Alzheimer Disease: Texas

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.

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Doody RS. · Effie Marie Cain Chair in Alzheimer's Disease Research, Baylor College of Medicine, Houston, TX, USA. · Alzheimers Dement. · Pubmed #19328443 No free full text.

Abstract: Despite enormous worldwide public and private interest in improving the prevention and treatment of Alzheimer's disease (AD), we have not made as much of an impact as we would like, and the number of affected individuals continues to grow. Even more alarmingly, whereas global efforts to identify AD cases and to develop new treatments are increasing, patient-care options are disappearing, so that even if a highly efficacious therapy or prevention approach arose, it would not be used effectively. As a first step toward organizing a better way forward, we should establish AD centers of excellence that mandate both patient care and research in the same setting. These centers would benefit from changes in public health policies related to chronic-disease surveillance, Center for Medicare and Medicaid Services funding for the care of chronic diseases, institutional review boards, good clinical practice guidelines, National Institutes of Health regulations for the use of research funds, Food and Drug Administration guidelines for the approval of AD drugs, and Department of Commerce regulations related to patent protection of AD diagnostic aids and treatments. This new form of AD centers of excellence would also provide direct care to many patients and their families, model care for communities and medical trainees, enhance the voluntary recruitment of AD patients to clinical trials, and improve our understanding of AD and its management.

Weiner MF. · Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA. · Alzheimers Dement. · Pubmed #18631972 links to  free full text

Abstract: There are adequate scientific, public health, and ethical justifications for studying Alzheimer's disease (AD) in persons of varying race and ethnicity, but to be meaningful variables, race and ethnicity must be examined in context. The complex interactions between race, ethnicity, lifestyle, and environmental factors, such as climate and diet, require that future studies of AD in specific racial or ethnic groups attend to measures of racial/ethnic homogeneity and the assessment of the environment and the elements that comprise the ethnicity of groups under study. Instead of arbitrarily selecting specific racial or ethnic groups in the hope of finding important differences, it may be in the long run less costly and more efficient to recruit families with highly positive (or negative) family histories, to search within these groups for possible racial or ethnic differences, and to investigate the possible racial or ethnic reasons for those differences.

Royall DR. · Division of Aging and Geriatric Psychiatry, The University of Texas, Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900, Mail Code 7792, United States. · Neurobiol Aging. · Pubmed #17055613 No free full text.

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Herz J. · Department of Molecular Genetics, UT Southwestern, Dallas, Texas 75390-9046, USA. · Curr Opin Lipidol. · Pubmed #19433918 No free full text.

Abstract: PURPOSE OF REVIEW: Over the past few years, apolipoprotein E (ApoE) receptors, also known as LDL receptor-related proteins, have distinguished themselves as functionally diverse signaling receptors with pivotal roles not only in the vascular system but also in the nervous system and during development. RECENT FINDINGS: The expanding roles of ApoE receptors for cellular signal transduction at the same time transcend and integrate their lipid transport roles into a larger biological and clinical context. ApoE receptors are essential for the development of the nervous system, the regulation of synaptic plasticity, neuroprotection and the innervation of the muscle. They also regulate the metabolism of the amyloid precursor protein on multiple levels, implicating them in the pathogenesis of Alzheimer's disease. SUMMARY: ApoE, a common ligand for all members of the evolutionarily ancient LDL receptor gene family, is the major genetic modifier of the age of onset of Alzheimer's disease. The underlying molecular mechanisms remain shrouded in mystery, but the numerous critical functions of ApoE receptors within and outside the nervous system that have recently emerged make it likely that these multifunctional signal modulators participate in Alzheimer's disease pathogenesis. This review attempts to summarize the most recent and relevant findings in this area.

Smith DA. · Family Medicine, College of Medicine, Texas A&M University, College Station, TX, USA. · Am J Health Syst Pharm. · Pubmed #19420308 No free full text.

