Faculty Bibliography

Soluble forms of oligomeric beta-amyloid (Aβ) are thought to play a central role in Alzheimer's disease (AD). Transgenic manipulation of methylation of the serine/threonine protein phosphatase, PP2A, was recently shown to alter the sensitivity of mice to AD-related impairments resulting from acute exposure to elevated levels of Aβ. In addition, eicosanoyl-5-hydroxytryptamide (EHT), a naturally occurring component from coffee beans that modulates PP2A methylation, was shown to confer therapeutic benefits in rodent models of AD and Parkinson's disease. Here, we tested the hypothesis that EHT protects animals from the pathological effects of exposure to elevated levels of soluble oligomeric Aβ. We treated mice with EHT-containing food at two different doses and assessed the sensitivity of these animals to Aβ-induced behavioral and electrophysiological impairments. We found that EHT administration protected animals from Aβ-induced cognitive impairments in both a radial-arm water maze and contextual fear conditioning task. We also found that both chronic and acute EHT administration prevented Aβ-induced impairments in long-term potentiation. These data add to the accumulating evidence suggesting that interventions with pharmacological agents, such as EHT, that target PP2A activity may be therapeutically beneficial for AD and other neurological conditions.

Numerous genes and molecular pathways are implicated in neurodegenerative proteinopathies, but their inter-relationships are poorly understood. We systematically mapped molecular pathways underlying the toxicity of alpha-synuclein (α-syn), a protein central to Parkinson's disease. Genome-wide screens in yeast identified 332 genes that impact α-syn toxicity. To "humanize" this molecular network, we developed a computational method, TransposeNet. This integrates a Steiner prize-collecting approach with homology assignment through sequence, structure, and interaction topology. TransposeNet linked α-syn to multiple parkinsonism genes and druggable targets through perturbed protein trafficking and ER quality control as well as mRNA metabolism and translation. A calcium signaling hub linked these processes to perturbed mitochondrial quality control and function, metal ion transport, transcriptional regulation, and signal transduction. Parkinsonism gene interaction profiles spatially opposed in the network (ATP13A2/PARK9 and VPS35/PARK17) were highly distinct, and network relationships for specific genes (LRRK2/PARK8, ATXN2, and EIF4G1/PARK18) were confirmed in patient induced pluripotent stem cell (iPSC)-derived neurons. This cross-species platform connected diverse neurodegenerative genes to proteinopathy through specific mechanisms and may facilitate patient stratification for targeted therapy.

Background: The assessment of HRQoL in RKSF is important for following disease course and evaluating treatment. Previously, using a non-disease specific instrument we showed that RKSF present differently, with the worst domain scores in cystinuria. These are the first follow-up data based on summary scores for adults in a cross-sectional comparison.
Method(s): RKSF were enrolled from 4 RKSC registries: primary hyperoxaluria, cystinuria, Dent disease and APRTd. HRQoL is measured with the generic non-disease specific SF-36v2. Results are norm-based scores (NBS) based on US Standard Population (Domain score mean = 50). Group means < 47 indicate the presence of impaired functioning in associated dimension.
Result(s): We scored 545 surveys of the adult population at different time points, adjusted for the last stone event and compared the Physical and Mental Component Scores (PCS and MCS). We found the lowest PCS in Dent, and the highest in PH. The lowest MCS was found in cystinuria, the highest was found in PH. Low PCS indicate restrictions in self-care, physical, social and role activities; bodily pain, tiredness and poor rated health. Low MCS are associated with frequent psychological distress, social and role disability due to emotional problems, and poor rated health. Participants with cystinuria reported more stone events with related procedures than other RKSF (X2 (9) 23.375, p=.005).
Conclusion(s): HRQoL in RKSF is influenced by stone events and can be assessed with a non-disease specific SF-36v2. Adjusting for time between the survey and last event allows for the interpretation of more meaningful HRQoL profiles. The time from the last stone event and related procedures affect HRQOL in RKSF significantly. (Table Presented)

Background: Urine chemistry is a determinant of stone formation in cystinuria. We previously showed that positive cystine capacity (CysCap), a measure of higher cystine solubility, led to fewer stone events. We queried the RKSC Cystinuria Registry to determine urinary and medication variables associated with positive (CysCap+), rather than negative (CysCap-) values.
Method(s): This is the 1st report from the Cystinuria Registry, with data on 300 people with cystinuria (142 males, 158 females; age at enrollment 38 +/- 17 years). 112 participants had 306 determinations of CysCap, measured by Litholink (Chicago, IL). In this cross-sectional study we compared variables associated with CysCap+ vs CysCap-.
Result(s): Lower urine Na (r=0.48; Fig 1A) and creatinine (r=0.62, not shown) were associated with lower 24h urine cystine (UC; P<0.001). Increasing CysCap values were seen with increasing urine pH (rs=0.45, Fig 1B), volume (rs=0.44) and decreasing UC (rs=-0.44 Fig 1C; all P<0.001). Dividing Cyscap determinations into CysCap+ and CysCapgroups (Table), only higher urine volume and greater daily citrate doses were different. Relatively few participants were taking citrate or tiopronin.
Conclusion(s): Higher urine pH and volume and lower UC were associated with less lithogenic urine; lower UC was seen with less Na and creatinine. Higher volume and citrate doses distinguished patients with less lithogenic urine. Many patients with cystinuria may be undertreated and would benefit from better dietary adherence. (Table Presented)

