Alix de Calignon
Harvard University
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Alix de Calignon.
Neuron | 2012
Alix de Calignon; Manuela Polydoro; Marc Suárez-Calvet; Christopher M. William; David H. Adamowicz; Kathy J. Kopeikina; Rose Pitstick; Naruhiko Sahara; Karen H. Ashe; George A. Carlson; Tara L. Spires-Jones; Bradley T. Hyman
Neurofibrillary tangles advance from layer II of the entorhinal cortex (EC-II) toward limbic and association cortices as Alzheimers disease evolves. However, the mechanism involved in this hierarchical pattern of disease progression is unknown. We describe a transgenic mouse model in which overexpression of human tau P301L is restricted to EC-II. Tau pathology progresses from EC transgene-expressing neurons to neurons without detectable transgene expression, first to EC neighboring cells, followed by propagation to neurons downstream in the synaptic circuit such as the dentate gyrus, CA fields of the hippocampus, and cingulate cortex. Human tau protein spreads to these regions and coaggregates with endogenous mouse tau. With age, synaptic degeneration occurs in the entorhinal target zone and EC neurons are lost. These data suggest that a sequence of progressive misfolding of tau proteins, circuit-based transfer to new cell populations, and deafferentation induced degeneration are part of a process of tau-induced neurodegeneration.
Nature | 2008
Melanie Meyer-Luehmann; Tara L. Spires-Jones; Claudia M. Prada; Monica Garcia-Alloza; Alix de Calignon; Anete Rozkalne; Jessica Koenigsknecht-Talboo; David M. Holtzman; Brian J. Bacskai; Bradley T. Hyman
Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer’s disease. A fundamental tenet of the amyloid hypothesis of Alzheimer’s disease is that the deposition of amyloid-β precedes and induces the neuronal abnormalities that underlie dementia. This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques. The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice. Here we show that plaques form extraordinarily quickly, over 24 h. Within 1–2 days of a new plaque’s appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.
Nature | 2010
Alix de Calignon; Leora M. Fox; Rose Pitstick; George A. Carlson; Brian J. Bacskai; Tara L. Spires-Jones; Bradley T. Hyman
Studies of post-mortem tissue have shown that the location of fibrillar tau deposits, called neurofibrillary tangles (NFT), matches closely with regions of massive neuronal death, severe cytological abnormalities, and markers of caspase activation and apoptosis, leading to the idea that tangles cause neurodegeneration in Alzheimer’s disease and tau-related frontotemporal dementia. However, using in vivo multiphoton imaging to observe tangles and activation of executioner caspases in living tau transgenic mice (Tg4510 strain), we find the opposite: caspase activation occurs first, and precedes tangle formation by hours to days. New tangles form within a day. After a new tangle forms, the neuron remains alive and caspase activity seems to be suppressed. Similarly, introduction of wild-type 4-repeat tau (tau-4R) into wild-type animals triggered caspase activation, tau truncation and tau aggregation. Adeno-associated virus-mediated expression of a construct mimicking caspase-cleaved tau into wild-type mice led to the appearance of intracellular aggregates, tangle-related conformational- and phospho-epitopes, and the recruitment of full-length endogenous tau to the aggregates. On the basis of these data, we propose a new model in which caspase activation cleaves tau to initiate tangle formation, then truncated tau recruits normal tau to misfold and form tangles. Because tangle-bearing neurons are long-lived, we suggest that tangles are ‘off pathway’ to acute neuronal death. Soluble tau species, rather than fibrillar tau, may be the critical toxic moiety underlying neurodegeneration.
Trends in Neurosciences | 2009
Tara L. Spires-Jones; William H. Stoothoff; Alix de Calignon; Phillip B. Jones; Bradley T. Hyman
Neurodegenerative tauopathies are marked by their common pathologic feature of aggregates formed of hyperphosphorylated tau protein, which are associated with synapse and neuronal loss. Changes in tau conformation result in both loss of normal function and gain of fibrillogenicity that leads to aggregation. Here, we discuss the pathophysiology of tau and emerging evidence of how changes in this protein might ultimately lead to neuronal death. In particular, based on recent evidence, we propose that a non-apoptotic caspase-associated form of death is occurring in tauopathy.