Abstract: PURPOSE: Pharmacologic treatment for patients with Alzheimer's disease (AD) who reside in long-term-care (LTC) facilities is discussed. SUMMARY: The recognition of AD can be problematic in patients residing in LTC who do not have a preexisting diagnosis of dementia. Residents in LTC facilities generally have fewer day-to-day cognitive demands, and, thus, nursing staff or caregivers may not recognize cognitive deficits until the disease is more advanced. The current therapeutic options for the treatment of AD are the cholinesterase inhibitors (ChEIs) and the N-methyl-d-aspartate receptor antagonist memantine. The ChEIs rivastigmine and galantamine are currently approved for the treatment of mild-to-moderate AD, and memantine is approved for the treatment of moderate-to-severe AD. The ChEI donepezil is presently approved for the treatment of mild, moderate, and severe AD in the United States. Two placebo-controlled trials in nursing-home patients receiving donepezil have been published. In both studies, donepezil appeared to be safe and effective for the treatment of AD in patients residing in LTC facilities. Data from an open-label study suggest that rivastigmine treatment might also provide benefits in nursing-home patients with moderate-to-severe AD. Another study demonstrated that treatment with galantamine might delay the need for transfer from an assisted-living facility to a nursing home. The effectiveness and safety of memantine have been assessed in a subgroup of patients with severe AD residing in LTC facilities. There were no major differences in safety and tolerability between the active treatment group and placebo. The relative and clinical importance of the cognitive, functional, and behavioral changes observed in LTC patients treated with ChEIs and memantine remain to be identified. CONCLUSION: Pharmacologic treatment should be recommended for most patients with AD who reside in LTC facilities.

Bezprozvanny I. · Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. · Sci Signal. · Pubmed #19318622 No free full text.

Abstract: The brains of patients with Alzheimer's disease (AD) contain abundant plaques composed of beta-amyloid (Abeta) peptides. It has been assumed that amyloid plaques and soluble Abeta oligomers induce neuronal pathology in AD; however, the mechanism by which amyloid mediates pathological effects is not clearly understood. In vivo calcium (Ca2+) imaging and array tomography studies with AD mouse models are providing new insights into the changes that occur in brain structure and function as a result of amyloid plaque accumulation. The unexpected lesson from these studies is that amyloid plaques result in both localized and global changes in brain function. The amyloid-induced effects include short-range changes in neuronal Ca2+ concentrations, medium-range changes in neuronal activity and synaptic density, and long-range changes in Ca2+ signaling in astrocytes and induction of intracellular Ca2+ waves spreading through a network of astrocytes. These results have potential implications for understanding synaptic and neuronal network dysfunction in AD brains.

Shub D, Darvishi R, Kunik ME. · Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas, USA. · Geriatrics. · Pubmed #19256583 No free full text.

Abstract: The prevalence of insomnia increases with age and affects up to 35% of community-dwelling adults with dementia. Sleep disturbances and associated cognitive and behavioral symptoms in this patient population can be a significant contributor to morbidity, mortality, and caregiver burden. Despite the frequency with which sleep disorders are encountered in primary care, few evidence-based guidelines are available to guide physician treatment plans. Sedative-hypnotic medications are commonly prescribed but are associated with significant adverse effects and have limited efficacy data. Non-pharmacologic treatments can be safe and effective adjuncts or alternatives to medications but are often underused in clinical practice. This article reviews practical applications of modalities such as light therapy, exercise, and sleep-hygiene modification in treating insomnia in persons with dementia.

Aliev G, Obrenovich ME, Reddy VP, Shenk JC, Moreira PI, Nunomura A, Zhu X, Smith MA, Perry G. · Department of Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249, USA. · Mini Rev Med Chem. · Pubmed #18991755 No free full text.

Abstract: Alzheimer disease treatment has yet to yield a successful therapy that addresses the source of the damage found in brains. Of the varied proposed theories of AD etiology, reactive oxygen species (ROS) generation is cited as a common factor. Efforts to reduce the pathology associated with ROS via antioxidants therefore offer new hope to patients suffering from this devastative disease.

