Vulnerability of calbindin, calretinin and parvalbumin in a transgenic/knock-in APPswe/PS1dE9 mouse model of Alzheimer disease together with disruption of hippocampal neurogenesis

Verdaguer, Ester; Brox, Susana; Петров, Д. С.; Olloquequi, Jordi; Romero, Rafael; Lemos, Miguel; Camins, Antoni; Auladell, Carme

doi:10.1016/j.exger.2015.06.013

Cited by 32 publications

(21 citation statements)

References 54 publications

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“…Although the density of PV+ processes was boosted in APPPS1 hippocampus, the number of PV+ interneurons was not appreciably increased compared to WT. This is in concordance with recent studies showing enhanced immunoreactivity but no or little change in the number of PV+ cells in the hippocampus and entorhinal cortex of relative young (3–6 months) APPPS1 mice [38, 54, 55]. Quantification of overlapping PV/VGAT/gephyrin immunoreactivities in triple immunolabeled brain sections disclosed a statistically significant increase in the density of perisomatic GABAergic synapses originating from PV+ interneurons and terminating around pyramidal cells in both CA1 and CA3 subregions of the hippocampus of APPPS1 mice as compared to WT.…”

Section: Discussionsupporting

confidence: 93%

Early alterations in hippocampal perisomatic GABAergic synapses and network oscillations in a mouse model of Alzheimer’s disease amyloidosis

et al. 2019

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Several lines of evidence imply changes in inhibitory interneuron connectivity and subsequent alterations in oscillatory network activities in the pathogenesis of Alzheimer’s Disease (AD). Recently, we provided evidence for an increased immunoreactivity of both the postsynaptic scaffold protein gephyrin and the GABAA receptor γ2-subunit in the hippocampus of young (1 and 3 months of age), APPPS1 mice. These mice represent a well-established model of cerebral amyloidosis, which is a hallmark of human AD. In this study, we demonstrate a robust increase of parvalbumin immunoreactivity and accentuated projections of parvalbumin positive (PV+) interneurons, which target perisomatic regions of pyramidal cells within the hippocampal subregions CA1 and CA3 of 3-month-old APPPS1 mice. Colocalisation studies confirmed a significant increase in the density of PV+ projections labeled with antibodies against a presynaptic (vesicular GABA transporter) and a postsynaptic marker (gephyrin) of inhibitory synapses within the pyramidal cell layer of CA1 and CA3. As perisomatic inhibition by PV+-interneurons is crucial for the generation of hippocampal network oscillations involved in spatial processing, learning and memory formation we investigated the impact of the putative enhanced perisomatic inhibition on two types of fast neuronal network oscillations in acute hippocampal slices: 1. spontaneously occurring sharp wave-ripple complexes (SPW-R), and 2. cholinergic γ-oscillations. Interestingly, both network patterns were generally preserved in APPPS1 mice similar to WT mice. However, the comparison of simultaneous CA3 and CA1 recordings revealed that the incidence and amplitude of SPW-Rs were significantly lower in CA1 vs CA3 in APPPS1 slices, whereas the power of γ-oscillations was significantly higher in CA3 vs CA1 in WT-slices indicating an impaired communication between the CA3 and CA1 network activities in APPPS1 mice. Taken together, our data demonstrate an increased GABAergic synaptic output of PV+ interneurons impinging on pyramidal cells of CA1 and CA3, which might limit the coordinated cross-talk between these two hippocampal areas in young APPPS1 mice and mediate long-term changes in synaptic inhibition during progression of amyloidosis.

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Section: Discussionsupporting

confidence: 93%

Early alterations in hippocampal perisomatic GABAergic synapses and network oscillations in a mouse model of Alzheimer’s disease amyloidosis

et al. 2019

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“…Moreover, CR neurons decreased during the early stages of the pathology, while PV neurons decreased at the later stages of the disease in the olfactory bulbs of APP/PS1 mice (Saiz-Sanchez et al, 2013;Zallo et al, 2018). However, there have been contradictory analyses of these neurons in AD mice, with other studies revealing no changes in either the hippocampus or the entorhinal cortex (Lemmens et al, 2011;Verdaguer et al, 2015). A recent study showed that SOM (SST)-positive neurons were significantly less frequent in the perirhinal cortex of 6-month-old APP/PS1 mice and in AD patients (91% in Braak V,VI cases) (Sanchez-Mejias et al, 2019).…”

