Alzheimer Disease: Simpkins JW

Simpkins JW, Gatson JW, Wigginton JG. · Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX, USA. · Alzheimers Dement. · Pubmed #19328446 No free full text.

This publication has no abstract.

Simpkins JW, Singh M. · Department of Pharmacology and Neuroscience, Institute for Aging and Alzheimer's Disease Research, University of North Texas Health Science Center, Fort Worth, TX, USA. · Alzheimers Dement. · Pubmed #18631989 No free full text.

Abstract: Considerable evidence has emerged through more than a decade of research supporting the neuroprotective and cognition-preserving effects of estrogens. Such basic research coupled with various epidemiological studies led quickly to the assessment of Premarin for the treatment of mild to moderate Alzheimer's disease (AD), initiated by the Alzheimer's Disease Cooperative Study Group and headed by Dr. Leon Thal. While this and subsequent trials with Premarin (Wyeth Research, Monmouth Junction, New Jersey) and PremPro (Wyeth Research), a conjugated equine estrogen preparation plus medoxyprogresterone acetate, have not supported the use of estrogens in treating advanced AD, considerable inferences have been made from these placebo controlled trials of estrogens. Here, we aimed to put these AD trials of estrogens in perspective by considering the potential mechanisms of these potent neuroprotective estrogens, the role of estrogens in other neurodegenerative conditions, such as cerebral ischemia, and based on our current understanding of estrogen neurobiology, offer insight into the design of future clinical trails of estrogens for neuronal protection.

Singh M, Sumien N, Kyser C, Simpkins JW. · Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. · Front Biosci. · Pubmed #17981614 links to  free full text

Abstract: Estradiol and progesterone are two steroid hormones that target a variety of organ systems, including the heart, the bone and the brain. With respect to the latter, a large volume of basic science studies support the neuroprotective role of estradiol and/or progesterone. In fact, the results of such studies prompted the assessment of these hormones as protective agents against such disorders as Alzheimer's disease, stroke and traumatic brain injury. Interestingly, results from the Women's Health Initiative (WHI) yielded results that appeared to be inconsistent with the data derived from in vitro and in vivo models. However, we argue that the results from the basic science studies were not inconsistent with the clinical trials, but rather, are consistent with, and may even have predicted, the results from the WHI. To illustrate this point, we review here certain in vivo paradigms that have been used to assess the protective effects of estrogens and progesterone, and describe how the results from these animal models point to the importance of the type of hormone, the age of the subjects and the method of hormone administration, in determining whether or not hormones are neuroprotective.

Singh M, Dykens JA, Simpkins JW. · Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA. · Exp Biol Med (Maywood). · Pubmed #16636299 links to  free full text

Abstract: Estrogens are gonadal steroid hormones that are present in the circulation of both males and females and that can no longer be considered within the strict confines of reproductive function. In fact, the bone, the cardiovascular system, and extrahypothalamic regions of the brain are now well-established targets of estrogens. Among the numerous aspects of brain function regulated by estrogens are their effects on mood, cognitive function, and neuronal viability. Here, we review the supporting evidence for estrogens as neuroprotective agents and summarize the various mechanisms that may be involved in this effect, focusing particularly on the mitochondria as an important target. On the basis of this evidence, we discuss the clinical applicability of estrogens in treating various age-related disorders, including Alzheimer disease and stroke, and identify the caveats that must be considered.

Simpkins JW, Wen Y, Perez E, Yang S, Wang X. · Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA. · Ann N Y Acad Sci. · Pubmed #16024766 No free full text.

Abstract: Estrogens are potent and efficacious neuroprotectants both in vitro and in vivo in a variety of models of neurotoxicity. We determined the structural requirements for neuroprotection in in vitro assays using a library of more than 70 novel estratrienes, synthesized to reduce or eliminate estrogen receptor (ER) binding. We observed that neuroprotection could be enhanced by as much as 200-fold through modifications that positioned a large, bulky group at the C2 and/or C4 position of the phenolic A ring of the estratriene. Further, substitutions on the B, C, or D rings either reduced or did not markedly change neuroprotection. For this library of compounds, there was a negative correlation between ER binding and neuroprotection, as the more potent compounds showed weaker or no ER binding. In an in vivo model for neuroprotection, transient cerebral ischemia, efficacious compounds were active in protection of brain tissue from this pro-oxidant insult. Finally, estradiol protected brains from insult-induced Alzheimer's disease (AD) neuropathology, including activation of apoptosis, stimulation of Abeta production, hyperphosphorylation of tau, activation of cyclin-dependent kinases, and activation of catastrophic attempts at neuronal mitosis. Collectively, these results demonstrate that nonfeminizing estrogens are neuroprotective and protect the brain from the induction of AD-like neuropathology in an animal model. These features of nonfeminizing estrogens make them attractive compounds for assessment of efficacy in AD and stroke, because they are not expected to show the side effects of chronic estrogen therapy that are ER mediated in the liver, uterus, and breast.

Green PS, Simpkins JW. · Center for the Neurobiology of Aging, College of Pharmacy, University of Florida, Gainesville, Florida 32610, USA. · Ann N Y Acad Sci. · Pubmed #11193809 No free full text.

Abstract: The present position paper is intended to provide evidence that estrogen deprivation contributes to the occurrence and course of Alzheimer's disease (AD) and that currently available estrogen preparations may be useful in the prevention and treatment of AD in women. Additionally, there is now substantial preclinical evidence to support the development of novel non-feminizing estrogens for use in male and female subjects for the protection of neurons from damage and death that underlies the neuropathology of AD. Estrogens and non-feminizing estrogen-like compounds may exert their beneficial effects in AD through a variety of mechanisms, directly through their neuroprotective actions and indirectly through their neurotrophic effects. Inasmuch as estrogens are comparatively free of both acute and chronic toxicities, and non-feminizing estrogens are expected to be even safer, their use for years to decades for the prevention or treatment of AD is possible.

