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Craig S Atwood

Publications and source records attributed to Craig S Atwood.

At least 19 recordsLinked to original sources
PubMed2025

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

BACKGROUND: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. RESULTS: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). CONCLUSIONS: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.

Humans↗
PubMed2006

Identification of a gonadotropin-releasing hormone receptor orthologue in Caenorhabditis elegans.

BACKGROUND: The Caenorhabditis elegans genome is known to code for at least 1149 G protein-coupled receptors (GPCRs), but the GPCR(s) critical to the regulation of reproduction in this nematode are not yet known. This study examined whether GPCRs orthologous to human gonadotropin-releasing hormone receptor (GnRHR) exist in C. elegans. RESULTS: Our sequence analyses indicated the presence of two proteins in C. elegans, one of 401 amino acids [GenBank: NP_491453; WormBase: F54D7.3] and another of 379 amino acids [GenBank: NP_506566; WormBase: C15H11.2] with 46.9% and 44.7% nucleotide similarity to human GnRHR1 and GnRHR2, respectively. Like human GnRHR1, structural analysis of the C. elegans GnRHR1 orthologue (Ce-GnRHR) predicted a rhodopsin family member with 7 transmembrane domains, G protein coupling sites and phosphorylation sites for protein kinase C. Of the functionally important amino acids in human GnRHR1, 56% were conserved in the C. elegans orthologue. Ce-GnRHR was actively transcribed in adult worms and immunoanalyses using antibodies generated against both human and C. elegans GnRHR indicated the presence of a 46-kDa protein, the calculated molecular mass of the immature Ce-GnRHR. Ce-GnRHR staining was specifically localized to the germline, intestine and pharynx. In the germline and intestine, Ce-GnRHR was localized specifically to nuclei as revealed by colocalization with a DNA nuclear stain. However in the pharynx, Ce-GnRHR was localized to the myofilament lattice of the pharyngeal musculature, suggesting a functional role for Ce-GnRHR signaling in the coupling of food intake with reproduction. Phylogenetic analyses support an early evolutionary origin of GnRH-like receptors, as evidenced by the hypothesized grouping of Ce-GnRHR, vertebrate GnRHRs, a molluscan GnRHR, and the adipokinetic hormone receptors (AKHRs) and corazonin receptors of arthropods. CONCLUSION: This is the first report of a GnRHR orthologue in C. elegans, which shares significant similarity with insect AKHRs. In vertebrates, GnRHRs are central components of the reproductive endocrine system, and the identification of a GnRHR orthologue in C. elegans suggests the potential use of C. elegans as a model system to study reproductive endocrinology.

Animals↗
PubMed2006

Metabolic clues regarding the enhanced performance of elite endurance athletes from orchiectomy-induced hormonal changes.

This article examines the metabolic performance of an elite cyclist, Lance Armstrong, before and after his diagnosis with testicular cancer. Although a champion cyclist in 1-day events prior to his diagnosis of testicular cancer at age 25, he was not a contender in multi-day endurance cycle races such as the 3-week Tour de France. His genetic makeup and physiology (high VO2max, long femur, strong heavy build) coupled with his ambition and motivation enabled him at an early age to become one of the best 1-day cyclists in the world. Following his cancer diagnosis, he underwent a unilateral orchiectomy, brain surgery and four cycles of chemotherapy. After recovering, he returned to cycling and surprisingly excelled in the Tour de France, winning this hardest of endurance events 7 years running. This dramatic transformation from a 1-day to a 3-week endurance champion has led many to query how this is possible, and under the current climate, has led to suggestions of doping as to the answer to this metamorphosis. Physiological tests following his recovery indicated that physiological parameters such as VO2max were not affected by the unilateral orchiectomy and chemotherapy. We propose that his dramatic improvement in recovery between stages, the most important factor in winning multi-day stage races, is due to his unilateral orchiectomy, a procedure that results in permanent changes in serum hormones. These hormonal changes, specifically an increase in gonadotropins (and prolactin) required to maintain serum testosterone levels, alter fuel metabolism; increasing hormone sensitive lipase expression and activity, promoting increased free fatty acid (FFA) mobilization to, and utilization by, muscles, thereby decreasing the requirement to expend limiting glycogen stores before, during and after exercise. Such hormonal changes also have been associated with ketone body production, improvements in muscle repair and haematocrit levels and may facilitate the loss of body weight, thereby increasing power to weight ratio. Taken together, these hormonal changes act to limit glycogen utilization, delay fatigue and enhance recovery thereby allowing for optimal performances on a day-to-day basis. These insights provide the foundation for future studies on the endocrinology of exercise metabolism, and suggest that Lance Armstrong's athletic advantage was not due to drug use.

