Valerie Guss

Bristol-Myers Squibb (United States)

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Co-Authors

Craig Polson

Bristol-Myers Squibb (United States)

Jere E. Meredith

Bristol-Myers Squibb (United States)

Donna M. Barten

Bristol-Myers Squibb (United States)

Jason A. Corsa

Bristol-Myers Squibb (Germany)

Charles F. Albright

Bristol-Myers Squibb (United States)

Michael K. Ahlijanian

Ribon Therapeutics (United States)

Jeremy H. Toyn

Bristol-Myers Squibb (United States)

John E. Macor

Bristol-Myers Squibb (Germany)

Ming Zheng

MicroPort (China)

Susan B. Roberts

Bristol-Myers Squibb (United States)

Cooperative Institutions

Bristol-Myers Squibb (United States)

169

Bristol-Myers Squibb (Germany)

120

Pfizer (United States)

Yale University

GlaxoSmithKline (United States)

Eisai (United States)

Teva Pharmaceuticals (United States)

Hartford Financial Services (United States)

University of California, San Francisco

Merck & Co., Inc., Rahway, NJ, USA (United States)

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Divergent CSF alterations in two common tauopathies: Alzheimer's disease and progressive supranuclear palsy

Journal of Neurology Neurosurgery & Psychiatry (2014)

Dana Wagshal S. Sankaranarayanan Valerie Guss T. A. Hall F. Berisha

Background

Elevated CSF τ is considered a biomarker of neuronal injury in newly developed Alzheimer9s disease (AD) and mild cognitive impairment (MCI) criteria. However, previous studies have failed to detect alterations of τ species in other primary tauopathies. We assessed CSF τ protein abnormalities in AD, a tauopathy with prominent Aβ pathology, and progressive supranuclear palsy (PSP), a primary tauopathy characterised by deposition of four microtubule-binding repeat (4R) τ with minimal Aβ pathology.

Methods

26 normal control (NC), 37 AD, and 24 patients with PSP participated in the study. AD and PSP were matched for severity using the clinical dementia rating sum of boxes (CDR-sb) scores. The INNO BIA AlzBio3 multiplex immunoassay was used to measure CSF Aβ, total τ, and ptau181. Additional, novel ELISAs targeting different N-terminal and central τ epitopes were developed to examine CSF τ components and to investigate interactions between diagnostic group, demographics and genetic variables.

Results

PSP had lower CSF N-terminal and C-terminal τ concentrations than NC and AD measured with the novel τ ELISAs and the standard AlzBio3 τ and ptau assays. AD had higher total τ and ptau levels than NC and PSP. There was a gender by diagnosis interaction in AD and PSP for most τ species, with lower concentrations for male compared to female patients.

Conclusions

CSF τ fragment concentrations are different in PSP compared with AD despite the presence of severe τ pathology and neuronal injury in both disorders. CSF τ concentration likely reflects multiple factors in addition to the degree of neuronal injury.

10.1136/jnnp-2014-308004

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Citations (121)

Dynamics of β-Amyloid Reductions in Brain, Cerebrospinal Fluid, and Plasma of β-Amyloid Precursor Protein Transgenic Mice Treated with a γ-Secretase Inhibitor

Journal of Pharmacology and Experimental Therapeutics (2004)

Donna M. Barten Valerie Guss Jason A. Corsa Alice Loo Steven Hansel

γ-Secretase inhibitors are one promising approach to the development of a therapeutic for Alzheimer9s disease (AD). γ-Secretase inhibitors reduce brain β-amyloid peptide (Aβ), which is believed to be a major contributor in the etiology of AD. Transgenic mice overexpressing the human β-amyloid precursor protein (APP) are valuable models to examine the dynamics of Aβ changes with γ-secretase inhibitors in plaque-free and plaque-bearing animals. BMS-299897 2-[(1R)-1-[[(4-chlorophenyl)sulfony](2,5-difluorophenyl)amino]ethyl]-5-fluorobenzenepropanoic acid, a γ-secretase inhibitor, showed dose- and time dependent reductions of Aβ in brain, cerebrospinal fluid (CSF), and plasma in young transgenic mice, with a significant correlation between brain and CSF Aβ levels. Because CSF and brain interstitial fluid are distinct compartments in composition and location, this correlation could not be assumed. In contrast, aged transgenic mice with large accumulations of Aβ in plaques showed reductions in CSF Aβ in the absence of measurable changes in plaque Aβ in the brain after up to 2 weeks of treatment. Hence, CSF Aβ levels were a valuable measure of γ-secretase activity in the central nervous system in either the presence or absence of plaques. Transgenic mice were also used to examine potential side effects due to Notch inhibition. BMS-299897 was 15-fold more effective at preventing the cleavage of APP than of Notch in vitro. No changes in the maturation of CD8+ thymocytes or of intestinal goblet cells were observed in mice treated with BMS-299897, showing that it is possible for γ-secretase inhibitors to reduce brain Aβ without causing Notch-mediated toxicity.

