Down‐regulation of glutamatergic terminals (VGLUT1) driven by Aβ in Alzheimer's disease

Rodriguez‐Perdigon, Manuel; Tordera, Rosa M.; Gil-Bea, Francisco J.; Gereñu, Gorka; Ramı́rez, Marı́a J.; Solas, Maite

doi:10.1002/hipo.22607

Cited by 42 publications

(19 citation statements)

References 55 publications

(62 reference statements)

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“…Also in retinitis pigmentosa, alterations in synapse and glutamate receptors are supposed to take part in its pathomechanism [ 71 , 72 , 73 ]. In addition to synapse alterations occurring in ocular diseases, they also play a decisive role in other diseases, especially in relation to Alzheimer’s disease [ 74 , 75 , 76 , 77 ], as reduced levels of VGluT1 heighten beta amyloid-induced neuroinflammation and affect synaptic plasticity [ 78 ]. Likewise, in an animal model that examined the impact of apolipoprotein E4, lower levels of VGluT1 were noted in retinas [ 79 ].…”

Section: Discussionmentioning

confidence: 99%

Synapse and Receptor Alterations in Two Different S100B-Induced Glaucoma-Like Models

Benning¹,

Reinehr²,

Grotegut³

et al. 2020

IJMS

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Glaucoma is identified by an irreversible retinal ganglion cell (RGC) loss and optic nerve damage. Over the past few years, the immune system gained importance in its genesis. In a glaucoma-like animal model with intraocular S100B injection, RGC death occurs at 14 days. In an experimental autoimmune glaucoma model with systemic S100B immunization, a loss of RGCs is accompanied by a decreased synaptic signal at 28 days. Here, we aimed to study synaptic alterations in these two models. In one group, rats received a systemic S100B immunization (n = 7/group), while in the other group, S100B was injected intraocularly (n = 6–7/group). Both groups were compared to appropriate controls and investigated after 14 days. While inhibitory post-synapses remained unchanged in both models, excitatory post-synapses degenerated in animals with intraocular S100B injection (p = 0.03). Excitatory pre-synapses tendentially increased in animals with systemic S100B immunization (p = 0.08) and significantly decreased in intraocular ones (p = 0.04). Significantly more n-methyl-d-aspartate (NMDA) receptors (both p ≤ 0.04) as well as gamma-aminobutyric acid (GABA) receptors (both p < 0.03) were observed in S100B animals in both models. We assume that an upregulation of these receptors causes the interacting synapse types to degenerate. Heightened levels of excitatory pre-synapses could be explained by remodeling followed by degeneration.

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Section: Discussionmentioning

confidence: 99%

Synapse and Receptor Alterations in Two Different S100B-Induced Glaucoma-Like Models

Benning¹,

Reinehr²,

Grotegut³

et al. 2020

IJMS

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“…This study, however, does not examine the cause for this accumulation, and does not offer any insight into the potential mechanisms involved in this change. This accumulation of Aβ in AD has been shown to result in selective decline in VGluT1 expression (Rodriguez-Perdigon et al, 2016). Rodríguez-Moreno and Lerma (1998) noted a reduction in both glutamatergic terminals and VGluT1 levels in hippocampal cell cultures exposed to Aβ, with intracerebroventricular administration of Aβ 1−42 resulting in altered synaptic plasticity and neuroinflammation.…”

Section: Vglut Expression Alterations 3 Days Post-aβ Injectionmentioning

confidence: 99%

The Acute Effects of Amyloid-Beta1–42 on Glutamatergic Receptor and Transporter Expression in the Mouse Hippocampus