Adult↗
PubMed2006

Gonadotropins: a cohesive gender-based etiology of Alzheimer disease.

While there is ample experimental evidence supporting the role of estrogen in the pathogenesis of Alzheimer disease, recent inconclusive data regarding hormone replacement therapy (HRT), specifically, the unexpected results of the Women's Health Initiative (WHI) Memory Study has raised serious questions regarding the protective effects of estrogen. Because of this and other inconsistencies in the estrogen hypothesis, we propose that another hormone of the hypothalamic-pituitary-gonadal axis, luteinizing hormone, is a major factor in the pathogenesis of Alzheimer disease. Specifically, we suspect that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a primary causative factor for the development of Alzheimer disease. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, Alzheimer disease.

Alzheimer Disease↗
PubMed2006

Steroidogenic acute regulatory protein (StAR): evidence of gonadotropin-induced steroidogenesis in Alzheimer disease.

BACKGROUND: Alzheimer disease (AD) is clinically characterized by progressive memory loss, impairments in behavior, language and visual-spatial skills and ultimately, death. Epidemiological data reporting the predisposition of women to AD has led to a number of lines of evidence suggesting that age-related changes in hormones of the hypothalamic-pituitary-gonadal (HPG) axis following reproductive senescence, may contribute to the etiology of AD. Recent studies from our group and others have reported not only increases in circulating gonadotropins, namely luteinizing hormone (LH) in individuals with AD compared with control individuals, but also significant elevations of LH in vulnerable neuronal populations in individuals with AD compared to control cases as well as the highest density of gonadotropin receptors in the brain are found within the hippocampus, a region devastated in AD. However, while LH is higher in AD patients, the downstream consequences of this are incompletely understood. To begin to examine this issue, here, we examined the expression levels of steroidogenic acute regulatory (StAR) protein, which regulates the first key event in steroidogenesis, namely, the transport of cholesterol into the mitochondria, and is regulated by LH through the cyclic AMP second messenger pathway, in AD and control brain tissue. RESULTS: Our data revealed that StAR protein was markedly increased in both the cytoplasm of hippocampal pyramidal neurons as well as in the cytoplasm of other non-neuronal cell types from AD brains when compared with age-matched controls. Importantly, and suggestive of a direct mechanistic link, StAR protein expression in AD brains colocalized with LH receptor expression. CONCLUSION: Therefore, our findings suggest that LH is not only able to bind to its receptor and induce potentially pathogenic signaling in AD, but also that steroidogenic pathways regulated by LH may play a role in AD.

Journal Article↗
PubMed2006

Luteinizing hormone modulates cognition and amyloid-beta deposition in Alzheimer APP transgenic mice.

Until recently, the study of hormonal influences in Alzheimer disease was limited to the role of sex steroids. Despite numerous epidemiological studies supporting a protective role for estrogen in Alzheimer disease, recent studies show that estrogen administration in elderly women increases the risk of disease. Reconciling these contradictory reports, we previously hypothesized that other hormones of the hypothalamic-pituitary-gonadal axis, such as luteinizing hormone, may be involved in the onset and development of the disease. In this regard, luteinizing hormone is elevated in Alzheimer disease and is known to modulate amyloidogenic processing of amyloid-beta protein precursor. Therefore, in this study, to evaluate the therapeutic potential of luteinizing hormone ablation, we administered a gonadotropin-releasing hormone analogue, leuprolide acetate, to an aged transgenic mouse model of Alzheimer disease (Tg 2576) and measured cognitive Y-maze performance and amyloid-beta deposition after 3 months of treatment. Our data indicate that luteinizing hormone ablation significantly attenuated cognitive decline and decreased amyloid-beta deposition as compared to placebo-treated animals. Importantly, leuprolide acetate-mediated reduction of amyloid-beta correlated with improved cognition. Since both cognitive loss and amyloid-beta deposition are features of Alzheimer disease, leuprolide acetate treatment may prove to be a useful therapeutic strategy for this disease.

Alzheimer Disease↗
PubMed2006

Targeting gonadotropins: an alternative option for Alzheimer disease treatment.