Interstitial fluid

Amyloid (mycology)

P3 peptide

10.1124/jpet.104.075408

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Citations (159)

P1‐009: Novel human CSF tau‐fragment and pTau assays for distinguishing Alzheimer's from control subjects

Alzheimer s & Dementia (2012)

Sethu Sankaranarayanan Jere E. Meredith Valerie Guss Alan Xu‐Lin Holly Soares

Alzheimer's disease (AD) patients show an early decline in CSF Aβ42 and an increase in CSF Total Tau and pT181 Tau, compared to age-matched control subjects. These CSF endpoints have been predictive in the transition of subjects from incipient / prodromal AD to dementia. Evidence has also been growing that CSF Tau may exist as smaller fragments with multiple posttranslational modifications. To better understand the nature of Tau in CSF we systematically evaluated Tau-specific antibodies for identification and development of novel Tau fragment and pTau assays that can further refine classification of AD from control subjects. We have developed 4 Tau fragment ELISA assays using antibody pairs that are specific to the mid-domain, the amino (N)-terminal region (N-terminus to the beginning of microtubule repeat domain of Tau), and the carboxy (C)-terminus of Tau (mid to C-terminus of Tau), respectively. In addition, we have developed a novel pT231 Tau assay and an N-terminal fragment version of pT181 Tau assay to complement the well established mid-domain pT181 Tau assay. Fit for purpose validation of assays was done prior to examination of AD and age-matched control CSF samples. We observed 2–3 fold greater levels of mid domain containing Tau when compared to N-terminus containing Tau in control human CSF, while minimal signal was observed with the C-terminal specific Tau assay. In AD subjects, a 3–4 fold elevation of the mid-domain of Tau is observed while ∼2 fold elevation of the N-terminal Tau domain was observed compared to age-matched control subjects. Consistent with these results, we observed 3–4 fold elevation of the mid-domain pT181 and pT231 Tau endpoints while the N-terminal version of pT181 Tau showed ∼2 fold elevation in AD subjects. These results indicate higher levels of mid-domain and N-terminal containing Tau fragments and phospho-Tau in AD CSF. While mechanisms underlying the generation of these fragments are unclear, these assays will enable better characterization of disease-specific changes in Tau fragments and pTau in CSF from CNS disorders and may provide novel pharmacodynamic biomarkers for Tau-based therapies.

Tau protein

Tau Pathology

C-terminus

10.1016/j.jalz.2012.05.284

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Citations (1)

Identification and characterization of a MAPT-targeting locked nucleic acid antisense oligonucleotide therapeutic for tauopathies

Molecular Therapy — Nucleic Acids (2022)

Amy Easton Marianne L. Jensen Congwei Wang Peter Hagedorn Yu-Wen Li

Tau is a microtubule-associated protein (MAPT, tau) implicated in the pathogenesis of tauopathies, a spectrum of neurodegenerative disorders characterized by accumulation of hyperphosphorylated, aggregated tau. Because tau pathology can be distinct across diseases, a pragmatic therapeutic approach may be to intervene at the level of the tau transcript, as it makes no assumptions to mechanisms of tau toxicity. Here we performed a large library screen of locked-nucleic-acid (LNA)-modified antisense oligonucleotides (ASOs), where careful tiling of the MAPT locus resulted in the identification of hot spots for activity in the 3' UTR. Further modifications to the LNA design resulted in the generation of ASO-001933, which selectively and potently reduces tau in primary cultures from hTau mice, monkey, and human neurons. ASO-001933 was well tolerated and produced a robust, long-lasting reduction in tau protein in both mouse and cynomolgus monkey brain. In monkey, tau protein reduction was maintained in brain for 20 weeks post injection and corresponded with tau protein reduction in the cerebrospinal fluid (CSF). Our results demonstrate that LNA-ASOs exhibit excellent drug-like properties and sustained efficacy likely translating to infrequent, intrathecal dosing in patients. These data further support the development of LNA-ASOs against tau for the treatment of tauopathies.

