Differential vulnerability of hippocampal CA3-CA1 synapses to Aβ

Brain Pathology

N-methyl-D-aspartate receptors (NMDARs) are pivotal players in the synaptic transmission and synaptic plasticity underlying learning and memory. Accordingly, dysfunction of NMDARs has been implicated in the pathophysiology of Alzheimer disease (AD). Here, we used histoblot and sodium dodecylsulphatedigested freeze-fracture replica labelling (SDS-FRL) techniques to investigate the expression and subcellular localisation of GluN1, the obligatory subunit of NMDARs, in the hippocampus of P301S mice. Histoblots showed that GluN1 expression was significantly reduced in the hippocampus of P301S mice in a laminar-specific manner at 10 months of age but was unaltered at 3 months. Using the SDS-FRL technique, excitatory synapses and extrasynaptic sites on spines of pyramidal cells and interneuron dendrites were analysed throughout all dendritic layers in the CA1 field. Our ultrastructural approach revealed a high density of GluN1 in synaptic sites and a substantially lower density at extrasynaptic sites. Labelling density for GluN1 in excitatory synapses established on spines was significantly reduced in P301S mice, compared with agematched wild-type mice, in the stratum oriens (so), stratum radiatum (sr) and stratum lacunosum-moleculare (slm). Density for synaptic GluN1 on interneuron dendrites was significantly reduced in P301S mice in the so and sr but unaltered in the slm. Labelling density for GluN1 at extrasynaptic sites showed no significant differences in pyramidal cells, and only increased density in the interneuron dendrites of the sr. This differential alteration of synaptic versus extrasynaptic NMDARs supports the notion that the progressive accumulation of phospho-tau is associated with changes in NMDARs, in the absence of amyloid-β pathology, and may be involved in the mechanisms causing abnormal network activity of the hippocampal circuit.

PLoS ONE, 2013

Alzheimer disease is characterized by a gradual decrease of synaptic function and, ultimately, by neuronal loss. There is considerable evidence supporting the involvement of oligomeric amyloid-beta (Ab) in the etiology of Alzheimer's disease. Historically, AD research has mainly focused on the long-term changes caused by Ab rather than analyzing its immediate effects. Here we show that acute perfusion of hippocampal slice cultures with oligomeric Ab depresses synaptic transmission within 20 minutes. This depression is dependent on synaptic stimulation and the activation of NMDAreceptors, but not on NMDA-receptor mediated ion flux. It, therefore, appears that Ab dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDAreceptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.

Acta Neuropathologica Communications

Many mouse models of Alzheimer’s disease (AD) exhibit impairments in hippocampal long-term-potentiation (LTP), seemingly corroborating the strong correlation between synaptic loss and cognitive decline reported in human studies. In other AD mouse models LTP is unaffected, but other defects in synaptic plasticity may still be present. We recently reported that THY-Tau22 transgenic mice, that overexpress human Tau protein carrying P301S and G272 V mutations and show normal LTP upon high-frequency-stimulation (HFS), develop severe changes in NMDAR mediated long-term-depression (LTD), the physiological counterpart of LTP. In the present study, we focused on putative effects of AD-related pathologies on depotentiation (DP), another form of synaptic plasticity. Using a novel protocol to induce DP in the CA1-region, we found in 11–15 months old male THY-Tau22 and APPPS1–21 transgenic mice that DP was not deteriorated by Aß pathology while significantly compromised by Tau pathology. Our fin...

2020

ABSTRACTThe patterns of Aβ-induced synaptic injury were examined after targeting of the amyloid precursor protein (APP) preferentially to either CA1 or CA3 neurons using Cre-lox technology combined with tetracycline-regulated expression. Both CA1- and CA3-APP-expressing transgenic mouse lines exhibited reduction in long-term potentiation (LTP) only when APP was expressed in neurons presynaptic to the recording site, whereas LTP remained comparable to wild-type mice when APP was expressed in postsynaptic neurons. As quantified by both light and electron microscopy, this orientation-specific impairment in synaptic plasticity was mirrored by synaptic loss in regions receiving axonal inputs from neurons expressing APP. Furthermore, A(plaque deposition also occurred only in the postsynaptic axonal fields of APP-expressing neurons. These deficits were reversed not only with doxycycline to inhibit APP expression but also with γ-secretase and Fyn kinase inhibitors, supporting the interpreta...

The Journal of Neuroscience, 2011

Amyloid β (Aβ) and tau protein are both implicated in memory impairment, mild cognitive impairment (MCI), and early Alzheimer's disease (AD), but whether and how they interact is unknown. Consequently, we asked whether tau protein is required for the robust phenomenon of Aβ-induced impairment of hippocampal long-term potentiation (LTP), a widely accepted cellular model of memory. We used wild-type mice and mice with a genetic knock-out of tau protein and recorded field potentials in an acute slice preparation. We demonstrate that the absence of tau protein prevents Aβ-induced impairment of LTP. Moreover, we show that Aβ increases tau phosphorylation and that a specific inhibitor of the tau kinase glycogen synthase kinase 3 blocks the increased tau phosphorylation induced by Aβ and prevents Aβ-induced impairment of LTP in wild-type mice. Together, these findings show that tau protein is required for Aβ to impair synaptic plasticity in the hippocampus and suggest that the Aβ-induc...

