Alzheimer Disease: Casadesus G

Tezapsidis N, Johnston JM, Smith MA, Ashford JW, Casadesus G, Robakis NK, Wolozin B, Perry G, Zhu X, Greco SJ, Sarkar S. · Neurotez, Inc., Bridgewater, New Jersey 08807, USA. · J Alzheimers Dis. · Pubmed #19387109 No free full text.

Abstract: Adipocyte-derived leptin appears to regulate a number of features defining Alzheimer's disease (AD) at the molecular and physiological level. Leptin has been shown to reduce the amount of extracellular amyloid beta, both in cell culture and animal models, as well as to reduce tau phosphorylation in neuronal cells. Importantly, chronic administration of leptin resulted in a significant improvement in the cognitive performance of transgenic animal models. In AD, weight loss often precedes the onset of dementia and the level of circulating leptin is inversely proportional to the severity of cognitive decline. It is speculated that a deficiency in leptin levels or function may contribute to systemic and CNS abnormalities leading to disease progression. Furthermore, a leptin deficiency may aggravate insulin-controlled pathways, known to be aberrant in AD. These observations suggest that a leptin replacement therapy may be beneficial for these patients.

Lee HG, Casadesus G, Zhu X, Castellani RJ, McShea A, Perry G, Petersen RB, Bajic V, Smith MA. · Department of Pathology, Case Western Reserve University, Cleveland, OH, USA. · Neurochem Int. · Pubmed #19114068 No free full text.

Abstract: As one of the earliest pathologic changes, the aberrant re-expression of many cell cycle-related proteins and inappropriate cell cycle control in specific vulnerable neuronal populations in Alzheimer's disease (AD) is emerging as an important component in the pathogenesis leading to AD and other neurodegenerative diseases. These events are clearly representative of a true cell cycle, rather than epiphenomena of other processes since, in AD and other neurodegenerative diseases, there is a true mitotic alteration that leads to DNA replication. While the exact role of cell cycle re-entry is unclear, recent studies using cell culture and animal models strongly support the notion that the dysregulation of cell cycle in neurons leads to the development of AD-related pathology such as hyperphosphorylation of tau and amyloid-beta deposition and ultimately causes neuronal cell death. Importantly, cell cycle re-entry is also evident in mutant amyloid-beta precursor protein and tau transgenic mice and, as in human disease, occurs prior to the development of the pathological hallmarks, neurofibrillary tangles and amyloid-beta plaques. Therefore, the study of aberrant cell cycle regulation in model systems, both cellular and animal, may provide extremely important insights into the pathogenesis of AD and also serve as a means to test novel therapeutic approaches.

Pallas M, Camins A, Smith MA, Perry G, Lee HG, Casadesus G. · Unitat de Farmacologia, Facultat de Farmàcia Institut de Biomedicina Universitat de Barcelona (IBUB), Nucli Universitari de Pedralbes, Barcelona, Spain. · J Alzheimers Dis. · Pubmed #19096160 No free full text.

Abstract: Current mouse models of Alzheimer's disease (AD) are restricted to the expression of AD-related pathology associated with specific mutations present in early-onset familial AD and thus represent < 5% of AD cases. To date there are no mouse lines that model late-onset/age-related AD, the feature which accounts for the vast majority of cases. As such, based on current mutation-associated models, the chronology of events that lead to the disease in the aged population is difficult to establish. However, published data show that senescence-accelerated mouse (SAMP8), as a model of aging, display many features that are known to occur early in the pathogenesis of AD such as increased oxidative stress, amyloid-beta alterations, and tau phosphorylation. Therefore, SAMP8 mice may be an excellent model for studying the earliest neurodegenerative changes associated with AD and provide a more encompassing picture of human disease, a syndrome triggered by a combination of age-related events. Here, the neurochemical, neuropathological, and behavioral alterations, characterized in SAMP8 mice are critically reviewed and discussed in relation to the potential use of this mouse model in the study of AD pathogenesis.

Casadesus G, Rolston RK, Webber KM, Atwood CS, Bowen RL, Perry G, Smith MA. · Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106, USA. · Adv Clin Chem. · Pubmed #18429496 No free full text.