Tau protein

Tauopathy

Tau Pathology

Pathogenesis

Antisense therapy

10.1016/j.omtn.2022.07.027

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Citations (12)

An Assessment of the Effects of Serotonin 6 (5-HT6) Receptor Antagonists in Rodent Models of Learning

Journal of Pharmacology and Experimental Therapeutics (2003)

Mark D. Lindner Donald B. Hodges John B. Hogan Anitra F. Orie Jason A. Corsa

Antagonists of serotonin 6 (5-HT6) receptors have been reported to enhance cognition in animal models of learning, although this finding has not been universal. We have assessed the therapeutic potential of the specific 5-HT6 receptor antagonists 4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide (Ro 04-6790) and 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046) in rodent models of cognitive function. Although mice express the 5-HT6 receptor and the function of this receptor has been investigated in mice, all reports of activity with 5-HT6 receptor antagonists have used rat models. In the present study, receptor binding revealed that the pharmacological properties of the mouse receptor are different from the rat and human receptor: Ro 04-6790 does not bind to the mouse 5-HT6 receptor, so all in vivo testing included in the present report was conducted in rats. We replicated previous reports that 5-HT6 receptor antagonists produce a stretching syndrome previously shown to be mediated through cholinergic mechanisms, but Ro 04-6790 and SB-271046 failed to attenuate scopolamine-induced deficits in a test of contextual fear conditioning. We also failed to replicate the significant effects reported previously in both an autoshaping task and in a version of the Morris water maze. The results of our experiments are not consistent with previous reports that suggested that 5-HT6 antagonists might have therapeutic potential for cognitive disorders.

5-HT6 receptor

Serotonin Antagonists

10.1124/jpet.103.056002

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Citations (102)

Measurement of Aβ1–42 in cerebrospinal fluid is influenced by matrix effects

Journal of Neurochemistry (2011)

J. Randall Slemmon Jere E. Meredith Valerie Guss Ulf Andréasson Niels Andreasen

Aβ1-42 measurement in CSF is an important biochemical marker for Alzheimer disease (AD). However, our understanding of why this biomarker is predictive and why it is often difficult to measure in a reproducible fashion is still lacking. To study these questions, the concentration of Aβ1-42 in CSF was compared before and after denaturation with 6M guanidine and reverse-phase HPLC. Measurement of the Aβ1-42 after denaturation and reverse-phase HPLC demonstrated that considerably more Aβ1-42 was present in CSF than revealed when assaying non-denatured CSF. A comparison of Aβ1-42 concentrations before and after HPLC in AD CSF with that in normal controls suggested that matrix interference may affect the differentiation between the diagnostic groups. A similar effect was observed with dilutions of crude CSF. Together, these results suggested that at least part of the mechanism by which low Aβ1-42 concentrations in CSF function as a biomarker of AD is related to matrix components which preferentially hide a portion of the Aβ1-42 from detection in AD CSF. In contrast, we show that the association of the APOEε4 allele with lower Aβ1-42 concentrations in CSF is preserved even after denaturation and HPLC. A similar relationship between the presence of the APOEε4 allele and lower concentrations of Aβ1-40 was also apparent, thereby generating similar ratios of Aβ1-42/ Aβ1-40 across the APOE genotypes. The results from the present study suggested that Aβ1-42 in CSF functions as a biomarker of AD in tandem with other CSF matrix components that are increased in AD CSF. Further studies are needed to identify which matrix factors (e.g. binding of Aβ to proteins) underlie the increased detection of Aβ1-42 concentrations after denaturation and HPLC. The data also suggested that denaturation and HPLC of CSF may be a useful approach for studies using Aβ1-42 as a pharmacodynamic marker or in other paradigms where measurement of total non-covalently bound Aβ1-42 is required.