Recent evidence indicates that, alongside oxidative stress, dysregulation of the cell cycle in neurons susceptible to degeneration in Alzheimer disease may play a crucial role in the initiation of the disease. As such, the role of reproductive hormones, which are closely associated with the cell cycle both during development and after birth, may be of key import. While estrogen has been the primary focus, the protective effects of hormone replacement therapy on cognition and dementia only during a crucial period led us to expand the study of hormonal influences to other members of the hypothalamic pituitary axis. Specifically, in this review, we focus on luteinizing hormone, which is not only increased in the sera of patients with Alzheimer disease but, like estrogen, is modulated by hormone replacement therapy and also influences cognitive behavior and pathogenic processing in animal models of the disease. Targeting gonadotropins may be a useful treatment strategy for disease targeting multiple pleiotropic downstream consequences.

Journal Article↗
PubMed2006

Human neurons express type I GnRH receptor and respond to GnRH I by increasing luteinizing hormone expression.

Gonadotropin-releasing hormone receptor I (GnRHR I) has been localized to the limbic system of the rat brain, although the functional consequences of GnRH signaling through these receptors is unknown. In this paper, we characterize the expression of GnRHR I in the human hippocampus and cortex, and the functionality of GnRHR I in human neuroblastoma cells. Robust GnRHR I immunoreactivity was detected in the cell body as well as along the apical dendrites of pyramidal neurons in the CA2, CA1, and end plate, but was clearly lower in the subiculum of the hippocampus. Immunolabeling was also evident in cortical neurons, including those located in the entorhinal cortex and occipitotemporal gyrus but was not observed within the granular layer of the dentate gyrus. No differences in immunohistochemical staining were observed between control and Alzheimer's disease brain. GnRHR I mRNA and protein (mature, immature, and other variant) expression was detected in human neuroblastoma cells (M17, SH-SY5Y) and rat embryonic primary neurons and varied with differentiation and GnRH treatment. Since GnRHR I was expressed by extrapituitary cells, and hypothalamic GnRH I secretion markedly increases post-menopause/andropause, we treated human M17 neuroblastoma cells cultured in serum-free conditions with GnRH I for 6 h and measured LH expression. M17 neuroblastoma cells express LHbeta mRNA, while immunoblot analysis indicated the presence of three LH variants (approximately 30, 47, and 60 kDa) that were upregulated by low concentrations of GnRH I, but down-regulated at higher GnRH I concentrations. LH expression was also found to increase in differentiating embryonic rat primary cortical neurons. Our results demonstrate that neurons expressing GnRHR I are functional, responding to GnRH I by upregulating LH production. Post-reproductive surges in GnRH I secretion may explain the accumulation of LH in pyramidal neurons of the aged human and rat.

Alzheimer Disease↗
PubMed2006

The estrogen myth: potential use of gonadotropin-releasing hormone agonists for the treatment of Alzheimer's disease.

Estrogen and other sex hormones have received a great deal of attention for their speculative role in Alzheimer's disease (AD), but at present a direct connection between estrogen and the pathogenesis of AD remains elusive and somewhat contradictory. For example, on one hand there is a large body of evidence suggesting that estrogen is neuroprotective and improves cognition, and that hormone replacement therapy (HRT) at the onset of menopause reduces the risk of developing AD decades later. However, on the other hand, studies such as the Women's Health Initiative demonstrate that HRT initiated in elderly women increases the risk of dementia. While estrogen continues to be investigated, the disparity of findings involving HRT has led many researchers to examine other hormones of the hypothalamic-pituitary-gonadal axis such as luteinising hormone (LH) and follicle-stimulating hormone. In this review, we propose that LH, rather than estrogen, is the paramount player in the pathogenesis of AD. Notably, both men and women experience a 3- to 4-fold increase in LH with aging, and LH receptors are found throughout the brain following a regional pattern remarkably similar to those neuron populations affected in AD. With respect to disease, serum LH level is increased in women with AD relative to non-diseased controls, and levels of LH in the brain are also elevated in AD. Mechanistically, we propose that elevated levels of LH may be a fundamental instigator responsible for the aberrant reactivation of the cell cycle that is seen in AD. Based on these aforementioned aspects, clinical trials underway with leuprolide acetate, a gonadotropin-releasing hormone agonist that ablates serum LH levels, hold great promise as a ready means of treatment in individuals afflicted with AD.

Alzheimer Disease↗
PubMed2006

Antigonadotropins: a novel strategy to halt Alzheimer's disease progression.

