Early Improved and Late Defective Cognition Is Reflected by Dendritic Spines in Tau.P301L Mice

Kremer, Anna; Maurin, Hervé; Demedts, David; Devijver, Herman; Borghgraef, Peter; Leuven, Freddy Van

doi:10.1523/jneurosci.4859-11.2011

Cited by 44 publications

(65 citation statements)

References 44 publications

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“…This change in AMPA receptor content has been likened to long-term depression, a form of synaptic plasticity that can lead to regression of dendritic spines (Berridge, 2011; Crimins et al, 2011; D'Amelio et al, 2011; Huang and Mucke, 2012; Spires-Jones and Knafo, 2012; Yu and Lu, 2012; Yu et al, 2012). Contrary to these findings, however, others have reported no evidence of change in receptor composition, pre- and/or post-synaptic markers and have, therefore, postulated that synapse loss does not occur in conjunction with alterations to the same isoforms or mutations of tau that are associated with deficits in other studies (Hoover et al, 2010; Kimura et al, 2010; Kremer et al, 2011; Shahani et al, 2006; Tackenberg and Brandt, 2009). …”

Section: Introductionmentioning

confidence: 69%

“…Western blots of mouse or human tissue with PHF1 reveal a band in the 64-68kD range and immunohistochemistry shows fibrillar pathology of both NFT and neuropil threads with little to no reactivity in control tissues (de Calignon et al, 2012; Fox et al, 2011; Polydoro et al, 2009; Tai et al, 2012). The third tau antibody used was human tau specific HT7 (Thermo Scientific), a mouse monoclonal antibody raised to purified human tau (AA159-163) that recognizes 55-64kD species of human tau in western blots (de Calignon et al, 2012; Eckermann et al, 2007; Kremer et al, 2011). In transgenic mouse tissue, HT7 recognizes human tau over-expression, including NFT and neuropil threads, and yields no staining in control animals (de Calignon et al, 2012).…”

Section: Methodsmentioning

confidence: 99%

“…Disruptions to normal tau function via hyperphosphorylation, mislocalization, misfolding and fibrilization occur in AD, and are thought to impede transport and result in distal sites devoid of essential machinery (Coleman and Yao, 2003; Cuchillo-Ibanez et al, 2008; Dixit et al, 2008; Hollenbeck and Saxton, 2005; Morfini et al, 2009; Stamer et al, 2002; Thies and Mandelkow, 2007; Zempel et al, 2010), ultimately leading to axonal and dendritic ‘dying back’ and neuronal death (Coleman and Yao, 2003; Morfini et al, 2009; Yoshiyama et al, 2007). In addition, recent studies place tau both physiologically and pathologically in dendritic spines, suggesting that tau may have a more direct role in dendritic degeneration as well (Hoover et al, 2010; Ittner et al, 2010; Kremer et al, 2011; Tai et al, 2012; Yu et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

“…Yet another series of studies have proposed not only that tau does not induce synapse loss, but rather that compensatory mechanisms in remaining neurons may be at play in tau models, leading to increases in synaptic proteins or synapses themselves, particularly at early stages (Amadoro et al, 2010; Bittner et al, 2010; Boekhoorn et al, 2006; Crimins et al, 2011; David et al, 2005; Dickstein et al, 2010; Kimura et al, 2010; Kremer et al, 2011). In human wild type or P301L tau over-expressing mice, formation of new synapses or changes in spine morphology, provide potential mechanisms for maintenance of normal network activity even at advanced stages of tauopathy (Crimins et al, 2011; Dickstein et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Synaptic alterations in the rTg4510 mouse model of tauopathy

Kopeikina

Polydoro

Tai

et al. 2013

J of Comparative Neurology

101

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Synapse loss, rather than the hallmark amyloid-β (Aβ) plaques or tau filled neurofibrillary tangles (NFT), is considered the most predictive pathological feature associated with cognitive status in the Alzheimer disease (AD) brain. The role of Aβ in synapse loss is well established, but despite data linking tau to synaptic function, the role of tau in synapse loss remains largely undetermined. Here we test the hypothesis that human mutant P301L tau over-expression in a mouse model (rTg4510) will lead to age-dependent synaptic loss and dysfunction. Using array tomography and two methods of quantification (automated, threshold-based counting and a manual stereology based technique) we demonstrate that overall synapse density is maintained in the neuropil, implicating synapse loss commensurate with the cortical atrophy known to occur in this model. Multi-photon in-vivo imaging reveals close to 30% loss of apical dendritic spines of individual pyramidal neurons suggesting these cells may be particularly vulnerable to tau-induced degeneration. Post-mortem, we confirm the presence of tau in dendritic spines of rTg4510-YFP mouse brain by array tomography. These data implicate tau-induced loss of a subset of synapses that may be accompanied by compensatory increases in other synaptic subtypes thereby preserving overall synapse density. Biochemical fractionation of synaptosomes from rTg4510 brain demonstrates a significant decrease in expression of several synaptic proteins, suggesting a functional deficit of remaining synapses in the rTg4510 brain. Together these data show morphological and biochemical synaptic consequences in response to tau over-expression in the rTg4510 mouse model.

