Chad Dickey

The article also contains an error in Fig. 6c (Cortex Tau-P301S), where an incorrect merged image was inadvertently placed while compiling this figure. The corrected Fig. 6c is as follows:

The present technology provides compounds according to Formula I or Formula III as well as compositions including such compounds useful for the treatment of metastatic cancer and/or glaucoma.

Abisambra et al.,“Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degrada tion,” J. Neurosci., 33: 9498-9507, 2013. Alamed et al.,“Two-day radial-arm water maze learning and memory task; robust resolution of amyloid-related memory deficits in transgenic mice,” Nat. Protoc.,(1): 1671-1679, 2006. Blair et al.," Accelerated neurodegeneration through chaperone mediated oligomerization of tau,” The Journal of Clinical Investi gation, 123: 4158-4169, 2013. CTFA Cosmetic Ingredient Handbook, 587-592, 1992. Dickey et al.,“Aging analysis reveals slowed tau turnover and enhanced stress response in a mouse model of tauopathy,” Am. J. Pathol., 174: 228-238, 2009. Donnelly et al.,“DNA vaccines,” Ann. Rev. Immunol., 15: 617-648,

The accumulation and aggregation of the microtubule-associated protein tau (tau) into intracellular neuronal tangles are a hallmark of a range of progressive neurodegenerative tauopathies, including Alzheimer’s disease (AD), frontotemporal dementia, Pick’s disease, and progressive supranuclear palsy. The aberrant phosphorylation of tau is associated with tau aggregates in AD. Members of the heat shock protein 70 kDa (Hsp70) family of chaperones bind directly to tau and modulate tau clearance and aggregation. Small molecules that inhibit the Hsp70 family of chaperones have been shown to reduce the accumulation of tau, including phosphorylated tau. Here, eight analogs of the rhodacyanine inhibitor, JG-98, were synthesized and evaluated. Like JG-98, many of the compounds inhibited ATPase activity of the cytosolic heat shock cognate 70 protein (Hsc70) and reduced total, aggregated, and …

Tauopathies, such as Alzheimer's disease, are characterized by the misfolding and progressive accumulation of the microtubule associated protein tau. Chaperones, tasked with maintaining protein homeostasis, can become imbalanced with age and contribute to the progression of neurodegenerative disease. Cyclophilins are a promising pool of underinvestigated chaperones with peptidyl‐prolyl isomerase activity that may play protective roles in regulating tau aggregation. Using a Thioflavin T fluorescence‐based assay to monitor in vitro tau aggregation, all eight cyclophilins, which include PPIA to PPIH prevent tau aggregation, with PPIB, PPIC, PPID, and PPIH showing the greatest inhibition. The low thermal stability of PPID and the strong heparin binding of PPIB undermines the simplistic interpretation of reduced tau aggregation. In a cellular model of tau accumulation, all cyclophilins, except PPID and PPIH …

The microtubule-associated protein tau pathologically accumulates and aggregates in Alzheimer’s disease (AD) and other tauopathies, leading to cognitive dysfunction and neuronal loss. Molecular chaperones, like small heat-shock proteins (sHsps), can help deter the accumulation of misfolded proteins, such as tau. Here, we tested the hypothesis that the overexpression of wild-type Hsp22 (wtHsp22) and its phosphomimetic (S24,57D) Hsp22 mutant (mtHsp22) could slow tau accumulation and preserve memory in a murine model of tauopathy, rTg4510. Our results show that Hsp22 protected against deficits in synaptic plasticity and cognition in the tauopathic brain. However, we did not detect a significant change in tau phosphorylation or levels in these mice. This led us to hypothesize that the functional benefit was realized through the restoration of dysfunctional pathways in hippocampi of tau transgenic mice since no significant benefit was measured in non-transgenic mice expressing wtHsp22 or mtHsp22. To identify these pathways, we performed mass spectrometry of tissue lysates from the injection site. Overall, our data reveal that Hsp22 overexpression in neurons promotes synaptic plasticity by regulating canonical pathways and upstream regulators that have been characterized as potential AD markers and synaptogenesis regulators, like EIF4E and NFKBIA.

