Using R to improve rigour and transparency in translational neuroscience-or is it just a rabbit hole?

Our Editor explores the use of R for improving rigour, reproducibility and transparency in translational neuroscience. She also provides an example of how to waste enormous amounts of time playing with data in R instead of doing her day job

Alzheimer's disease: synapses gone cold

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by insidious cognitive decline and memory dysfunction. Synapse loss is the best pathological correlate of cognitive decline in AD and mounting evidence suggests that AD is primarily a disease of synaptic dysfunction. Soluble oligomeric forms of amyloid beta (Aβ), the peptide that aggregates to form senile plaques in the brain of AD patients, have been shown to be toxic to neuronal synapses both in vitro and in vivo. Aβ oligomers inhibit long-term potentiation (LTP) and facilitate long-term depression (LTD), electrophysiological correlates of memory formation. Furthermore, oligomeric Aβ has also been shown to induce synapse loss and cognitive impairment in animals. The molecular underpinnings of these observations are now being elucidated, and may provide clear therapeutic targets for effectively treating the disease. Here, we review recent findings concerning AD pathogenesis with a particular focus on how Aβ impacts synapses

Tangle-bearing neurons survive despite disruption of membrane integrity in a mouse model of tauopathy

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 was labeled with the caspase probe or with PI fluorescence. These markers of cell stress were localized in the same cells and appeared to be specifically within NFT-bearing neurons. Contrary to expectations, the PI-stained neurons did not die over a day of observation; the presence of Hoechst-positive nuclei in them on the subsequent day indicated that the NFT-associated membrane disruption suggested by PI staining and caspase activation do not lead to acute death of neurons in this tauopathy model. This unique combination of in vivo multiphoton imaging with markers of cell death and pathologic alteration is a powerful tool for investigating neuronal damage associated with neurofibrillary pathology

Calcineurin inhibition with FK506 ameliorates dendritic spine density deficits in plaque-bearing Alzheimer model mice

Synapse loss is the strongest correlate of cognitive decline in Alzheimer’s disease, and synapses are an attractive therapeutic target due to their plastic nature that allows for potential recovery with intervention. We have previously demonstrated in transgenic mice that form senile plaques that dendrites surrounding plaques become dystrophic and lose postsynaptic dendritic spines. Furthermore, we found strong evidence that plaque-associated dendritic changes are mediated by calcineurin, a calcium-dependent phosphatase involved in cell signaling, using in vitro models and genetically encoded inhibitors in mouse models. In this study, we pharmacologically inhibited calcineurin with FK506 treatment to test the hypothesis that calcineurin inhibition will allow recovery of plaque-associated synapse loss. We found that in plaque bearing transgenic mice, short term (1 week) FK506 treatment results in an amelioration of dendritic spine loss. We also observe an effect on spine morphology in wild-type mice with FK506 treatment. These data show that systemic FK506 administration, and hence calcineurin inhibition, may be neuroprotective for amyloid beta induced synaptic alterations

Soluble tau species, not neurofibrillary aggregates, disrupt neural system integration in a tau transgenic model

Neurofibrillary tangles are a feature of Alzheimer disease and other tauopathies, and while they are generally believed to be markers of neuronal pathology, there is little evidence evaluating whether tangles directly impact neuronal function. To investigate the response of cells in hippocampal circuits to complex behavioral stimuli, we used an environmental enrichment paradigm to induce expression of an immediate-early gene, Arc, in the rTg4510 mouse model of tauopathy. These mice reversibly overexpress P301L tau and exhibit substantial neurofibrillary tangle deposition, neuronal loss, and memory deficits. Employing fluorescent in situ hybridization to detect Arc mRNA, we found that rTg4510 mice have impaired hippocampal Arc expression both without stimulation and in response to environmental enrichment; this likely reflects the combination of functional impairments of existing neurons and loss of neurons. However, tangle-bearing cells were at least as likely as non-tangle-bearing neurons to exhibit Arc expression in response to enrichment. Transgene suppression with doxycycline for 6 weeks resulted in increased percentages of Arc-positive cells in rTg4510 brains compared to untreated transgenics, restoring enrichment-induced Arc mRNA levels to that of wild-type controls despite the continued presence of neurofibrillary pathology. We interpret these data to indicate that soluble tau contributes to impairment of hippocampal function, while tangles do not preclude neurons from responding in a functional circuit