Doody RS. · Alzheimer's Disease and Memory Disorders Center, Baylor College of Medicine, Houston, Texas, USA. · CNS Spectr. · Pubmed #18955960 links to  free full text

This publication has no abstract.

Bogdanov M, Mileykovskaya E, Dowhan W. · Department of Biochemistry and Molecular Biology, University of Texas-Houston, Houston, TX 77030, USA. · Subcell Biochem. · Pubmed #18751913 links to  free full text

Abstract: Lipids play important roles in cellular dysfunction leading to disease. Although a major role for phospholipids is in defining the membrane permeability barrier, phospholipids play a central role in a diverse range of cellular processes and therefore are important factors in cellular dysfunction and disease. This review is focused on the role of phospholipids in normal assembly and organization of the membrane proteins, multimeric protein complexes, and higher order supercomplexes. Since lipids have no catalytic activity, it is difficult to determine their function at the molecular level. Lipid function has generally been defined by affects on protein function or cellular processes. Molecular details derived from genetic, biochemical, and structural approaches are presented for involvement of phosphatidylethanolamine and cardiolipin in protein organization. Experimental evidence is presented that changes in phosphatidylethanolamine levels results in misfolding and topological misorientation of membrane proteins leading to dysfunctional proteins. Examples are presented for diseases in which proper protein folding or topological organization is not attained due to either demonstrated or proposed involvement of a lipid. Similar changes in cardiolipin levels affects the structure and function of individual components of the mitochondrial electron transport chain and their organization into supercomplexes resulting in reduced mitochondrial oxidative phosphorylation efficiency and apoptosis. Diseases in which mitochondrial dysfunction has been linked to reduced cardiolipin levels are described. Therefore, understanding the principles governing lipid-dependent assembly and organization of membrane proteins and protein complexes will be useful in developing novel therapeutic approaches for disorders in which lipids play an important role.

Adler G, Silverstein NM. · Graduate College of Social Work, University of Houston, Houston, Texas 77204-4013, USA. · Traffic Inj Prev. · Pubmed #18696385 No free full text.

Abstract: OBJECTIVE: This manuscript addresses the following questions for licensing authorities: 1) Are drivers with Alzheimer's disease (AD) an issue that should concern licensing authorities? 2) What critical driving skills impacted by AD should authorities recognize? 3) What should their response be? 4) Do licensing authorities have a role in providing information about or referral to community agencies that offer alternative transportation options and other services? METHODS: To address issues important to licensing authorities the authors reviewed pertinent driving and dementia literature. RESULTS: Drivers with AD have unique impairments that should be recognized and responded to early on in the disease process, with sensitivity and respect for continued mobility. As the disease progresses and they must stop driving, former drivers and their families could benefit from resource referrals that provide information about transportation alternatives and support services in their communities. CONCLUSIONS: The authors believe that drivers with AD should be a concern for licensing authorities. Licensing decisions and policies to assess and regulate drivers are in the end made individually by each state. Policymakers will make their decisions based upon current research and concerns of their constituency and need to consider a seamless approach to addressing safe mobility. Licensing authorities are an important partner along with individuals, family members, health care professionals, social service providers, researchers, and policymakers in assuring public safety and individual mobility. All of the partners should confront the concern directly-none should "look the other way." The goal is to keep people driving safely for as long as possible. The responsibility is to recognize, respond, and refer when driving safely is no longer assured.

Bezprozvanny I, Mattson MP. · Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · Trends Neurosci. · Pubmed #18675468 links to  free full text

Abstract: Perturbed neuronal Ca(2+) homeostasis is implicated in age-related cognitive impairment and Alzheimer's disease (AD). With advancing age, neurons encounter increased oxidative stress and impaired energy metabolism, which compromise the function of proteins that control membrane excitability and subcellular Ca(2+) dynamics. Toxic forms of amyloid beta-peptide (Abeta) can induce Ca(2+) influx into neurons by inducing membrane-associated oxidative stress or by forming an oligomeric pore in the membrane, thereby rendering neurons vulnerable to excitotoxicity and apoptosis. AD-causing mutations in the beta-amyloid precursor protein and presenilins can compromise these normal proteins in the plasma membrane and endoplasmic reticulum, respectively. Emerging knowledge of the actions of Ca(2+) upstream and downstream of Abeta provides opportunities to develop novel preventative and therapeutic interventions for AD.

