Hippocampal interneuron loss in an APP/PS1 double mutant mouse and in Alzheimer’s disease

Takahashi, Hiroyuki; Brasnjevic, Ivona; Rutten, Bart P. F.; Kolk, Nicolien Van Der; Perl, Daniel P.; Bouras, Constantin; Steinbusch, Harry W.M.; Schmitz, Christoph; Hof, Patrick R.; Dickstein, Dara L.

doi:10.1007/s00429-010-0242-4

Cited by 104 publications

(101 citation statements)

References 79 publications

(102 reference statements)

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“…Notably, in association with the putative role of Cygb in neuroprotection, a selective reduction of PV-ir neurons were observed in the hippocampus of the AD patients and transgenic animal models of AD (35)(36)(37)(38). Of note, HO-1-ir The merged image of A-C is shown.…”

Section: Discussionmentioning

confidence: 83%

Neurochemical phenotype of cytoglobin-expressing neurons in the rat hippocampus

2014

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Abstract. Cytoglobin (Cygb), a novel oxygen-binding protein, is expressed in the majority of tissues and has been proposed to function in nitric oxide (NO) metabolism in the vasculature and to have cytoprotective properties. However, the overall functions of Cygb remain elusive. Cygb is also expressed in a subpopulation of brain neurons. Recently, it has been shown that stress upregulates Cygb expression in the brain and the majority of neuronal nitric oxide synthase (nNOS)-positive neurons, an enzyme that produces NO, co-express Cygb. However, there are more neurons expressing Cygb than nNOS, thus a large number of Cygb neurons remain uncharacterized by the neurochemical content. The aim of the present study was to provide an additional and more detailed neurochemical phenotype of Cygb-expressing neurons in the rat hippocampus. The rat hippocampus was chosen due to the abundance of Cygb, as well as this limbic structure being an important target in a number of neurodegenerative diseases. Using triple immunohistochemistry, it was demonstrated that nearly all the parvalbumin-and heme oxygenase 1-positive neurons co-express Cygb and to a large extent, these neuron populations are distinct from the population of Cygb neurons co-expressing nNOS. Furthermore, it was shown that the majority of neurons expressing somastostatin and vasoactive intestinal peptide also co-express Cygb and nNOS. Detailed information regarding the neurochemical phenotype of Cygb neurons in the hippocampus can be a valuable tool in determining the function of Cygb in the brain.

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Section: Discussionmentioning

confidence: 83%

Neurochemical phenotype of cytoglobin-expressing neurons in the rat hippocampus

2014

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“…For example, there was little evidence of widespread neuronal loss. Others have found cell loss in APP mouse models of AD pathology (27) or mice with multiple mutations (28). However, the degree of neuronal damage in mouse models of AD is limited, in general, and is typically less than in patients at the end stage of AD, after progressive hippocampal and entorhinal neurodegeneration.…”

Section: Of Mice and Men: Pathology In Mouse Models Of Ad Suggest Simmentioning

confidence: 99%

“Untangling” Alzheimer's Disease and Epilepsy

Scharfman

2012

Epilepsy Curr

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There is a substantial body of evidence that spontaneous recurrent seizures occur in a subset of patients with Alzheimer disease (AD), especially the familial forms that have an early onset. In transgenic mice that simulate these genetic forms of AD, seizures or reduced seizure threshold have also been reported. Mechanisms underlying the seizures or reduced seizure threshold in these mice are not yet clear and are likely to be complex, because the synthesis of amyloid β (Aβ) involves many peptides and proteases that influence excitability. Based on transgenic mouse models of AD where Aβ and its precursor are elevated, it has been suggested that seizures are caused by the downregulation of the Nav1.1 sodium channel in a subset of GABAergic interneurons, leading to a reduction in GABAergic inhibition. Another mechanism of hyperexcitability appears to involve tau, because deletion of tau reduces seizures in some of the same transgenic mouse models of AD. Therefore, altered excitability may be as much a characteristic of AD as plaques and tangles—especially for the familial forms of AD.

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“…Moreover, the preferential susceptibility of interneurons to Aβ toxicity has been previously documented (Davies et al 1980, Ramos et al 2006, Takahashi et al 2010, Verret et al 2012). …”

Section: Discussionmentioning

confidence: 85%

“…In order to further confirm the first hypothesis on a decreased GABA pathway function, we studied the results obtained from the microarray analysis of GABAergic pathway-related genes. Previous research has established the loss of different interneurons or a reduction in the function of such interneurons in AD (Takahashi et al 2010). Compared to the observed gene changes in the hippocampus, results from the microarray analysis show more differentially expressed genes in the prefrontal cortex of APP/PS1 mice as compared to the littermates.…”

Section: Discussionmentioning

confidence: 99%

Age‑dependent concomitant changes in synaptic function and GABAergic pathway in the APP/PS1 mouse model

Tutu¹,

Bondt²,

Wyngaert³

et al. 2016

Acta Neurobiologiae Experimentalis

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Synaptic dysfunction is a well-documented manifestation in animal models of Alzheimer's disease pathology. In this context, numerous studies have documented reduction in the functionality of synapses in various models. In addition, recent research has shed more light on increased excitability and its link to seizures and seizure-like activities in AD patients as well as in mouse models. These reports of hyperexcitability contradict the observed reduction in synaptic function and have been suggested to be as a result of the interplay between inhibitory and excitatory neuronal mechanism. The present study therefore investigates functional deficiency in the inhibitory system as complementary to the identified alterations in the glutamate excitatory pathway in AD. Since synaptic function deficit in AD is typically linked to progression/pathology of the disease, it is important to determine whether the deficits in the GABAergic system are functional and can be directly linked to the pattern of the disruption documented in the glutamate system. To build on previous research in this field, experiments were designed to determine if previously documented synaptic dysfunction in AD models is concomitantly observed with excitation/inhibition imbalance as suggested by observation of seizure and seizure-like pathology in such models. We report changes in synaptic function in aged APPPS1 mice not observable in the younger cohort. These changes in synaptic function are furthermore accompanied by alteration in the GABAergic neurotransmission. Thus, age-dependent alteration in the inhibitory/ excitatory balance might underpin the symptomatic changes observed with the progression of Alzheimer's disease pathology including sleep disturbance and epileptic events.

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Hippocampal interneuron loss in an APP/PS1 double mutant mouse and in Alzheimer’s disease

Cited by 104 publications

References 79 publications

Neurochemical phenotype of cytoglobin-expressing neurons in the rat hippocampus

Neurochemical phenotype of cytoglobin-expressing neurons in the rat hippocampus

“Untangling” Alzheimer's Disease and Epilepsy

Age‑dependent concomitant changes in synaptic function and GABAergic pathway in the APP/PS1 mouse model

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