Section: Targeting Increased Numbers Of Gaba Inhibitory Interneuronsmentioning

confidence: 99%

GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

et al. 2020

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by severe cognitive deficits and pathologically by amyloid plaques, neuronal loss, and neurofibrillary tangles. Abnormal amyloid β-protein (Aβ) deposition in the brain is often thought of as a major initiating factor in AD neuropathology. However, gammaaminobutyric acid (GABA) inhibitory interneurons are resistant to Aβ deposition, and Aβ decreases synaptic glutamatergic transmission to decrease neural network activity. Furthermore, there is now evidence suggesting that neural network activity is aberrantly increased in AD patients and animal models due to functional deficits in and decreased activity of GABA inhibitory interneurons, contributing to cognitive deficits. Here we describe the roles played by excitatory neurons and GABA inhibitory interneurons in Aβ-induced cognitive deficits and how altered GABA interneurons regulate AD neuropathology. We also comprehensively review recent studies on how GABA interneurons and GABA receptors can be exploited for therapeutic benefit. GABA interneurons are an emerging therapeutic target in AD, with further clinical trials urgently warranted.

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“…Although the concept of a reduction in hippocampal neurogenesis preceding the development of A␤ plaques may account for the onset of cognitive decline, further studies are required to pinpoint exactly where alterations in hippocampal neurogenesis occur in relation to other pathologies in the development of AD. There have also been reports of increased hippocampal neurogenesis in mouse models of AD (Ermini et al, 2008;Jin et al, 2004a;Mirochnic et al, 2009;Verdaguer et al, 2015;Yu et al, 2009). It is likely that differences in animal models, the age at which they are studied, extent of A␤ pathology and method of assessment of neurogenesis, in particular BrdU administration protocols, all affect comparisons across these studies and may account for some of the differences observed with some studies reporting reductions in neurogenesis and others reporting increases.…”

Section: Alterations In Hippocampal Neurogenesis In Ad Mouse Modelsmentioning

confidence: 99%

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer’s disease

Ryan

Kelly

2016

Ageing Research Reviews

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a b s t r a c tIt is now well established, at least in animal models, that exercise elicits potent pro-cognitive and proneurogenic effects. Alzheimer's disease (AD) is one of the leading causes of dementia and represents one of the greatest burdens on healthcare systems worldwide, with no effective treatment for the disease to date. Exercise presents a promising non-pharmacological option to potentially delay the onset of or slow down the progression of AD. Exercise interventions in mouse models of AD have been explored and have been found to reduce amyloid pathology and improve cognitive function. More recent studies have expanded the research question by investigating potential pro-neurogenic and anti-inflammatory effects of exercise. In this review we summarise studies that have examined exercise-mediated effects on AD pathology, cognitive function, hippocampal neurogenesis and neuroinflammation in transgenic mouse models of AD. Furthermore, we attempt to identify the optimum exercise conditions required to elicit the greatest benefits, taking into account age and pathology of the model, as well as type and duration of exercise.© 2016 Elsevier B.V. All rights reserved. Please cite this article in press as: Ryan, S.M., Kelly, Á.M., Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer's disease. Ageing Res. Rev. (2016), http://dx

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Vulnerability of calbindin, calretinin and parvalbumin in a transgenic/knock-in APPswe/PS1dE9 mouse model of Alzheimer disease together with disruption of hippocampal neurogenesis

Cited by 32 publications

References 54 publications

Early alterations in hippocampal perisomatic GABAergic synapses and network oscillations in a mouse model of Alzheimer’s disease amyloidosis

Early alterations in hippocampal perisomatic GABAergic synapses and network oscillations in a mouse model of Alzheimer’s disease amyloidosis

GABAergic Inhibitory Interneuron Deficits in Alzheimer’s Disease: Implications for Treatment

Exercise as a pro-cognitive, pro-neurogenic and anti-inflammatory intervention in transgenic mouse models of Alzheimer’s disease

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