Denaturation (fissile materials)

Apolipoprotein E

Guanidine

10.1111/j.1471-4159.2011.07553.x

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Citations (37)

N-(5-Chloro-2-(hydroxymethyl)-N-alkyl-arylsulfonamides as γ-secretase inhibitors

Bioorganic & Medicinal Chemistry Letters (2007)

Michael F. Parker Donna M. Barten Carl P. Bergstrom Joanne J. Bronson Jason A. Corsa

Hydroxymethyl

10.1016/j.bmcl.2007.06.022

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Citations (10)

Characterization of Novel CSF Tau and ptau Biomarkers for Alzheimer’s Disease

PLoS ONE (2013)

Jere E. Meredith Sethu Sankaranarayanan Valerie Guss Anthony J. Lanzetti Flora Berisha

Cerebral spinal fluid (CSF) Aβ42, tau and p181tau are widely accepted biomarkers of Alzheimer’s disease (AD). Numerous studies show that CSF tau and p181tau levels are elevated in mild-to-moderate AD compared to age-matched controls. In addition, these increases might predict preclinical AD in cognitively normal elderly. Despite their importance as biomarkers, the molecular nature of CSF tau and ptau is not known. In the current study, reverse-phase high performance liquid chromatography was used to enrich and concentrate tau prior to western-blot analysis. Multiple N-terminal and mid-domain fragments of tau were detected in pooled CSF with apparent sizes ranging from <20 kDa to ~40 kDa. The pattern of tau fragments in AD and control samples were similar. In contrast, full-length tau and C-terminal-containing fragments were not detected. To quantify levels, five tau ELISAs and three ptau ELISAs were developed to detect different overlapping regions of the protein. The discriminatory potential of each assay was determined using 20 AD and 20 age-matched control CSF samples. Of the tau ELISAs, the two assays specific for tau containing N-terminal sequences, amino acids 9-198 (numbering based on tau 441) and 9-163, exhibited the most significant differences between AD and control samples. In contrast, CSF tau was not detected with an ELISA specific for a more C-terminal region (amino acids 159-335). Significant discrimination was also observed with ptau assays measuring amino acids 159-p181 and 159-p231. Interestingly, the discriminatory potential of p181 was reduced when measured in the context of tau species containing amino acids 9-p181. Taken together, these results demonstrate that tau in CSF occurs as a series of fragments and that discrimination of AD from control is dependent on the subset of tau species measured. These assays provide novel tools to investigate CSF tau and ptau as biomarkers for other neurodegenerative diseases.

10.1371/journal.pone.0076523

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Citations (188)

P3-288: Gamma-secretase inhibitors have intrinsically different potencies against Aβ production and Notch signaling

Alzheimer s & Dementia (2010)

Catherine R. Burton Jere E. Meredith Jeremy H. Toyn Jodi D. Bradley Qian Wang

Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly and currently only symptomatic treatments are available. The underlying biochemistry of the disease appears to involve accumulation of the toxic amyloid-β peptide (Aβ) in the brain. Aβ is formed through proteolytic cleavage of the amyloid precursor protein (APP) by the proteases BACE and γ-secretase making development of inhibitors to both enzymes attractive therapeutic approaches for Alzheimer's disease. In addition to APP, γ-secretase cleaves other proteins thereby complicating the development of γ-secretase inhibitors. Of particular concern are the Notch-family of proteins which require γ-secretase cleavage to control cell fate decisions in several tissues, including the gastrointestinal tract and spleen. Here we describe γ-secretase inhibitors possessing intrinsically different inhibitory potencies for Aβ production and Notch signaling, observing a 500-fold range in the Notch/Aβ IC50 ratios among the set of inhibitors studied. To explore the biological relevance of these findings, a cellular model for differentiation of intestinal goblet cells was developed using the HT29 colon cancer cell line. Using this assay, we found that induction of goblet cell-like differentiation could be induced by γ-secretase inhibitors at potencies similar to those measured for inhibition of Notch signaling and that Notch signaling was required for this induction. Taken together, these findings demonstrate that inhibition of Aβ formation and Notch signaling can be partially separated in cultured cells and raise the possibility that Aβ can be inhibited without Notch toxicity in vivo leading to an increased therapeutic index with select γ-secretase inhibitors.

Gamma secretase

Notch proteins

10.1016/j.jalz.2010.05.1788

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Citations (0)

CCDC 639765: Experimental Crystal Structure Determination

The Cambridge Structural Database (2007)

C. V. C. Prasad Ming Zheng Shikha Vig Christel A. S. Bergström David W. Smith

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

10.5517/ccpgqlf

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Citations (0)