Abstract: For decades, Alzheimer's disease (AD) has been linked to aging, gender, and menopause. Not surprisingly, this led most investigators to focus on the role of estrogen. While undoubtedly important, estrogen is unlikely the key determinant of disease pathogenesis. Rather, it appears that estrogen may work in conjunction with a novel determinant of disease pathogenesis, namely gonadotropins. The fact that gonadotropins, specifically luteinizing hormone, play a pivotal role in disease is apparent from significant etiological, epidemiological, and pathological evidences. Moreover, targeting gonadotropins appears to have beneficial actions as a therapeutic regimen.

Webber KM, Casadesus G, Bowen RL, Perry G, Smith MA. · Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106, USA. · Endocr Metab Immune Disord Drug Targets. · Pubmed #18220951 No free full text.

Abstract: Epidemiological and experimental data supporting a role for luteinizing hormone in Alzheimer disease is accumulating. Paralleling the female predominance for developing Alzheimer disease, luteinizing hormone levels are significantly higher in females as compared to males and luteinizing hormone levels are higher still in individuals who succumb to Alzheimer disease. Importantly, luteinizing hormone, which is capable of modulating cognitive behavior, is not only present in the brain, but also has the highest receptor levels in the hippocampus, a key processor of cognition that is severely deteriorated in Alzheimer disease. These findings, together with data indicating that luteinizing hormone modulates amyloid-beta protein precursor processing in vivo and in vitro, suggests that luteinizing hormone may contribute to Alzheimer disease pathology through an amyloid-dependent mechanism. Indeed, abolishing luteinizing hormone, using a potent gonadotropin-lowering agent, leuprolide acetate, in the amyloid-beta protein precursor transgenic mice improved hippocampally-related cognitive performance and decreased amyloid-beta deposition. These promising findings support the importance of luteinizing hormone in Alzheimer disease and bring to the forefront an alternative, and much needed therapeutic avenue for the treatment of this insidious disease.

Webber KM, Perry G, Smith MA, Casadesus G. · Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · Clin Med Res. · Pubmed #18056027 links to  free full text

Abstract: Several hypotheses have been proposed that attempt to explain the pathogenesis of Alzheimer Disease (AD) including theories involving senile plaque and neurofibrillary tangle formation, increased oxidative stress, and cell cycle abnormalities, since evidence for each of these pathological phenomena have been well documented in AD. Recent epidemiological and experimental data also support a role for the gonadotropin luteinizing hormone in AD. Paralleling the female predominance for developing AD, luteinizing hormone levels are significantly higher in females as compared to males, and furthermore, luteinizing hormone levels are higher still in individuals who succumb to AD. Luteinizing hormone, which is capable of modulating cognitive behavior, is not only present in the brain, but also has the highest receptor levels in the hippocampus, a key processor of cognition that is severely deteriorated in AD. Furthermore, we recently examined cognitive performance in a well-characterized transgenic mouse that over-expresses luteinizing hormone and found that these animals show decreased cognitive performance when compared to controls. We have also found that abolishing luteinizing hormone in amyloid-beta protein precursor transgenic mice (Tg2576) using a potent gonadotropin-lowering gonadotropin-releasing hormone agonist, leuprolide acetate, resulted in improved hippocampally-related cognitive performance and decreased amyloid-beta deposition. These findings, together with data indicating that luteinizing hormone modulates amyloid-beta protein precursor processing in vivo and in vitro, suggest that luteinizing hormone may contribute to AD pathology through an amyloid-dependent mechanism. These promising findings support the importance of luteinizing hormone in AD and bring to the forefront an alternative, and much needed, therapeutic avenue for the treatment of this insidious disease.

Petersen RB, Nunomura A, Lee HG, Casadesus G, Perry G, Smith MA, Zhu X. · Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. · J Alzheimers Dis. · Pubmed #17522439 No free full text.