A significant amount of research has been focused on the relationship between hormones and Alzheimer's disease. However, the majority of this work has been on estrogen and more recently testosterone. A serendipitous patient encounter led one of us (RLB) to question whether other hormones of the hypothalamic-pituitary-gonadal axis could be playing a role in the pathogenesis of Alzheimer's disease. The age-related decline in reproductive function results in a dramatic decrease in serum estrogen and testosterone concentrations and an equally dramatic compensatory increase in serum luteinizing hormone concentrations. Indeed, there is growing evidence that the gonadotropin, luteinizing hormone, which regulates serum estrogen and testosterone concentrations, could be an important causative factor in the development of Alzheimer's disease. This review provides information supporting the "gonadotropin hypothesis," puts forth a novel mechanism of how changes in serum luteinizing hormone concentrations could contribute to the pathogenesis of Alzheimer's disease, and discusses potential therapeutic anti-gonadotropin compounds.

Alzheimer Disease↗
PubMed2006

The cell cycle and hormonal fluxes in Alzheimer disease: a novel therapeutic target.

Several hypotheses have been proposed attempting to explain the pathogenesis of Alzheimer disease (AD) including theories involving amyloid deposition, tau phosphorylation, oxidative stress, metal ion dysregulation and inflammation. Strong evidence suggests that each one contributes to disease pathogenesis, though none of these mechanisms result in all the downstream changes that occur during the course of AD. For this reason, we and others have begun the search for a causative factor that predates known features found in AD, and that might be a fundamental initiator of the pathophysiological cascade. In this regard, we propose that the dysregulation of the cell cycle that occurs in neurons susceptible to degeneration in the hippocampus during AD is a potential causative factor that would initiate all known pathological events. Neuronal changes supporting alterations in cell cycle control in the etiology of AD include the ectopic expression of markers of the cell cycle, organelle kinesis and cytoskeletal alterations including tau phosphorylation. Given the early and presumably devastating consequences of cell cycle re-entry, we have made a concerted effort to elucidate the initiating factor that drives aberrant mitotic re-entry in AD. As a result of the gender bias present in AD, we suspect that postmenopausal and andropausal hormones may be involved and, with this in mind, in this review we specifically focus on the gonadotropins. Therapeutic interventions targeted at gonadotropins, if they are indeed the driving mitogenic force, could both prevent disease in those patients currently asymptomatic or halt, and even reverse, disease in those currently afflicted.

Alzheimer Disease↗
PubMed2005

Novel D-penicillamine carrying nanoparticles for metal chelation therapy in Alzheimer's and other CNS diseases.

Metal ions accumulate in the brain with aging and in several neurodegenerative diseases. Aside from the copper storage disease, Wilson's disease, recent attention has focused on the accumulation of zinc, copper and iron in the Alzheimer's disease (AD) brain and the accumulation of iron in Parkinson's disease. In particular, the parenchymal deposition of beta-amyloid (Abeta) and its interaction with metal ions has been postulated to play a role in the progression of AD. Thus, the strategy of lowering brain metal ions and targeting the interaction of Abeta peptide and metal ions through the administration of chelators has merit. Our recent finding that nanoparticle delivery systems can cross the blood-brain barrier has led us to investigate whether chelators delivered conjugated to nanoparticles could act to reverse metal ion induced protein precipitation. In the present studies, the Cu (I) chelator D-penicillamine was covalently conjugated to nanoparticles via a disulfide bond or a thioether bond. Nanoparticle-chelator conjugates were stable between pH 6-8 in aqueous suspension if stored at 4 degrees C, and did not aggregate when challenged with salts and serum. Release of D-penicillamine from the nanoparticles was achieved using reducing agents such as dithiothreitol (as a model for glutathione). Nanoparticles treated only under reducing conditions that released the conjugated D-penicillamine were able to effectively resolubilize copper-Abeta (1-42) aggregates. These results indicate that nanoparticles have potential to deliver D-penicillamine to the brain for the prevention of Abeta (1-42) accumulation, as well as to reduce metal ion accumulation in other CNS diseases.

Alzheimer Disease↗
PubMed2005

Dysregulation of the hypothalamic-pituitary-gonadal axis with menopause and andropause promotes neurodegenerative senescence.