Neural Plasticity, 2020

For more than five decades, the field of Alzheimer’s disease (AD) has focused on two main hypotheses positing amyloid-beta (Aβ) and Tau phosphorylation (pTau) as key pathogenic mediators. In line with these canonical hypotheses, several groups around the world have shown that the synaptotoxicity in AD depends mainly on the increase in pTau levels. Confronting this leading hypothesis, a few years ago, we reported that the increase in phosphorylation levels of dendritic Tau, at its microtubule domain (MD), acts as a neuroprotective mechanism that prevents N-methyl-D-aspartate receptor (NMDAr) overexcitation, which allowed us to propose that Tau protein phosphorylated near MD sites is involved in neuroprotection, rather than in neurodegeneration. Further supporting this alternative role of pTau, we have recently shown that early increases in pTau close to MD sites prevent hippocampal circuit overexcitation in a transgenic AD mouse model. Here, we will synthesize this new evidence that ...

PLOS ONE, 2017

In Alzheimer's disease (AD), dysregulation of intracellular Ca 2+ signalling has been observed as an early event prior to the presence of clinical symptoms and is believed to be a crucial factor contributing to AD pathogenesis. Amyloid-β oligomers (AβOs) disturb the Nmethyl-D-aspartate receptor (NMDAR)-mediated postsynaptic Ca 2+ signalling in response to presynaptic stimulation by increasing the availability of extracellular glutamate as well as directly disturbing the NMDARs. The abnormal Ca 2+ response can further lead to impairments in long-term potentiation (LTP), an important process in memory formation. In this study, we develop a mathematical model of a CA1 pyramidal dendritic spine and conduct computational experiments. We use this model to mimic alterations by AβOs under AD conditions to investigate how they are involved in the Ca 2+ dysregulation in the dendritic spine. The alterations in glutamate availability, as well as NMDAR availability and activity, are studied both individually and globally. The simulation results suggest that alterations in glutamate availability mostly affect the synaptic response and have limited effects on the extrasynaptic receptors. Moreover, overactivation of extrasynaptic NMDARs in AD is unlikely to be induced by presynaptic stimulation, but by upregulation of the resting level of glutamate, possibly resulting from these alterations. Furthermore, internalisation of synaptic NR2A-NMDAR shows greater damage to the postsynaptic Ca 2+ response in comparison with the internalisation of NR2B-NMDARs; thus, the suggested neuroprotective role of the latter is very limited during synaptic transmission in AD. We integrate a CaMKII state transition model with the Ca 2+ model to further study the effects of alterations of NMDARs in the CaM-KII state transition, an important downstream event in the early phase of LTP. The model reveals that cooperation between NR2A-and NR2B-NMDAR is required for LTP induction. Under AD conditions, internalisation of membrane NMDARs is suggested to be the cause of the loss of synapse numbers by disrupting CaMKII-NMDAR formation.

Journal of Clinical Investigation

Aging Cell, 2013

While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampusdependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptordependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N-methyl-D-Aspartate receptors (NMDAR). Using THY-Tau22 transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA-induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY-Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies.

Journal of Alzheimer's Disease, 2010

Synaptic dysfunction is an early event in the development of Alzheimer's disease (AD) and relates closely to the cognitive impairment characterizing this neurodegenerative process. A causative association has been proposed, largely on the basis of in vitro studies, between memory decline, soluble amyloid-β (Aβ) oligomers and alterations of glutamatergic neurotransmission. We aimed here to characterize in vivo N-methyl-D-aspartate receptor (NMDAR)-mediated signaling, at an early stage of AD, before extracellular amyloid plaques are deposited. We assessed the functional link between cognitive abilities and NMDAR-mediated pharmacological responses of six-month-old AβPP23 transgenic mice (AβPP23tg), overexpressing the human amyloid-β protein precursor carrying the Swedish double mutation. We found evidence of cognitive impairments in these mice, indicated by deficits in the delayed-non-matching-to-place task. Alterations of NMDAR-mediated signaling in this mouse model were confirmed by the reduced sensitivity of motor-activation and working memory to pharmacological inhibition of NMDAR activity. At the molecular level, AβPP23tg mice show hippocampal alterations in the trafficking of synaptic NMDAR subunits NR2A and NR2B and at an ultrastructural analysis show Aβ oligomers intracellularly localized in the synaptic compartments. Importantly, the behavioral and biochemical alterations of NMDAR signaling are associated with the inhibition of long-term synaptic potentiation and inversion of metaplasticity at CA1 synapses in hippocampal slices from AβPP23tg mice. These results indicate a general impairment of synaptic function and learning and memory in young AβPP23tg mice with Aβ oligomers but no amyloid plaques.