et al. 2020

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Alzheimer's disease (AD) is the leading type of dementia worldwide. Despite an increasing burden of disease due to a rapidly aging population, there is still a lack of complete understanding of the precise pathological mechanisms which drive its progression. Glutamate is the main excitatory neurotransmitter in the brain and plays an essential role in the normal function and excitability of neuronal networks. While previous studies have shown alterations in the function of the glutamatergic system in AD, the underlying etiology of beta amyloid (Aβ 1−42) induced changes has not been explored. Here we have investigated the acute effects of stereotaxic hippocampal Aβ 1−42 injection on specific glutamatergic receptors and transporters in the mouse hippocampus, using immunohistochemistry and confocal microscopy 3 days after Aβ 1−42 injection in aged male C57BL/6 mice, before the onset of neuronal cell death. We show that acute injection of Aβ 1−42 is sufficient to induce cognitive deficits 3 days post-injection. We also report no significant changes in glutamate receptor subunits GluA1, GluA2, VGluT1, and VGluT2 in response to acute injection of Aβ 1−42 when compared with the ACSF-vehicle injected mice. However, we observed increased expression in the DG hilus and ventral stratum (str.) granulosum, CA3 str. radiatum and str. oriens, and CA1 str. radiatum of the GluN1 subunit, and increased expression within the CA3 str. radiatum and decreased expression within the DG str. granulosum of the GluN2A subunit in Aβ 1−42 injected mice compared to NC, and a similar trend observed when compared to ACSF-injected mice. We also observed alterations in expression patterns of glutamatergic receptor subunits and transporters within specific layers of hippocampal subregions in response to a microinjection stimulus. These findings indicate that the pathological alterations in the glutamatergic system observed in AD are likely to be partially a result of both acute and chronic exposure to Aβ 1−42 and implies a much more complex circuit mechanism associated with glutamatergic dysfunction than simply glutamate-mediated excitotoxic neuronal death.

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“…Furthermore, Aβ could interact with the glutamatergic systems in a number of ways. Studies in transgene mouse models and AD brains have found that plaque load is correlated with lower expressions of VGLUT1 [ 47 ]. The model further assumes linear effects of therapeutic interventions by amyloid-lowering agents.…”

Section: Discussionmentioning

confidence: 99%

Impact of amyloid-beta changes on cognitive outcomes in Alzheimer’s disease: analysis of clinical trials using a quantitative systems pharmacology model

2018

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BackgroundDespite a tremendous amount of information on the role of amyloid in Alzheimer’s disease (AD), almost all clinical trials testing this hypothesis have failed to generate clinically relevant cognitive effects.MethodsWe present an advanced mechanism-based and biophysically realistic quantitative systems pharmacology computer model of an Alzheimer-type neuronal cortical network that has been calibrated with Alzheimer Disease Assessment Scale, cognitive subscale (ADAS-Cog) readouts from historical clinical trials and simulated the differential impact of amyloid-beta (Aβ40 and Aβ42) oligomers on glutamate and nicotinic neurotransmission.ResultsPreclinical data suggest a beneficial effect of shorter Aβ forms within a limited dose range. Such a beneficial effect of Aβ40 on glutamate neurotransmission in human patients is absolutely necessary to reproduce clinical data on the ADAS-Cog in minimal cognitive impairment (MCI) patients with and without amyloid load, the effect of APOE genotype effect on the slope of the cognitive trajectory over time in placebo AD patients and higher sensitivity to cholinergic manipulation with scopolamine associated with higher Aβ in MCI subjects. We further derive a relationship between units of Aβ load in our model and the standard uptake value ratio from amyloid imaging.When introducing the documented clinical pharmacodynamic effects on Aβ levels for various amyloid-related clinical interventions in patients with low Aβ baseline, the platform predicts an overall significant worsening for passive vaccination with solanezumab, beta-secretase inhibitor verubecestat and gamma-secretase inhibitor semagacestat. In contrast, all three interventions improved cognition in subjects with moderate to high baseline Aβ levels, with verubecestat anticipated to have the greatest effect (around ADAS-Cog value 1.5 points), solanezumab the lowest (0.8 ADAS-Cog value points) and semagacestat in between. This could explain the success of many amyloid interventions in transgene animals with an artificial high level of Aβ, but not in AD patients with a large variability of amyloid loads.ConclusionsIf these predictions are confirmed in post-hoc analyses of failed clinical amyloid-modulating trials, one should question the rationale behind testing these interventions in early and prodromal subjects with low or zero amyloid load.

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Down‐regulation of glutamatergic terminals (VGLUT1) driven by Aβ in Alzheimer's disease

Cited by 42 publications

References 55 publications

Synapse and Receptor Alterations in Two Different S100B-Induced Glaucoma-Like Models

Synapse and Receptor Alterations in Two Different S100B-Induced Glaucoma-Like Models

The Acute Effects of Amyloid-Beta1–42 on Glutamatergic Receptor and Transporter Expression in the Mouse Hippocampus

Impact of amyloid-beta changes on cognitive outcomes in Alzheimer’s disease: analysis of clinical trials using a quantitative systems pharmacology model

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