDAR blockade. On the other hand, another form of NMDAR-independent synaptic plasticity, endogenous acetylcholine-induced muscarinic receptor-dependent long-term enhancement, was not hindered by Aβ1–42. Interestingly, augmenting endogenous acetylcholine activation of nicotinic receptors prior to the injection of Aβ1–42 prevented the inhibition of NMDAR-dependent LTP, whereas the same intervention when introduced after the infusion of Aβ was ineffective. We also examined the duration of action of Aβ, including water soluble Aβ from Alzheimer's disease (AD) brain. Remarkably, the inhibition of LTP induction caused by a single injection of sodium dodecyl sulfate-stable Aβ dimer-containing AD brain extract persisted for at least a week. These findings highlight the need to increase our understanding of non-NMDAR mechanisms and of developing novel means of overcoming, rather than just preventing, the deleterious synaptic actions of Aβ.

Background Exosomes, small extracellular vesicles of endosomal origin, have been suggested to be involved in both the metabolism and aggregation of Alzheimer’s disease (AD)-associated amyloid β-protein (Aβ). Despite their ubiquitous presence and the inclusion of components which can potentially interact with Aβ, the role of exosomes in regulating synaptic dysfunction induced by Aβ has not been explored. Results We here provide in vivo evidence that exosomes derived from N2a cells or human cerebrospinal fluid can abrogate the synaptic-plasticity-disrupting activity of both synthetic and AD brain-derived Aβ. Mechanistically, this effect involves sequestration of synaptotoxic Aβ assemblies by exosomal surface proteins such as PrP C rather than Aβ proteolysis. Conclusions These data suggest that exosomes can counteract the inhibitory action of Aβ, which contributes to perpetual capability for synaptic plasticity.