Abstract: It has now been established through multiple lines of evidence that oxidative stress is an early event in Alzheimer's disease, occurring prior to the canonical cytopathology. Thus, oxidative stress likely plays a key pathogenic role in the disease and is clearly involved in the cell loss and other neuropathology associated with Alzheimer's disease as demonstrated by the large number of metabolic signs of oxidative stress and by markers of oxidative damage. One puzzling observation, however, is that oxidative damage decreases with disease progression, such that levels of markers of rapidly formed oxidative damage, which are initially elevated, decrease as the disease progresses to advanced Alzheimer's disease. This finding indicates that reactive oxygen species not only cause damage to cellular structures but also provoke cellular responses, such as the compensatory upregulation of antioxidant enzymes found in vulnerable neurons in Alzheimer's disease. Not surprisingly, stress-activated protein kinase pathways, which are activated by oxidative stress, are extensively activated during Alzheimer's disease. In this review, we present the evidence of oxidative stress and compensatory responses that occur in Alzheimer's disease with a particular focus on the roles and mechanism of activation of stress-activated protein kinase pathways.

Casadesus G, Moreira PI, Nunomura A, Siedlak SL, Bligh-Glover W, Balraj E, Petot G, Smith MA, Perry G. · Department of Neuroscience, Case Western Reserve University, Cleveland, OH, USA. · Neurochem Res. · Pubmed #17342408 No free full text.

Abstract: Metabolic alterations are a key player involved in the onset of Alzheimer disease pathophysiology and, in this review, we focus on diet, metabolic rate, and neuronal size differences that have all been shown to play etiological and pathological roles in Alzheimer disease. Specifically, one of the earliest manifestations of brain metabolic depression in these patients is a sustained high caloric intake meaning that general diet is an important factor to take in account. Moreover, atrophy in the vasculature and a reduced glucose transporter activity for the vessels is also a common feature in Alzheimer disease. Finally, the overall size of neurons is larger in cases of Alzheimer disease than that of age-matched controls and, in individuals with Alzheimer disease, neuronal size inversely correlates with disease duration and positively associates with oxidative stress. Overall, clarifying cellular and molecular manifestations involved in metabolic alterations may contribute to a better understanding of early Alzheimer disease pathophysiology.

Zhu X, Smith MA, Honda K, Aliev G, Moreira PI, Nunomura A, Casadesus G, Harris PL, Siedlak SL, Perry G. · Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · J Neurol Sci. · Pubmed #17337008 links to  free full text

Abstract: Alzheimer disease and cerebrovascular dementia are two common causes of dementia and, by present diagnostic criteria, are mutually exclusive using vascular pathology as an arbitrary demarcation in differential diagnosis. However, evidence from epidemiological, neuropathological, clinical, pharmacological, and functional studies suggest considerable overlap in risk factors and pathological changes suggesting shared common pathogenic mechanisms between these two diseases such that vascular factors play a vital role in the pathogenesis of Alzheimer disease. A high energy demand and lack of an endogenous fuel reserve make the brain highly dependent upon a continuous blood supply where disruption of cerebral blood vessels and blood flow can have serious consequences on neural activities. Indeed, many studies implicate metabolic defects in Alzheimer disease, such a reduced brain metabolism is one of the best documented abnormalities in the disease. Notably, since endothelial reactive oxygen species such as nitric oxide act as vasodilators at low concentrations, increased production coupled with elevated reactive oxygen species scavenging of nitric oxide, can lead to reduced bioavailability of nitric oxide and increased oxidative stress that damage sensitive vascular cells. In this respect, we and others have demonstrated that oxidative stress is one of the earliest pathological changes in the brain of Alzheimer disease patients and plays a critical role in the vascular abnormalities underlying metabolic defects in Alzheimer disease. Here, we discuss vascular factors in relation to Alzheimer disease and review hypoperfusion as a potential cause by triggering mitochondrial dysfunction and increased oxidative stress initiating the pathogenic process.

Webber KM, Casadesus G, Atwood CS, Bowen RL, Perry G, Smith MA. · Department of Pathology, Case Western Reserve University, Cleveland, OH, USA. · Mol Cell Endocrinol. · Pubmed #17052835 No free full text.

Abstract: 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.