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Section: Introductionmentioning

confidence: 69%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Synaptic alterations in the rTg4510 mouse model of tauopathy

Kopeikina

Polydoro

Tai

et al. 2013

J of Comparative Neurology

101

View full text Add to dashboard Cite

show abstract

“…There is also clear evidence that oligomerized tau is itself been identified in dendritic spines, where it has a tauopathy mutation-specific effect on synaptic function. [125][126][127] Thus the specific association and modification of tau with/by abnormal ligands may well play a key role in disease-associated tau misprocessing. Similarly, differential processing of PrP Sc in various TSEs suggest that TSE disease identity is to some extent dependent on differential interactions between PrP and ligands capable of stabilizing critical conformation intermediate states between PrP C and PrP Sc .…”

Section: Discussionmentioning

confidence: 99%

Is tau ready for admission to the prion club?

Hall

Patuto

2012

Prion

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A ggregation-prone proteins associated with neurodegenerative disease, such as α-synuclein and β-amyloid, now appear to share key prion-like features with mammalian prion protein, such as the ability to recruit normal proteins to aggregates and to translocate between neurons. These features may shed light on the genesis of stereotyped lesion development patterns in conditions such as Alzheimer disease and Lewy body dementia. We discuss the qualifications of tau protein as a possible "prionoid" mediator of lesion spread based on recent characterizations of the secretion, uptake and transneuronal transfer of human tau isoforms in a variety of tauopathy models, and in human patients. In particular, we consider (1) the possibility that prionoid behavior of misprocessed tau in neurodegenerative disease may involve other aggregation-prone proteins, including PrP itself and (2) whether "prionlike" tau lesion propagation might include mechanisms other than protein-protein templating. Prions and TSEs as a General Model for Neurodegenerative DiseaseThe formation of abnormal protein aggregates provides a common element in the pathogenesis of the vast majority of neurodegenerative diseases in humans, including Alzheimer disease (AD), non-AD tauopathies, α-synucleinopathies such as Lewy body dementia, transmissible spongiform encephalopathies (TSEs), trinucleotide repeat diseases and amyotrophic lateral sclerosis. Since aggregate formation is generally considered (and has been modeled) as a cell-autonomous Is tau ready for admission to the prion club?Garth F. Hall* and Brian A. PatutoDepartment of Biological Sciences; University of Massachusetts Lowell; Lowell, MA USA process, investigations into the pathogenesis of most neurodegenerative diseases have until very recently focused on cytotoxicity mechanisms associated with aggregate formation. As a consequence, intercellular aspects of most neurodegenerative diseases have been relatively neglected until very recently, and remain poorly understood. An exception to this pattern has been the study of TSEs, in which the consequences of prion protein (PrP) misfolding were addressed at the organismal level years before meaningful studies of cellular mechanisms could be attempted. This is because the transmissability and bizarre epidemiology of these diseases made a basic understanding of the transmission mechanism prerequisite to any meaningful studies of TSE cytopathogenesis. However, during the 1980s and 1990s, PrP was progressively established as the necessary and sufficient agent for TSE transmission via the promulgation, systematic testing and validation of the "Prion Hypothesis." [1][2][3] Since then, the study of PrP biology and pathobiology at the molecular, cellular and organismal levels has led to a deepening appreciation of the subtlety with which specific misfolded conformers of PrP can reproduce and propagate disease-specific properties that define specific TSEs. Investigators have recently begun to use PrP propagation in TSEs as a model to address interneuronal aspect...

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Longitudinal assessment of cerebral perfusion and vascular response to hypoventilation in a bigenic mouse model of Alzheimer's disease with amyloid and tau pathology

et al. 2018

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Alzheimer's disease is the most common neurodegenerative disease, and many patients also present with vascular dysfunction. In this study, we aimed to assess cerebral blood flow (CBF) and cerebrovascular response (CVR) as early, pre‐symptomatic (3 months of age), imaging markers in a bigenic model of Alzheimer's disease (APP.V717IxTau.P301L, biAT) and in the monogenic parental strains. We further developed our previously published combination of pulsed arterial spin labeling perfusion MRI and hypo‐ventilation paradigm, which allows weaning of the mice from the ventilator. Furthermore, the commonly used isoflurane anesthesia induces vasodilation and is thereby inherently a vascular challenge. We therefore assessed perfusion differences in the mouse models under free‐breathing isoflurane conditions. We report (i) that we can determine CBF and hypoventilation‐based CVR under ketamine/midazolam anesthesia and wean mice from the ventilator, making it a valuable tool for assessment of CBF and CVR in mice, (ii) that biAT mice exhibit lower cortical CBF than wild‐type mice at age 3 months, (iii) that CVR was increased in both biAT and APP.V717I mice but not in Tau.P301L mice, identifying the APP genotype as a strong influencer of brain CVR and (iv) that perfusion differences at baseline are masked by the widely used isoflurane anesthesia.

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Early Improved and Late Defective Cognition Is Reflected by Dendritic Spines in Tau.P301L Mice

Cited by 44 publications

References 44 publications

Synaptic alterations in the rTg4510 mouse model of tauopathy

Synaptic alterations in the rTg4510 mouse model of tauopathy

Is tau ready for admission to the prion club?

Longitudinal assessment of cerebral perfusion and vascular response to hypoventilation in a bigenic mouse model of Alzheimer's disease with amyloid and tau pathology

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