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.

Bernardo CG, Singh V, Thompson PM. · University of Texas Health Science Center at San Antonio, Center for Bipolar Intervention in the Hispanic Community, Division of Mood and Anxiety Disorders, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA. · Expert Opin Drug Saf. · Pubmed #18613807 No free full text.

Abstract: BACKGROUND: Psychiatric disorders and symptoms, ranging from mood dysregulation to delirium, are commonly observed in many neurological disorders. These manifestations complicate the illness and worsen prognosis. Pharmacological treatment options may be limited by the primary neurological illness and side effects. OBJECTIVE: This paper aims to review the safety and efficacy of pharmacological agents used to treat psychiatric manifestations of several common neurological conditions, including Alzheimer's disease (AD), post-stroke, traumatic brain injury (TBI) and epilepsy. METHODS: Systematic review of the Medline database for articles published between 2000 and 2007 was done to retrieve relevant articles. RESULTS: The paucity of controlled data on the pharmacological treatments of psychiatric manifestations of neurological conditions makes recommendations difficult. CONCLUSION: When secondary depression, mania, anxiety, and delirium remain after treatment of the underlying condition, clinical experience and the limited research indicates that judicious pharmacological interventions may effectively treat mood dysregulation, delirium and agitation.

Royall DR. · Department of Psychiatry, South Texas Veterans Health System Audie L. Murphy Division, Geriatric Research Education and Clinical Center, San Antonio, TX, USA. · Cleve Clin J Med. · Pubmed #18540156 links to  free full text

Abstract: Right hemisphere dysfunction is associated with mortality in Alzheimer's disease (AD) and other neurologic conditions. These associations may be mediated by insular pathology, as insular lesions result in demonstrable changes in cardiovascular and autonomic control. AD affects the insulae at a preclinical stage, and insular AD pathology may be present in up to 40% of nondemented septuagenarians and octogenarians. This pathology can affect in vivo cardiac conduction and thereby dispose to cardiac arrhythmias and sudden death. Thus, AD pathology should be considered as a possible explanation for autonomic morbidity and mortality in nondemented elderly persons.

Taguchi H, Planque S, Nishiyama Y, Szabo P, Weksler ME, Friedland RP, Paul S. · Chemical Immunology Research Center, University of Texas Houston Medical School, Houston, TX 77030, USA. · Autoimmun Rev. · Pubmed #18486927 links to  free full text

Abstract: Immunoglobulins (Igs) that bind amyloid beta peptide (Abeta) are under clinical trials for immunotherapy of Alzheimer disease (AD). We have identified IgMs and recombinant Ig fragments that hydrolyze Abeta. Hydrolysis of peripheral Abeta by the IgMs may induce increased Abeta release from the brain. The catalytic IgMs are increased in AD patients, presumably reflecting a protective autoimmune response. Reduced Abeta aggregation and neurotoxicity attributable to the catalytic function were evident. These findings provide a foundation for development of catalytic Igs for AD immunotherapy.

Boldogh I, Kruzel ML. · Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, TX 77555, USA. · J Alzheimers Dis. · Pubmed #18430998 No free full text.