Forero DA, Casadesus G, Perry G, Arboleda H. · Grupo de Neurociencias, Facultad de Medicina e Instituto de Genética, Universidad Nacional de Colombia, Bogotá, Colombia. · J Cell Mol Med. · Pubmed #16989739 No free full text.

Abstract: In this paper, we review experimental advances in molecular neurobiology of Alzheimer's disease (AD), with special emphasis on analysis of neural function of proteins involved in AD pathogenesis, their relation with several signaling pathways and with oxidative stress in neurons. Molecular genetic studies have found that mutations in APP, PS1 and PS2 genes and polymorphisms in APOE gene are implicated in AD pathogenesis. Recent studies show that these proteins, in addition to its role in beta-amyloid processing, are involved in several neuroplasticity-signaling pathways (NMDA-PKA-CREB-BDNF, reelin, wingless, notch, among others). Genomic and proteomic studies show early synaptic protein alterations in AD brains and animal models. DNA damage caused by oxidative stress is not completely repaired in neurons and is accumulated in the genes of synaptic proteins. Several functional SNPs in synaptic genes may be interesting candidates to explore in AD as genetic correlates of this synaptopathy in a "synaptogenomics" approach. Thus, experimental evidence shows that proteins implicated in AD pathogenesis have differential roles in several signaling pathways related to neuromodulation and neurotransmission in adult and developing brain. Genomic and proteomic studies support these results. We suggest that oxidative stress effects on DNA and inherited variations in synaptic genes may explain in part the synaptic dysfunction seen in AD.

Casadesus G, Garrett MR, Webber KM, Hartzler AW, Atwood CS, Perry G, Bowen RL, Smith MA. · Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · Drugs R D. · Pubmed #16752944 No free full text.

Abstract: 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.

Webber KM, Casadesus G, Zhu X, Obrenovich ME, Atwood CS, Perry G, Bowen RL, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106. USA. · Curr Pharm Des. · Pubmed #16472159 No free full text.

Abstract: 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.

Moreira PI, Honda K, Zhu X, Nunomura A, Casadesus G, Smith MA, Perry G. · Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. · Neurology. · Pubmed #16432155 No free full text.

Abstract: Neuronal oxidative stress occurs early in the progression of Alzheimer disease (AD), significantly before the development of the pathologic hallmarks, neurofibrillary tangles, and senile plaques. Study of Down syndrome, cases with autosomal dominant mutation, and sporadic AD all suggest amyloid-beta deposition and hyperphosphorylated tau function as compensatory responses and downstream adaptations to ensure that neuronal cells do not succumb to oxidative damage. Amyloid-beta and tau hyperphosphorylation also define vulnerable muscle cells in sporadic inclusion-body myositis (s-IBM). The role of the structural changes of s-IBM, as in AD, remains to be determined but may mark a critical response yielding a novel balance in oxidant homeostasis.

Joseph JA, Shukitt-Hale B, Casadesus G, Fisher D. · USDA-ARS, Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA. · Neurochem Res. · Pubmed #16187227 No free full text.

Abstract: Aging can be defined as the condition where stressors are not counteracted by protective functions, leading to a dysregulation in development. These changes can be translated into decrements in neuronal functioning accompanied by behavioral declines, such as decreases in motor and cognitive performance, in both humans and animals. When coupled with genetic alterations, the ultimate expression of these changes is seen in diseases such as Alzheimer disease (AD). This association will be discussed in the last section of this chapter. In this review we will describe motor and cognitive deficits in behavior due to aging, and show how these deficits are related to increased vulnerability to oxidative stress, inflammation or signaling. Importantly, using muscarinic receptors as examples, we will also try to show that the sensitivity to these insults may be differentially expressed among neurotransmitter receptor subtypes.

Webber KM, Casadesus G, Marlatt MW, Perry G, Hamlin CR, Atwood CS, Bowen RL, Smith MA. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Rd., Cleveland, OH 44106, USA. · Ann N Y Acad Sci. · Pubmed #16024763 No free full text.

Abstract: 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.