The Journal of Neuroscience | 2008
Tara L. Spires-Jones; Alix de Calignon; Toshifumi Matsui; Cindy Zehr; Rose Pitstick; Hai Yan Wu; Jennifer D. Osetek; Phillip B. Jones; Brian J. Bacskai; Mel B. Feany; George A. Carlson; Karen H. Ashe; Jada Lewis; Bradley T. Hyman
Accumulation of neurofibrillary tangles (NFTs) in Alzheimers disease correlates with neuronal loss and cognitive decline, but the precise relationship between NFTs and neuronal death and downstream mechanisms of cell death remain unclear. Caspase cleaved products accumulate in tangles, implying that tangles may contribute to apoptotic neuronal death. To test this hypothesis, we developed methods using multiphoton imaging to detect both neurofibrillary pathology and caspase activation in the living mouse brain. We examined rTg4510 mice, a reversible mouse model of tauopathy that develops tangles and neuronal loss. Only a small percentage of imaged neurons were caspase activity positive, but the vast majority of the cells with active caspases contained NFTs. We next tested the hypothesis that caspase activation led to acute, apoptotic neuronal death. Caspase positive cell bodies did not degenerate over hours of imaging, despite the presence of activated executioner caspases. Suppression of the transgene, which stops ongoing death, did not suppress caspase activity. Finally, histochemical assessments revealed evidence of caspase-cleaved tau, but no TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling) positive or apoptotic nuclei. With the novel technique of observing NFTs and caspase activation in the living brain, we demonstrate that aggregated tau in neurons can be associated with caspase activation, but that caspase activation is not sufficient to cause acute neuronal death in this model.
Neurobiology of Disease | 2009
Tara L. Spires-Jones; Matthew L. Mielke; Anete Rozkalne; Melanie Meyer-Luehmann; Alix de Calignon; Brian J. Bacskai; Dale Schenk; Bradley T. Hyman
Senile plaque-associated changes in neuronal connectivity such as altered neurite trajectory, dystrophic swellings, and synapse and dendritic spine loss are thought to contribute to cognitive dysfunction in Alzheimers disease and mouse models. Immunotherapy to remove amyloid beta is a promising therapy that causes recovery of neurite trajectory and dystrophic neurites over a period of days. The acute effects of immunotherapy on neurite morphology at a time point when soluble amyloid has been cleared but dense plaques are not yet affected are unknown. To examine whether removal of soluble amyloid beta (Abeta) has a therapeutic effect on dendritic spines, we explored spine dynamics within 1 h of applying a neutralizing anti Abeta antibody. This acute treatment caused a small but significant increase in dendritic spine formation in PDAPP brain far from plaques, without affecting spine plasticity near plaques or average dendritic spine density. These data support the hypothesis that removing toxic soluble forms of amyloid-beta rapidly increases structural plasticity possibly allowing functional recovery of neural circuits.
Journal of Neuropathology and Experimental Neurology | 2009
Alix de Calignon; Tara L. Spires-Jones; Rose Pitstick; George A. Carlson; Bradley T. Hyman
Neurofibrillary tangles (NFTs) are associated with neuronal loss and correlate with cognitive impairment in Alzheimer disease, but how NFTs relate to neuronal death is not clear. We studied cell death in Tg4510 mice that reversibly express P301L mutant human tau and accumulate NFTs using in vivo multiphoton imaging of neurofibrillary pathology, propidium iodide (PI) incorporation into cells, caspase activation, and DNA labeling. We first observed that in live mice, a minority of neurons were labeled with the caspase probe or with PI fluorescence. These markers of cell stress were localized in the same cells and appeared specifically within NFT-bearing neurons. Contrary to expectations, the PI-stained neurons did not die during a day of observation; the presence of Hoechst-positive nuclei in them on the subsequent day indicated that the NFT-associated membrane disruption, as suggested by PI staining, and caspase activation do not lead to immediate death of neurons in this tauopathy model. This unique combination of in vivo multiphoton imaging with markers of cell death and pathological alteration is a powerful tool for investigating neuronal damage associated with neurofibrillary pathology.