Propagation of tau pathology in Alzheimer’s disease: identification of novel therapeutic targets

Accumulation and aggregation of the microtubule-associated protein tau are a pathological hallmark of neurodegenerative disorders such as Alzheimer’s disease (AD). In AD, tau becomes abnormally phosphorylated and forms inclusions throughout the brain, starting in the entorhinal cortex and progressively affecting additional brain regions as the disease progresses. Formation of these inclusions is thought to lead to synapse loss and cell death. Tau is also found in the cerebrospinal fluid (CSF), and elevated levels are a biomarker for AD. Until recently, it was thought that the presence of tau in the CSF was due to the passive release of aggregated tau from dead or dying tangle-bearing neurons. However, accumulating evidence from different AD model systems suggests that tau is actively secreted and transferred between synaptically connected neurons. Transgenic mouse lines with localized expression of aggregating human tau in the entorhinal cortex have demonstrated that, as these animals age, tau becomes mislocalized from axons to cell bodies and dendrites and that human tau-positive aggregates form first in the entorhinal cortex and later in downstream projection targets. Numerous in vitro and in vivo studies have provided insight into the mechanisms by which tau may be released and internalized by neurons and have started to provide insight into how tau pathology may spread in AD. In this review, we discuss the evidence for regulated tau release and its specific uptake by neurons. Furthermore, we identify possible therapeutic targets for preventing the propagation of tau pathology, as inhibition of tau transfer may restrict development of tau tangles in a small subset of neurons affected in early stages of AD and therefore prevent widespread neuron loss and cognitive dysfunction associated with later stages of the disease

A single dose of passive immunotherapy has extended benefits on synapses and neurites in an Alzheimer's disease mouse model

Alzheimer’s disease (AD) is a neurodegenerative disorder that impairs memory and cognition. One of the major neuropathological hallmarks is the accumulation of the extracellular senile plaques that are mainly composed of amyloid beta (Aβ) protein. Plaques are associated with synapse loss, dystrophic neurites and altered neurite trajectories. A reversal of such morphological changes has been observed days after single dose anti Aβ immunotherapy. In this study we investigated the extended effects of a single dose of passive anti Aβ immunotherapy on morphological changes associated with senile plaques. We found that although plaque burden was not reduced 30 days after immunotherapy, there were fewer dystrophic neurites around each plaque, a recovery of synapse density, and normalization of neurite curvature near plaques. Taken together these results suggest that single dose immunotherapy is sufficient to cause lasting benefits to the morphology of cortical neurons, implying substantial plasticity of neural circuits despite the continued presence of plaques

Associations between cerebrospinal fluid markers and cognition in ageing and dementia: A systematic review

A biomarker associated with cognition in neurodegenerative dementias would aid in the early detection of disease progression, complement clinical staging and act as a surrogate endpoint in clinical trials. The current systematic review evaluates the association between cerebrospinal fluid protein markers of synapse loss and neuronal injury and cognition. We performed a systematic search which revealed 67 studies reporting an association between cerebrospinal fluid markers of interest and neuropsychological performance. Despite the substantial heterogeneity between studies, we found some evidence for an association between neurofilament‐light and worse cognition in Alzheimer's diseases, frontotemporal dementia and typical cognitive ageing. Moreover, there was an association between cerebrospinal fluid neurogranin and cognition in those with an Alzheimer's‐like cerebrospinal fluid biomarker profile. Some evidence was found for cerebrospinal fluid neuronal pentraxin‐2 as a correlate of cognition across dementia syndromes. Due to the substantial heterogeneity of the field, no firm conclusions can be drawn from this review. Future research should focus on improving standardization and reporting as well as establishing the importance of novel markers such as neuronal pentraxin‐2 and whether such markers can predict longitudinal cognitive decline