Khachaturian ZS, Snyder PJ, Doody R, Aisen P, Comer M, Dwyer J, Frank RA, Holzapfel A, Khachaturian AS, Korczyn AD, Roses A, Simpkins JW, Schneider LS, Albert MS, Egge R, Deves A, Ferris S, Greenberg BD, Johnson C, Kukull WA, Poirier J, Schenk D, Thies W, Gauthier S, Gilman S, Bernick C, Cummings JL, Fillit H, Grundman M, Kaye J, Mucke L, Reisberg B, Sano M, Pickeral O, Petersen RC, Mohs RC, Carrillo M, Corey-Bloom JP, Foster NL, Jacobsen S, Lee V, Potter WZ, Sabbagh MN, Salmon D, Trojanowski JQ, Wexler N, Bain LJ. · Lou Ruvo Brain Institute, Las Vegas, NV 89106, USA. · Alzheimers Dement. · Pubmed #19328434 No free full text.

Abstract: This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of key scientific and public-policy needs identified in this document will be incorporated by the Alzheimer Study Group into a broader National Alzheimer's Strategic Plan, which will be presented to the 111th Congress and the Obama administration in March 2009. The Alzheimer's Strategic Plan is expected to include additional recommendations for governance, family support, healthcare, and delivery of social services.

Tesco G, Koh YH, Kang EL, Cameron AN, Das S, Sena-Esteves M, Hiltunen M, Yang SH, Zhong Z, Shen Y, Simpkins JW, Tanzi RE. · Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, MA 02129, USA. · Neuron. · Pubmed #17553422 links to  free full text

Abstract: Beta-site APP-cleaving enzyme (BACE) is required for production of the Alzheimer's disease (AD)-associated Abeta protein. BACE levels are elevated in AD brain, and increasing evidence reveals BACE as a stress-related protease that is upregulated following cerebral ischemia. However, the molecular mechanism responsible is unknown. We show that increases in BACE and beta-secretase activity are due to posttranslational stabilization following caspase activation. We also found that during cerebral ischemia, levels of GGA3, an adaptor protein involved in BACE trafficking, are reduced, while BACE levels are increased. RNAi silencing of GGA3 also elevated levels of BACE and Abeta. Finally, in AD brain samples, GGA3 protein levels were significantly decreased and inversely correlated with increased levels of BACE. In summary, we have elucidated a GGA3-dependent mechanism regulating BACE levels and beta-secretase activity. This mechanism may explain increased cerebral levels of BACE and Abeta following cerebral ischemia and existing in AD.

Wen Y, Yang S, Liu R, Brun-Zinkernagel AM, Koulen P, Simpkins JW. · Department of Pharmacology, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA. · J Biol Chem. · Pubmed #14982935 links to  free full text

Abstract: Aberrant mitosis occurs in many tauopathy-related neurodegenerative diseases and is believed to precede the formation of neurofibrillary tangles. In this study, we report for the first time that transient cerebral ischemia induces aberrant mitotic proteins and hyperphosphorylation of tau protein with neurofibrillary tangle-like conformational epitopes in adult female rat cortex. Following transient cerebral ischemia in rats, initiation of apoptosis precedes and is potentially integrated with subsequent aberrant mitosis and tau hyperphosphorylation. Furthermore, inhibition of mitosis-related cyclin-dependent kinases (Cdks) by roscovitine significantly reduced the hyperphosphorylation of tau. Administration of the female sex steroid and potent neuroprotective agent, 17beta-estradiol, reduced ischemia-reperfusion-induced cerebral damage and the subsequent aberrant mitosis and tauopathies. These results provide a neuropathological basis for the higher prevalence of dementia in stroke patients and support the hypothesis that apoptosis and aberrant mitosis are integrated pathological events in neurons that may play a critical role in the development of Alzheimer's disease and other tauopathy-related neuropathology.

Liang Y, Belford S, Tang F, Prokai L, Simpkins JW, Hughes JA. · Department of Pharmaceutics, University of Florida, Gainesville, FL 32610, USA. · Brain Res Bull. · Pubmed #11403993 No free full text.

Abstract: Estrogens have demonstrable neuroprotective effects. This fact has lead to the proposed use of estrogens for the prevention and/or treatment of Alzheimer's disease. The exact protective mechanism estrogens provide is not fully understood. In this report, a potential non-genomic mechanism for estratrienes involving alterations in membrane fluidity was studied. Steroids, such as estrogen, are known to be membrane-active and can alter the lipid packing. In this study we used fluorescent methodologies to address the effect of naturally occurring steroids (17alpha and 17beta-estradiol, testosterone, and progesterone) and new estratriene analogs on membrane fluidity using liposomes and HT-22 hippocampal cells. The study's results indicate steroids, based on the estratriene nucleus, can modulate lipid packing as evidenced by (1) decreased membrane fusion events and (2) decreased membrane fluidity. The effects on the membrane were both time and concentration dependent. It was also demonstrated through rational design estratriene analogs can be synthesized with enhanced membrane effects. Finally, in a glutamate-induced toxicity HT-22 model, we also demonstrated cellular protection with the estratriene-based molecules and analogs. The data suggest the plethora of cellular actions of estrogens may relate to or be influenced by membrane effects of the steroid.

Simpkins JW, Singh M. · No affiliation provided · J Womens Health (Larchmt). · Pubmed #15650349 No free full text.

This publication has no abstract.