Alzheimer's disease is a progressive fatal neurodegenerative disease with no cure or effective treatments. The hallmarks of disease include extracellular plaques and intracellular tangles of aggregated protein. The intracellular tangles consist of the microtubule associated protein tau. Preventing the pathological aggregation of tau may be an important therapeutic approach to treat disease. In this study we show that small heat shock protein 22 kDa (Hsp22) can prevent the aggregation of tau in vitro. Additionally, tau can undergo liquid–liquid phase separation (LLPS) in the presence of crowding reagents which causes it to have an increased aggregation rate. We show that Hsp22 can modulate both the aggregation and LLPS behavior of tau in vitro.

Abnormal accumulation of hyperphosphorylated tau induces pathogenesis in neurodegenerative diseases, like Alzheimer’s disease. Molecular chaperones with peptidyl-prolyl cis/trans isomerase (PPIase) activity are known to regulate these processes. Previously, in vitro studies have shown that the 52 kDa FK506-binding protein (FKBP52) interacts with tau inducing its oligomerization and fibril formation to promote toxicity. Thus, we hypothesized that increased expression of FKBP52 in the brains of tau transgenic mice would alter tau phosphorylation and neurofibrillary tangle formation ultimately leading to memory impairments. To test this, tau transgenic (rTg4510) and wild-type mice received bilateral hippocampal injections of virus overexpressing FKBP52 or GFP control. We examined hippocampal-dependent memory, synaptic plasticity, tau phosphorylation status, and neuronal health. This work revealed that …

Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell’s response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer’s disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to the greatest extent. We showed that sustained AZIN2 overexpression elicited a maladaptive PSR in mice with underlying tauopathy (MAPT …

BACKGROUND [0003] Glaucoma is a collection of diseases which result in damage to the optic nerve. Despite advances in treatment strategies, glaucoma remains the second leading cause of blindness worldwide, affecting 70 million people worldwide (Quigley, HA et al. Br J Ophthalmol, 2006. 90 (3): p. 262-7). Damage to the optic nerve and surrounding retinal cells is often the result of increased intraocular pressure (IOP). Elevated IOP develops from an imbalance of aqueous humor production and clearance. Current treatments include topical and surgical options to reduce IOP, but there are currently no therapeutic options to treat the underlying cause of the disease, and a large percentage of patients on IOP lowering drugs eventually reach blindness. The lack of therapeutic options for glaucoma is, in part, due to the diverse nature of how glaucoma develops as well as a lack of understanding into the origin of …

The present invention concerns the use of peptidyl-prolyl isomerase cyclophilin 40 (CyP40) for reduction of neurotoxic fibrils and treatment and prevention of neurodegenerative diseases associated with amyloid fibril aggregation. Aspects of the invention include compositions, methods, dosage forms, and kits for treating or preventing a neurodegenerative disease or condition associated with amyloid fibril aggregation in a human or animal subject, and for disaggregating neurofibrillary aggregates in vitro or in vivo, using CyP40, or a biologically active fragment thereof.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question …

Hsp90 plays an important role in health and is a therapeutic target for managing misfolding disease. Compounds that disrupt co-chaperone delivery of clients to Hsp90 target a subset of Hsp90 activities, thereby minimizing the toxicity of pan-Hsp90 inhibitors. Here, we have identified SEW04784 as a first-in-class inhibitor of the Aha1-stimulated Hsp90 ATPase activity without inhibiting basal Hsp90 ATPase. Nuclear magnetic resonance analysis reveals that SEW84 binds to the C-terminal domain of Aha1 to weaken its asymmetric binding to Hsp90. Consistent with this observation, SEW84 blocks Aha1-dependent Hsp90 chaperoning activities, including the in vitro and in vivo refolding of firefly luciferase, and the transcriptional activity of the androgen receptor in cell-based models of prostate cancer and promotes the clearance of phosphorylated tau in cellular and tissue models of neurodegenerative tauopathy. We …

Early life stress (ELS) adversely affects the brain and is commonly associated with the etiology of mental health disorders, like depression. In addition to the mood-related symptoms, patients with depression show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, increased peripheral inflammation, and structural brain alterations. Although the underlying causes are unknown, polymorphisms in the FK506-binding protein 5 (FKBP5) gene, a regulator of glucocorticoid receptor (GR) activity, interact with childhood adversities to increase vulnerability to depressive disorders. We hypothesized that high FKBP5 protein levels combined with early life stress (ELS) would alter the HPA axis and brain, promoting depressive-like behaviors. To test this, we exposed males and females of a mouse model overexpressing FKBP5 in the brain (rTgFKBP5 mice), or littermate controls, to maternal separation for 14 days …