Abstract: Colostrum-derived proline-rich polypeptide, also known as Colostrinin (CLN), has been shown to have a stabilizing effect on cognitive function in Alzheimer's disease patients. This complex action of CLN could be related to prevention of amyloid-beta peptide aggregation, as shown in in vitro studies, and its impact on delicate cassettes of signaling pathways common to cellular redox regulation, proliferation and differentiation. Studies on cultured cells showed that CLN modulates intracellular levels of reactive oxygen species (ROS), via regulation of glutathione metabolism, activity of antioxidant enzymes and mitochondria function. Due to an improvement in senescence-associated mitochondrial dysfunction and a decrease in ROS generation, CLN decelerates the aging processes of both cultured cells and experimental animals. When given orally to mice, CLN increased the lifespan and improved various motor and sensory activities. Although the molecular basis by which CLN exerts its diverse effects are still under investigation, the regulatory effect on the cellular redox state via maintenance of mitochondrial function and modification of ROS-induced cell signaling seem to be of great importance. In this article, we examine experimental data pertinent to the mechanism of action, including a review of CLN's utility in the maintenance of physiological processes in which oxidative stress has an etiological role.

Dries DR, Yu G. · Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA. · Curr Alzheimer Res. · Pubmed #18393798 links to  free full text

Abstract: In this review, we discuss the biology of gamma-secretase, an enigmatic enzyme complex that is responsible for the generation of the amyloid-beta peptide that constitutes the amyloid plaques of Alzheimer's disease. We begin with a brief review on the processing of the amyloid precursor protein and a brief discussion on the family of enzymes involved in regulated intramembrane proteolysis, of which gamma-secretase is a member. We then identify the four major components of the gamma-secretase complex - presenilin, nicastrin, Aph-1, and Pen-2 - with a focus on the identification of each and the role that each plays in the maturation and activity of the complex. We also discuss two new proteins that may play a role in modulating the assembly and activity of the gamma-secretase complex. Next, we summarize the known subcellular locations of each gamma-secretase component and the sites of gamma-secretase activity, as defined by the production of Abeta. Finally, we close by synthesizing all of the included topics into an overarching model for the assembly and trafficking of the gamma-secretase complex, which serves as a launching point for further questions into the biology and function of gamma-secretase in Alzheimer's disease.

Orr JD. · Neurology Associates of Arlington, 2800 E. Broad Street, Mansfield, TX 76063, USA. · Curr Atheroscler Rep. · Pubmed #18366980 No free full text.

Abstract: Overwhelming evidence now shows that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (ie, statins) are safe and effective in primary and secondary prevention of cardiovascular disease. Atherosclerosis, the primary cause of heart disease, is directly and independently related to hypercholesterolemia and inflammation, and statins have multiple and independent effects on these conditions. New evidence for the use of statins in neurologic disease is mounting, and the range of therapeutic applications is formidable. Statins are beginning to show benefits in a wide range of neurologic conditions, from common ischemic stroke to rare congenital neurometabolic storage diseases, from acute brain injury to chronic central nervous system inflammation, and from prevention of neurodegenerative disease to acute neuroprotection. A diverse therapeutic spectrum is explained by shared pathogenetic mechanisms of neurologic disease and the manifold pharmacodynamic effects of statins.

Antai-Otong D. · Fort Worth Outpatient Clinic, Department of Veterans Affairs in Fort Worth, TX, USA. <> · Perspect Psychiatr Care. · Pubmed #18366366 No free full text.

This publication has no abstract.

Waring SC, Rosenberg RN. · Department of Epidemiology, The University of Texas School of Public Health, 1200 Herman Pressler, RAS-E629, Houston, TX 77030, USA. · Arch Neurol. · Pubmed #18332245 links to  free full text