Senescence is characterized neurologically by a decline in cognitive function, which we propose is the result of degenerative processes initiated by the dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis with menopause and andropause. Compelling epidemiologic evidence to support this assertion includes the increased prevalence of Alzheimer disease (AD) in women, the correlation of serum HPG hormones with disease and the decreased incidence, and delay in the onset of AD following hormone replacement therapy. Dysregulation of the axis at this time leads to alterations in the concentrations of all serum HPG hormones (decreased neuronal sex steroid signaling, but increased neuronal gonadotropin releasing hormone, luteinizing hormone, and activin signaling). Hormones of the HPG axis, receptors for which are present in the adult brain, are important regulators of cell proliferation and differentiation during growth and development. Based on this, we propose that dysregulated HPG hormone signaling with menopause/andropause leads to the abortive reentry of differentiated neurons into the cell cycle via a process we term "dyosis." Interestingly, the major biochemical and neuropathologic changes reported for the AD brain also are intimately associated with neuron division: altered AbetaPP metabolism, Abeta deposition, tau phosphorylation, mitochondrial alterations, chromosomal replication, synapse loss, and death of differentiated neurons. Recent evidence supports the premise that AD-related biochemical changes are likely the combined result of increased mitotic signaling by gonadotropins and GnRH, decreased differentiative and neuroprotective signaling via sex steroids, and increased differentiative signaling via activins. This results in a hormonal milieu that is permissive of cell cycle reentry but does not allow completion of metaphase. Partial resetting of the axis following administration of normal endogenous sex steroids delays the onset and decreases the incidence of AD. Ideally, supplementation with HPG hormones should mimic closely the serum concentrations of all HPG hormones in reproductive men and cycling women to prevent dyotic signaling and attempted neuron division.

Adult↗
PubMed2005

Estrogen bows to a new master: the role of gonadotropins in Alzheimer pathogenesis.

Epidemiological data showing a predisposition of women to develop Alzheimer disease (AD) led many researchers to investigate the role of sex steroids, namely estrogen, in disease pathogenesis. Although there is circumstantial support for the role of estrogen, the unexpected results of the Women's Health Initiative (WHI) Memory Study, which reported an increase in the risk for probable dementia and impaired cognitive performance in postmenopausal women treated with a combination of estrogen and progestin, have raised serious questions regarding the protective effects of estrogen. Although explanations for these surprising results vary greatly, the WHI Memory Study cannot be correctly interpreted without a complete investigation of the effects of the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis on the aging brain. Certain hormones of the HPG axis, namely, the gonadotropins (luteinizing hormone and follicle-stimulating hormone), are not only involved in regulating reproductive function via a complex feedback loop but are also known to cross the blood-brain barrier. We propose that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a potentially primary causative factor for the development of AD. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, AD. On this basis, we suggest that the results of the WHI Memory Study are not only predictable but also avoidable by therapeutically targeting the gonadotropins instead of the sex steroids.

Aged↗
PubMed2005

The gonadotropin connection in Alzheimer's disease.

Although not traditionally thought of as regulators of neuronal function, the hypothalamic-pituitary-gonadal (HPG) hormones luteinizing hormone (LH), gonadotropin-releasing hormone (GnRH), and activins possess neuronal receptors. These receptors are found throughout the limbic system on a number of different cell types, and, like reproductive tissues, the expression of these receptors is regulated by hormonal feedback loops. These hormones and their receptors regulate structure and a diverse range of functions in the brain. Therefore, it is not surprising that the dysregulation of the HPG axis with menopause and andropause (leading to elevated LH, GnRH, and activin signaling but decreased sex steroid signaling) might promote alterations in both the structure and function of neuronal cells. To date, most evidence has accumulated for a role of LH in promoting neurodegenerative changes. LH is known to cross the blood-brain barrier, receptors for LH are most concentrated in the hippocampus, that region of the brain most vulnerable to Alzheimer's disease (AD) and LH is significantly elevated in both the serum and the pyramidal neurons of AD subjects. LH promotes the amyloidogenic processing of the amyloid-beta precursor protein in vitro, and the antigonadotropin leuprolide acetate decreases amyloid generation in mice. Moreover, leuprolide acetate improves the cognitive performance and decreases amyloid-beta deposition in aged transgenic mice carrying the Swedish AbetaPP mutation. Therefore, the elevation of LH with the dysregulation of the HPG axis at menopause and andropause is a physiologically relevant signal that could promote neurodegeneration. Epidemiological support for a role of LH/GnRH in AD is evidenced by a reduction in neurodegenerative disease among prostate cancer patients a group known to GnRH agonists. Clinical trials are underway for the treatment of AD using GnRH analogs and should provide further insights into the gonadotropin connection in AD.

Activins↗