Zhu X, Lee HG, Casadesus G, Avila J, Drew K, Perry G, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, OH, USA. · Mol Neurobiol. · Pubmed #15953822 No free full text.

Abstract: Oxidative stress is a striking feature of susceptible neurons in the Alzheimer's disease brain. Importantly, because oxidative stress is an early event in Alzheimer's disease, proximal to the development of hallmark pathologies, it likely plays an important role in the pathogenesis of the disease. Investigations into the cause of such oxidative stress show that interactions between abnormal mitochondria and disturbed metal metabolism are, at least in part, responsible for cytoplasmic oxidative damage observed in these susceptible neurons, which could ultimately lead to their demise. Oxidative stress not only temporally precedes the pathological lesions of the disease but could also contribute to their formation, which, in turn, could provide some protective mechanism to reduce oxidative stress and ensure that neurons do not rapidly succumb to oxidative insults. In this review, we present the evidence for oxidative stress in Alzheimer's disease and its likely sources and consequence in relation to other pathological changes.

Webber KM, Casadesus G, Perry G, Atwood CS, Bowen R, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · Alzheimer Dis Assoc Disord. · Pubmed #15942328 No free full text.

Abstract: Epidemiological data reporting the predisposition of women to Alzheimer disease has provided researchers with an important clue as to the identity of the driving pathogenic force and lead many to question the potential role of sex steroids, namely estrogen, in disease pathogenesis. However, while estrogen has become the primary focus of research in the field, inconclusive data regarding estrogen replacement therapy has lead some researchers to begin investigating 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. Recently, we proposed that an increase in gonadotropin concentrations, not the decrease in steroid hormone (eg, estrogen) production following menopause/andropause, is a potentially 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. Based on this, we suggest that therapeutic interventions targeted at gonadotropins may both prevent disease in those patients currently asymptomatic or may halt, and even reverse, disease in those currently afflicted.

Webber KM, Raina AK, Marlatt MW, Zhu X, Prat MI, Morelli L, Casadesus G, Perry G, Smith MA. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA. · Mech Ageing Dev. · Pubmed #15936057 No free full text.

Abstract: Several hypotheses have been proposed attempting to explain the pathogenesis of Alzheimer disease including, among others, theories involving amyloid deposition, tau phosphorylation, oxidative stress, metal ion dysregulation and inflammation. While there is strong evidence suggesting that each one of these proposed mechanisms contributes to disease pathogenesis, none of these mechanisms are able to account for all the physiological changes that occur during the course of the disease. For this reason, we and others have begun the search for a causative factor that predates known features found in Alzheimer disease, and that might therefore be a fundamental initiator of the pathophysiological cascade. We propose that the dysregulation of the cell cycle that occurs in neurons susceptible to degeneration in the hippocampus during Alzheimer disease is a potential causative factor that, together with oxidative stress, would initiate all known pathological events. Neuronal changes supporting alterations in cell cycle control in the etiology of Alzheimer disease include the ectopic expression of markers of the cell cycle, organelle kinesis and cytoskeletal alterations including tau phosphorylation. Such mitotic alterations are not only one of the earliest neuronal abnormalities in the disease, but as discussed herein, are also intimately linked to all of the other pathological hallmarks of Alzheimer disease including tau protein, amyloid beta protein precursor and oxidative stress, and even risk factors such as mutations in the presenilin genes. Therefore, therapeutic interventions targeted toward ameliorating mitotic changes would be predicted to have a profound and positive impact on Alzheimer disease progression.

Marlatt MW, Webber KM, Moreira PI, Lee HG, Casadesus G, Honda K, Zhu X, Perry G, Smith MA. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, Ohio 44106, USA. · Curr Med Chem. · Pubmed #15892629 No free full text.