Abstract: The genetics of Alzheimer disease (AD) to date support an age-dependent dichotomous model whereby earlier age of disease onset (< 60 years) is explained by 3 fully penetrant genes (APP [NCBI Entrez gene 351], PSEN1 [NCBI Entrez gene 5663], and PSEN2 [NCBI Entrez gene 5664]), whereas later age of disease onset (> or = 65 years) representing most cases of AD has yet to be explained by a purely genetic model. The APOE gene (NCBI Entrez gene 348) is the strongest genetic risk factor for later onset, although it is neither sufficient nor necessary to explain all occurrences of disease. Numerous putative genetic risk alleles and genetic variants have been reported. Although all have relevance to biological mechanisms that may be associated with AD pathogenesis, they await replication in large representative populations. Genome-wide association studies have emerged as an increasingly effective tool for identifying genetic contributions to complex diseases and represent the next frontier for furthering our understanding of the underlying etiologic, biological, and pathologic mechanisms associated with chronic complex disorders. There have already been success stories for diseases such as macular degeneration and diabetes mellitus. Whether this will hold true for a genetically complex and heterogeneous disease such as AD is not known, although early reports are encouraging. This review considers recent publications from studies that have successfully applied genome-wide association methods to investigations of AD by taking advantage of the currently available high-throughput arrays, bioinformatics, and software advances. The inherent strengths, limitations, and challenges associated with study design issues in the context of AD are presented herein.

Miller LJ. · Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas 77030, USA. · Consult Pharm. · Pubmed #18198970 No free full text.

Abstract: OBJECTIVE: To review the literature for double-blind, placebo-controlled trials that examined the efficacy of cognitive enhancers in the psychopathology of Alzheimer's disease. DATA SOURCES: Literature searches were conducted using MEDLINE and EMBASE databases and clinicaltrials.gov. STUDY SELECTION: Overall, 55 articles were reviewed for inclusion. Several open-label studies and case reports were found on this topic, but only those involving both tacrine and use of the Neuropsychiatric Inventory were included. Regarding other drugs, only double-blind, placebo-controlled trials were selected for inclusion. DATA SYNTHESIS: Limited data suggest that the anticholinesterase inhibitors and memantine offer an alternative or adjunct to the antipsychotics for the treatment of moderate-to-severe behaviors. The author reviewed the literature for pharmacological management of behavioral and psychological symptoms of dementia (BPSD) using these cognitive enhancers. CONCLUSION: The majority of patients with Alzheimer's disease will experience behavioral disturbances during the course of their disease. Atypical antipsychotics are used routinely in these situations to treat the psychotic features and agitation. However, atypicals now carry a "black box" warning issued by the Food and Drug Administration on the basis of evidence that their use in geriatric patients with dementia-related psychosis may put patients at increased risk of mortality as a result of cardiovascular or infectious events. An alternative to the atypicals may be the acetylcholinesterase inhibitors and memantine, which have been shown to stabilize cognitive as well as behavioral issues in patients, utilizing the "gold standard" for behavior, the Neuropsychiatric Inventory. Efficacy varies among agents, with the greatest positive effects seen with donepezil, which also has the greatest number of studies. Drug benefits were harder to demonstrate for mild-to-moderate BPSD compared with moderate-to-severe symptoms.

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.

Das HK. · Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas 76107, USA. · Front Biosci. · Pubmed #17981591 No free full text.

Abstract: Two (amyloid and presenilin) hypotheses have been proposed to explain the pathogenesis of Alzheimer's disease (AD). According to amyloid hypothesis, the main amyloid plaques which are hallmark of AD are generated by beta- and gamma-secretase mediated proteolytic processing of amyloid precursor protein (APP). The amyloid hypothesis does not adequately address the pathogenesis of the disease, however, since transgenic mice that express the pathologic mutations of the APP and presenilin-1 (PS1) genes produce amyloid plaques but fail to exhibit neurodegeneration and memory loss observed in AD patients. According to presenilin hypothesis, loss of essential functions of PS due to decreased PS expression or mutations in the PS genes better explains the pathogenesis of AD. Recent studies have revealed that forebrain specific conditional knockouts of PS1 and PS2 genes (cPSKO) cause both neuronal degeneration and memory loss without evidence of formation of amyloid plaques. Another potential mechanism for the pathogenesis of AD may reside at the transcriptional regulation of the presenilin-1 gene. In this review, a detailed analysis of transcription factors that regulate PS1 transcription will be discussed. An in depth understanding of the regulatory mechanism of PS1 transcription can identify the targets that can potentially be used in therapeutic intervention of AD.