Tau dysfunction is common in several neurodegenerative diseases including Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Affective symptoms have often been associated with aberrant tau pathology and are commonly comorbid in patients with tauopathies, indicating a connection between tau functioning and mechanisms of depression. The current study investigated depression-like behavior in Mapt−/− mice, which contain a targeted deletion of the gene coding for tau. We show that 6-month Mapt−/− mice are resistant to depressive behaviors, as evidenced by decreased immobility time in the forced swim and tail suspension tests, as well as increased escape behavior in a learned helplessness task. Since depression has also been linked to deficient adult neurogenesis, we measured neurogenesis in the hippocampal dentate gyrus and subventricular zone using 5-bromo-2-deoxyuridine (BrdU) labeling. We found that neurogenesis is increased in the dentate gyrus of 14-month-old Mapt−/− brains compared to wild type, providing a potential mechanism for their behavioral phenotypes. In addition to the hippocampus, an upregulation of proteins involved in neurogenesis was observed in the frontal cortex and amygdala of the Mapt−/− mice using proteomic mass spectrometry. All together, these findings suggest that tau may have a role in the depressive symptoms observed in many neurodegenerative diseases and identify tau as a potential molecular target for treating depression.

The subject invention concerns materials and methods for treating depression, stress disorders, such as PTSD, anxiety disorders, and/or a neurodegenerative disease or condition in a person or animal. In one embodiment, a person or animal in need of treatment is administered one or more compounds or drugs, or a composition comprising the one or more compounds or drugs, that inhibit FKBP51 activity or function. The subject invention also concerns a method for inhibiting activity of the FKBP51 protein in a cell. The subject invention also concerns methods of screening for compounds or drugs that inhibit the FKBP51 protein.

The subject invention pertains to transgenic non-human animals comprising a transgenic nucleotide sequence, integrated into the genome of the animals, comprising a nucleotide sequence encoding human FKBP51 operably linked to a tetracycline response element. In some embodiments, the transgenic animal comprises an additional transgenic nucleotide sequence, integrated into the genome of the animal, comprising a nucleotide sequence encoding a tetracycline transactivator (tTA) operably linked to a promoter; wherein the tTA is expressed upon activation of the promoter and binds the tetracycline response element, thereby causing expression of FKBP51. The invention also pertains to methods for screening for agents for the prevention and/or treatment of psychiatric disorders, such as depression.

Misfolding, aggregation and accumulation of proteins are toxic elements in the progression of a broad range of neurodegenerative diseases. Molecular chaperones enable a cellular defense by reducing or compartmentalizing these insults. Small heat shock proteins (sHsps) engage proteins early in the process of misfolding and can facilitate their proper folding or refolding, sequestration, or clearance. Here, we evaluate the effects of the sHsp Hsp22, as well as a pseudophosphorylated mutant and an N-terminal domain deletion (NTDΔ) variant on tau aggregation in vitro and tau accumulation and aggregation in cultured cells. Hsp22 wild-type (WT) protein had a significant inhibitory effect on heparin-induced aggregation in vitro and the pseudophosphorylated mutant Hsp22 demonstrated a similar effect. When co-expressed in a cell culture model with tau, these Hsp22 constructs significantly reduced soluble tau protein levels when transfected at a high ratio relative to tau. However, the Hsp22 NTDΔ protein drastically reduced the soluble protein expression levels of both tau WT and tau P301L/S320F even at lower transfection ratios, which resulted in a correlative reduction of the triton-insoluble tau P301L/S320F aggregates.

A convergent approach for the synthesis of (±)-myricanol, a strained diarylheptanoid isolated from Myricacae, was undertaken using a Suzuki–Miyaura coupling followed by a ring-closing metathesis (RCM). Herein, we report the unintentional formation of a 26-membered macrocycle as RCM product resulting from a head-to-tail dimerization of the seco-precursor, even in relay ring-closing metathesis (RRCM) conditions.