Background: Multiple bacterial species are capable of degrading oxalate in vitro. Certain taxa degrade oxalate as their sole source of energy and carbon (e.g. Oxalobacter formigenes), whereas others use oxalate as an auxiliary carbon source. For oxalate metabolism, it is not yet well-understood how genomic potential relates to transcriptional regulation. We asked whether the human gut could have a community of oxalatedegrading taxa working synergistically to diminish the effects of this toxic metabolite. Our hypothesis is that oxalate metabolism is regulated by a multi-organism oxalatedegrading community (oxalobiome) that is dominated by specialist oxalate degraders.
Method(s): We used data from 2 public databases: (i)8 healthy subjects in the USA; and (ii)471 healthy subjects in the Netherlands as part of the Human Functional Genomic Project (HFGP). Both collected fecal samples for metagenomic and/or metatranscriptomic high throughput sequencing. Using HUMAnN2 with customized settings, we profiled the metabolic activity of oxalate-degrading bacterial species. Output from these analyses was expressed as Reads per Kilobase per Million mapped reads (RPKM).
Result(s): We identified the oxalate degradation pathway (ODP) in the metagenome and metatranscriptome of all 8 subjects. Mean ODP is 35.3+/-28.1 and 90.1+/-43.5 RPKM in the metagenome and the metatranscriptome, respectively, indicating active expression. O. formigenes, E. coli, and unclassified bacteria were present in metagenomic and metatranscriptomic reads. B. dentium had detectable ODP in its genome but was not transcribing it. In the HFGP database, we identified ODP in 328 subjects of the 471 tested (70%) (Mean=18.1+/-2.1 RPKM). ODP was detected in B. animalis, B. dentium, B. pseudocatenulatum, E.coli/Shigella, L. acidophilus, L. gasseri, L. mucosae, O. formigenes and unclassified bacteria. ODP was examined in the metagenome of 265 females (Mean ODP= 21.7+/-3.3) and 200 males (Mean ODP=13.3+/-1.9 RPKM; p=0.04 by unpaired t test).
Conclusion(s): We have identified a community of bacteria with the potential to degrade oxalate in healthy humans and species actively transcribing ODP. These include E.coli, which might be a common contributor of oxalate degradation in humans. The sex differences in ODP is consistent with the ~ 2:1 male/female incidence and prevalence of calcium oxalate stones

Background: USD is a preventable disease characterized by significant risk of recurrence. A "cascade of care" shows how many patients are lost to follow-up at diagnosis, referral, and treatment and is a useful tool in delivering HIV care. We can analyze our success, or failure, in the secondary prevention of kidney stones and retention of patients by constructing a cascade of care.
Method(s): We abstracted data from observational studies to identify impediments to care of patients with USD Results: In the US there are about 1.2 million ER visits per year. 37% of patients diagnosed with stones receive a follow-up consultation with a urologist and fewer see a nephrologist. Although 24h urine collection results may decrease stone recurrence rate, only 7.4% do them. 50% of patients experience a recurrent 2nd episode within 5 years. Of these 24% undergo a complete evaluation, 18% are referred to a nephrologist and 13.8% are prescribed medical therapy. 30% remain adherent to this pharmacotherapy. Of patients that are adherent 27% have lower odds of an ER visit than non-adherent patients. The cascade of care demonstrates that a low prevalence of patients receive proper followup. The impediments to the care of patients with kidney stones are (1) the unrecognized comorbidities of stones (2) disconnect between the ER and stone experts and (3) the low prevalence of 24h urine collections and prescribed medical therapy.
Conclusion(s): It is important to identify loci in the cascade of care that could represent opportunities to change practice. Prescription of appropriate fluid therapy and dietary changes and a referral to an expert should 1st be initiated by the ER. The low prevalence of 24h urine collections may reflect that the data are intimidating for some. Empiric therapy for calcium stones with fluids, diet, thiazides and potassium citrate may be a rational therapy to achieve significant supersaturation reductions and could be compared with targeted medical therapy in a randomized controlled trial. A greater effort needs to be devoted to develp a comprehensive flow of participants to retain patients in the cascade of care for USD. (Table Presented)

We develop a method for comparing hierarchical image representations in terms of their ability to explain perceptual sensitivity in humans. Specifically, we utilize Fisher information to establish a model-derived prediction of sensitivity to local perturbations of an image. For a given image, we compute the eigenvectors of the Fisher information matrix with largest and smallest eigenvalues, corresponding to the model-predicted most- and least-noticeable image distortions, respectively. For human subjects, we then measure the amount of each distortion that can be reliably detected when added to the image. We use this method to test the ability of a variety of representations to mimic human perceptual sensitivity. We find that the early layers of VGG16, a deep neural network optimized for object recognition, provide a better match to human perception than later layers, and a better match than a 4-stage convolutional neural network (CNN) trained on a database of human ratings of distorted image quality. On the other hand, we find that simple models of early visual processing, incorporating one or more stages of local gain control, trained on the same database of distortion ratings, provide substantially better predictions of human sensitivity than either the CNN, or any combination of layers of VGG16.

The entorhinal cortex (EC) is affected early in Alzheimer's disease, an illness defined by a co-occurrence of tau and amyloid-related pathologies. How the co-occurrence of these pathologies in the EC affects the hippocampal circuit remains unknown. Here we address this question by performing electrophysiological analyses of the EC circuit in mice that express mutant human amyloid precursor protein (hAPP) or tau (hTau), or both in the EC. We show that the alterations in the hippocampal circuit are divergent, with hAPP increasing but hTau decreasing neuronal/circuit excitability. Most importantly, mice co-expressing hAPP and hTau show that hTau has a dominant effect, dampening the excitatory effects of hAPP. Additionally, compensatory synaptic downscaling, in response to increased excitability in EC was observed in subicular neurons of hAPP mice. Based on simulations, we propose that EC interneuron pruning can account for both EC hyperexcitability and subicular synaptic downscaling found in mice expressing hAPP.