Synaptic deficits in layer 5 neurons precede overt structural decay in 5xFAD mice

Buskila, Yossi; Crowe, Sarah E.; Ellis‐Davies, Graham C. R.

doi:10.1016/j.neuroscience.2013.09.016

Cited by 57 publications

(48 citation statements)

References 35 publications

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“…That Vgf is also down‐regulated in our data suggests that it may be involved in a broader molecular mechanism associated with dementia. Previous electrophysiological investigations of 5XFAD mice in early stages of pathology revealed altered excitability of pyramidal cells in cortical layer five, even prior to observable plaque deposition (Buskila, Crowe, & Ellis‐Davies, ). If gene expression changes found in our dataset are generalizable to the cerebral cortex, these down‐regulated genes are molecular correlates of these changes in excitability.…”

Section: Discussionmentioning

confidence: 95%

Sex‐biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: A multi‐omic analysis

Bundy

Vied

Badger

et al. 2018

J of Comparative Neurology

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Alzheimer's disease is a progressive neurodegenerative disorder and the most common form of dementia. Like many neurological disorders, Alzheimer's disease has a sex‐biased epidemiological profile, affecting approximately twice as many women as men. The cause of this sex difference has yet to be elucidated. To identify molecular correlates of this sex bias, we investigated molecular pathology in females and males using the 5XFamilial Alzheimer's disease mutations (5XFAD) genetic mouse model of Alzheimer's disease. We profiled the transcriptome and proteome of the mouse hippocampus during early stages of disease development (1, 2, and 4 months of age). Our analysis reveals 42 genes that are differentially expressed between disease and wild‐type animals at 2 months of age, prior to observable plaque deposition. In 4‐month‐old animals, we detect 1,316 differentially expressed transcripts between transgenic and control 5XFAD mice, many of which are associated with immune function. Additionally, we find that some of these transcriptional perturbations are correlated with altered protein levels in 4‐month‐old transgenic animals. Importantly, our data indicate that female 5XFAD mouse exhibit more profound pathology than their male counterparts as measured by differences in gene expression. We also find that the 5XFAD transgenes are more highly expressed in female 5XFAD mice than their male counterparts, which could partially account for the sex‐biased molecular pathology observed in this dataset.

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Section: Discussionmentioning

confidence: 95%

Sex‐biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: A multi‐omic analysis

Bundy

Vied

Badger

et al. 2018

J of Comparative Neurology

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“…Despite a significant Aβ accumulation, the overall numbers of neurons in the frontal cortex and hippocampus in 5xFAD mice have been shown to equal those in age-matched controls, with the exception of a neuronal loss in cortical layer 5 [23]. Interestingly, before this specific structural dystrophy, synaptic deficits in layer 5 neurons were observed [24]. Thus, a deeper insight into the activities of different brain networks and their changes in the 5xFAD mice promises to aid effective analysis of the AD pathogenesis [18].…”

Section: Introductionmentioning

confidence: 98%

Loss of Midbrain Dopamine Neurons and Altered Apomorphine EEG Effects in the 5xFAD Mouse Model of Alzheimer’s Disease

Vorobyov

Bakharev

Medvinskaya

et al. 2019

JAD

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Cognitive malfunction, synaptic dysfunction, and disconnections in neural networks are core deficits in Alzheimer's disease (AD). 5xFAD mice, a transgenic model of AD, are characterised by an enhanced level of amyloid-beta and abnormal neurotransmission. The dopaminergic (DA) system has been shown to be involved in amyloid-beta transformations and neuronal plasticity; however, its role in functional network changes in familial AD still remains unclear. In 5xFAD and non-transgenic freely moving mice, electroencephalograms (EEGs) were simultaneously recorded from the secondary motor cortex (MC), superficial layers of the hippocampal CA1 area (HPC), substantia nigra (SN), and ventral tegmental area (VTA). EEGs and their frequency spectra were analysed before and after systemic injection of a DA receptor agonist, apomorphine (APO). In the baseline EEG from MC and HPC of 5xFAD mice, delta and alpha oscillations were enhanced and beta activity was attenuated, compared to control mice. In VTA and SN of 5xFAD mice, delta-theta activity was decreased and beta oscillations dominated. In control mice, APO suppressed delta activity in VTA to a higher extent than in MC, whereas in 5xFAD mice, this difference was eliminated due to attenuation of the delta suppression in VTA. APO increased beta activity in MC of mice from both groups while significant beta suppression was observed in VTA of 5xFAD mice. These mice were characterized by significant decrease of tyrosine hydroxylase immunopositive cells in both VTA and SN and of DA transporter in MC and hippocampal dentate gyrus. We suggest that the EEG modifications observed in 5xFAD mice are associated with alterations in dopaminergic transmission, resulting in adaptive changes in the cerebral networks in the course of familial AD development.

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“…Though they do not present a clear tau pathology, they develop cerebral amyloid plaques and gliosis as early as 2 months of age [ 1 ]. Electrophysiological studies detected hippocampal synaptic dysfunctions in M6 5XFAD animals, concomitant with synaptic loss and memory deficits [ 7 - 22 ]. Progressive neuronal death has been described from M9 onwards in cortical layer 5 neurons and subiculum of 5XFAD mice [ 12 , 23 ], a characteristic that is absent in most AD mouse models.…”

Section: Introductionmentioning

confidence: 99%

Temporal gene profiling of the 5XFAD transgenic mouse model highlights the importance of microglial activation in Alzheimer’s disease

Landel

Baranger

Virard

et al. 2014

Mol Neurodegeneration

143

120

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BackgroundThe 5XFAD early onset mouse model of Alzheimer’s disease (AD) is gaining momentum. Behavioral, electrophysiological and anatomical studies have identified age-dependent alterations that can be reminiscent of human AD. However, transcriptional changes during disease progression have not yet been investigated. To this end, we carried out a transcriptomic analysis on RNAs from the neocortex and the hippocampus of 5XFAD female mice at the ages of one, four, six and nine months (M1, M4, M6, M9).ResultsOur results show a clear shift in gene expression patterns between M1 and M4. At M1, 5XFAD animals exhibit region-specific variations in gene expression patterns whereas M4 to M9 mice share a larger proportion of differentially expressed genes (DEGs) that are common to both regions. Analysis of DEGs from M4 to M9 underlines the predominance of inflammatory and immune processes in this AD mouse model. The rise in inflammation, sustained by the overexpression of genes from the complement and integrin families, is accompanied by an increased expression of transcripts involved in the NADPH oxidase complex, phagocytic processes and IFN-γ related pathways.ConclusionsOverall, our data suggest that, from M4 to M9, sustained microglial activation becomes the predominant feature and point out that both detrimental and neuroprotective mechanisms appear to be at play in this model. Furthermore, our study identifies a number of genes already known to be altered in human AD, thus confirming the use of the 5XFAD strain as a valid model for understanding AD pathogenesis and for screening potential therapeutic molecules.

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Synaptic deficits in layer 5 neurons precede overt structural decay in 5xFAD mice

Cited by 57 publications

References 35 publications

Sex‐biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: A multi‐omic analysis

Sex‐biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: A multi‐omic analysis

Loss of Midbrain Dopamine Neurons and Altered Apomorphine EEG Effects in the 5xFAD Mouse Model of Alzheimer’s Disease

Temporal gene profiling of the 5XFAD transgenic mouse model highlights the importance of microglial activation in Alzheimer’s disease

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