Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice

Walker, Courtney K.; Greathouse, Kelsey M.; Boros, Benjamin D.; Poovey, Emily H; Clearman, Kelsey R.; Ramdas, Raksha; Muhammad, Hamad M.; Herskowitz, Jeremy H.

doi:10.1016/j.neuroscience.2020.12.006

Cited by 11 publications

(6 citation statements)

References 52 publications

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“…Tau is overexpressed from birth in P301S mice, and we tested whether hyperphosphorylated tau had age-related and region-specific changes. We found that P301S mice expressed constantly high levels of phosphorylated and total tau in both PFC and hippocampus since the early age, which is slightly different from a previous study showing that synaptic tau protein levels were significantly increased in the hippocampus, but reduced in the PFC, of P301S mice in response to age [ 40 ]. The conformational change in mutant tau renders it to be proaggregation, and aggregated tau can induce synaptic decay and neuronal loss [ 41 , 42 ].…”

Section: Discussioncontrasting

confidence: 99%

Longitudinal characterization of behavioral, morphological and transcriptomic changes in a tauopathy mouse model

Cao,

Kumar,

Frazier

et al. 2023

Aging

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Neurodegenerative disorders, such as Alzheimer’s disease (AD), have the gradual onset of neurobiological changes preceding clinical diagnosis by decades. To elucidate how brain dysfunction proceeds in neurodegenerative disorders, we performed longitudinal characterization of behavioral, morphological, and transcriptomic changes in a tauopathy mouse model, P301S transgenic mice. P301S mice exhibited cognitive deficits as early as 3 months old, and deficits in social preference and social cognition at 5–6 months. They had a significant decrease of arborization in basal dendrites of hippocampal pyramidal neurons from 3 months and apical dendrites of PFC pyramidal neurons at 9 months. Transcriptomic analysis of genome-wide changes revealed the enrichment of synaptic gene upregulation at 3 months of age, while most of these synaptic genes were downregulated in PFC and hippocampus of P301S mice at 9 months. These time-dependent changes in gene expression may lead to progressive alterations of neuronal structure and function, resulting in the manifestation of behavioral symptoms in tauopathies.

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Section: Discussioncontrasting

confidence: 99%

Longitudinal characterization of behavioral, morphological and transcriptomic changes in a tauopathy mouse model

Cao,

Kumar,

Frazier

et al. 2023

Aging

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“…Spine morphology analysis showed that thin spines, the most plastic and dynamic subtype, were most impacted in the 3xTg-AD model, similar to our observations in App NL−G−F mice. Selective reduction in thin spine density has also been reported in other neurodegeneration models and in the aged mouse, provoking the suggestion that they are the most susceptible spine type in neurodegeneration [ 66 , 67 ]. In 3xTg-AD mice, C6 deficiency completely prevented the loss; spine density in 3xTg-AD C6 −/− mice was not different from controls and was markedly increased compared to complement-sufficient 3xTg-AD mice in both DiOistic and immunohistochemical analysis.…”

Section: Discussionmentioning

confidence: 99%

Terminal complement pathway activation drives synaptic loss in Alzheimer’s disease models

Carpanini

Torvell

Bevan

et al. 2022

acta neuropathol commun

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Complement is involved in developmental synaptic pruning and pathological synapse loss in Alzheimer’s disease. It is posited that C1 binding initiates complement activation on synapses; C3 fragments then tag them for microglial phagocytosis. However, the precise mechanisms of complement-mediated synaptic loss remain unclear, and the role of the lytic membrane attack complex (MAC) is unexplored. We here address several knowledge gaps: (i) is complement activated through to MAC at the synapse? (ii) does MAC contribute to synaptic loss? (iii) can MAC inhibition prevent synaptic loss? Novel methods were developed and optimised to quantify C1q, C3 fragments and MAC in total and regional brain homogenates and synaptoneurosomes from WT and AppNL−G−F Alzheimer’s disease model mouse brains at 3, 6, 9 and 12 months of age. The impact on synapse loss of systemic treatment with a MAC blocking antibody and gene knockout of a MAC component was assessed in Alzheimer’s disease model mice. A significant increase in C1q, C3 fragments and MAC was observed in AppNL−G−F mice compared to controls, increasing with age and severity. Administration of anti-C7 antibody to AppNL−G−F mice modulated synapse loss, reflected by the density of dendritic spines in the vicinity of plaques. Constitutive knockout of C6 significantly reduced synapse loss in 3xTg-AD mice. We demonstrate that complement dysregulation occurs in Alzheimer’s disease mice involving the activation (C1q; C3b/iC3b) and terminal (MAC) pathways in brain areas associated with pathology. Inhibition or ablation of MAC formation reduced synapse loss in two Alzheimer’s disease mouse models, demonstrating that MAC formation is a driver of synapse loss. We suggest that MAC directly damages synapses, analogous to neuromuscular junction destruction in myasthenia gravis.

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“…Although behavioural and electrophysiological deficits have been reported in P301S mice, accompanied by a synapse loss detected using immunohistochemical staining of synaptic markers [ 22 , 53 , 54 , 55 ] , studies using microinjection of Lucifer yellow with confocal laser scanning microscopy and neuronal three‐dimensional reconstructions yielded no robust differences in spine density in the CA1 field of the hippocampus [ 56 ] . Despite any possible unaltered spine numbers, P301S mice exhibit deficits in synaptic function, including impaired long‐term potentiation in the CA1 field [ 22 ] .…”

Section: Discussionmentioning

confidence: 99%

Different modes of synaptic and extrasynaptic NMDA receptor alteration in the hippocampus of P301S tau transgenic mice

et al. 2022

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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 dodecylsulphate‐digested 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 age‐matched 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.

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Dendritic Spine Remodeling and Synaptic Tau Levels in PS19 Tauopathy Mice

Cited by 11 publications

References 52 publications

Longitudinal characterization of behavioral, morphological and transcriptomic changes in a tauopathy mouse model

Longitudinal characterization of behavioral, morphological and transcriptomic changes in a tauopathy mouse model

Terminal complement pathway activation drives synaptic loss in Alzheimer’s disease models

Different modes of synaptic and extrasynaptic NMDA receptor alteration in the hippocampus of P301S tau transgenic mice

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