The Journal of Neuroscience | 2013
Manuela Polydoro; Alix de Calignon; Marc Suárez-Calvet; Laura Sanchez; Kevin R. Kay; Samantha B. Nicholls; Allyson D. Roe; Rose Pitstick; George A. Carlson; Teresa Gomez-Isla; Tara L. Spires-Jones; Bradley T. Hyman
Neurofibrillary tangles (NFTs), a marker of neuronal alterations in Alzheimers disease (AD) and other tauopathies, are comprised of aggregates of hyperphosphorylated tau protein. We recently studied the formation of NFTs in the entorhinal cortex (EC) and their subsequent propagation through neural circuits in the rTgTauEC mouse model (de Calignon et al., 2012). We now examine the consequences of suppressing transgene expression with doxycycline on the NFT-associated pathological features of neuronal system deafferentation, NFT progression and propagation, and neuronal loss. At 21 months of age we observe that EC axonal lesions are associated with an abnormal sprouting response of acetylcholinesterase (AChE)-positive fibers, a phenotype reminiscent of human AD. At 24 months, NFTs progress, tau inclusions propagate to the dentate gyrus, and neuronal loss is evident. Suppression of the transgene expression from 18 to 24 months led to reversal of AChE sprouting, resolution of Gallyas-positive and Alz50-positive NFTs, and abrogation of progressive neuronal loss. These data suggest that propagation of NFTs, as well as some of the neural system consequences of NFTs, can be reversed in an animal model of NFT-associated toxicity, providing proof in principle that these lesions can be halted, even in established disease.
Handbook of Clinical Neurology | 2008
Teresa Gomez-Isla; Tara L. Spires; Alix de Calignon; Bradley T. Hyman
Publisher Summary This chapter emphasizes that neurofibrillary tangles correlate tightly with anatomical regions affected clinically and correlate well numerically with both neuronal loss and severity of cognitive changes. The initial involvement by neurofibrillary tangles involves the entorhinal cortex and subsequently CA1/ subiculum of hippocampus, other limbic and high order association cortices, and ascending neurotransmitter specific systems. This parallels in a general way the initial symptoms of short-term memory impairments followed by more generalized dementia with prominent language impairments and so forth. The chapter also focuses on the neurofibrillary tangles that are most prominent in a laminar distribution matching well with putative cortical-cortical projection neurons. There is a loss of synapses, dendritic spines, and marked abnormalities of dendrite and axonal morphology that leads to disconnection phenomena and at least loss of synchrony in major cortical projections. The chapter concludes that recent evidence suggests that dystrophic neurites around plaques, which are often axonal in origin, and even morphologically changed axons, have functional impairments in axon trafficking, although the details of this are still uncertain. To this effect on neural processes, plaques clearly attract and activate astrocytic or microglial cells in their immediate vicinity, leading to a wide cascade of potentially damaging inflammatory phenomena.
Methods | 2011
Tara L. Spires-Jones; Alix de Calignon; Melanie Meyer-Luehmann; Brian J. Bacskai; Bradley T. Hyman
Aggregation of amyloid beta peptide into senile plaques and hyperphosphorylated tau protein into neurofibrillary tangles in the brain are the pathological hallmarks of Alzheimers disease. Despite over a century of research into these lesions, the exact relationship between pathology and neurotoxicity has yet to be fully elucidated. In order to study the formation of plaques and tangles and their effects on the brain, we have applied multiphoton in vivo imaging of transgenic mouse models of Alzheimers disease. This technique allows longitudinal imaging of pathological aggregation of proteins and the subsequent changes in surrounding neuropil neurodegeneration and recovery after therapeutic interventions.