Abstract: In recent years, Alzheimer disease (AD) has received great attention as an incurable and fatal disease that threatens the lives of aging individuals. Debates regarding areas of research and treatment designs have made headlines as scientists in the field question ongoing work. Despite these academic quarrels, significant insights concerning the cellular and molecular basis of AD have illuminated the potential causes and consequences of AD pathogenesis in the human brain. Additionally, assigning relationships among scientific evidence is difficult due to the nature of the disease. It is crucial to note that all findings do not constitute causality as AD has many stages of progression, and therefore a particular finding may reflect disease epiphenomenon. Determining the primary causes of disease are even more problematic when considering that a succinct timeline in which a normal aging brain develops AD-like changes due to a single cause may not be appropriate, as increasing lines of evidence indicate that multiple factors likely contribute to the clinical manifestation of AD. Implications for therapeutic strategies are dramatically affected by viewing AD as a multi-factorial disease state, one specific treatment may not be able to prevent or reverse AD if this is indeed the case. In this regard, the current focus on individual therapeutic targets may prove to be ineffective in the successful treatment of AD; however, if taken in combination, these singular therapies may likely result in the global suppression of AD. In this review, the scientific basis for common AD therapeutics as well as the efficacy of these treatments will be discussed.

Casadesus G, Atwood CS, Zhu X, Hartzler AW, Webber KM, Perry G, Bowen RL, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · Cell Mol Life Sci. · Pubmed #15723165 No free full text.

Abstract: Differences in the prevalence and age of onset of Alzheimer disease (AD) in men and women, and observations that hormone replacement therapy (HRT) may prevent the development of AD, caused many to hypothesize that estrogen deficiency contributes to AD. However, recent trials using estrogen failed to show any benefit in preventing or alleviating the disease. To address this and other inconsistencies in the estrogen hypothesis, we suspect that another hormone of the hypothalamic-pituitary-gonadal axis, luteinizing hormone (LH), as a major factor in AD pathogenesis. Individuals with AD have elevated levels of LH when compared with controls, and both LH and its receptor are present in increased quantities in brain regions susceptible to degeneration in AD. LH is also known to be mitogenic, and could therefore initiate the cell cycle abnormalities known to be present in AD-affected neurons. In cell culture, LH increases amyloidogenic processing of amyloid-beta protein precursor, and in animal models of AD, pharmacologic suppression of LH and FSH reduces plaque formation. Given the evidence supporting a pathogenic role for LH in AD, a trial of leuprolide acetate, which suppresses LH release, has been initiated in patients.

Joseph JA, Shukitt-Hale B, Casadesus G. · US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, and the Institute of Pathology, Case Western Reserve University, Cleveland, USA. · Am J Clin Nutr. · Pubmed #15640496 links to  free full text

Abstract: Despite elegant research involving molecular biology studies and determination of the genetic mechanisms of aging, practical information on how to forestall or reverse the deleterious effects of aging may be years away. If this is the case, then it is prudent to try to establish other methods that can be used now to alter the course of aging. Numerous epidemiologic studies have indicated that individuals who consume diets containing large amounts of fruits and vegetables may reduce their risk for developing age-related diseases such as Alzheimer disease. Research from our laboratory suggested that dietary supplementation with fruit or vegetable extracts high in antioxidants (eg, blueberry or spinach extracts) might decrease the enhanced vulnerability to oxidative stress that occurs in aging. These reductions might be expressed as improvements in motor and cognitive behavior. Additional research suggested that mechanisms in addition to antioxidant and antiinflammatory activities might be involved in the beneficial effects of these extracts; the most important of these might be their ability to increase cellular signaling and neuronal communication.

Casadesus G, Zhu X, Atwood CS, Webber KM, Perry G, Bowen RL, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. · Curr Drug Targets CNS Neurol Disord. · Pubmed #15379604 No free full text.

Abstract: Based on epidemiological and observational studies, estrogen and hormone-replacement therapy were until recently viewed as major factors in the prevention of Alzheimer's disease (AD). However, a recent randomized clinical trial revealed that hormone replacement therapy using estrogen plus progestin may actually exacerbate the incidence of dementia when administered to elderly women. These contradictory reports have cast grave doubt on the role of estrogen in disease pathogenesis and led us to consider an alternate hypothesis that would be consistent with both observations. Specifically, we suspect that hormones of the hypothalamic pituitary gonadal axis such as gonadotropins, that are regulated by estrogen (or in males by testosterone), are involved in the pathogenesis of Alzheimer's disease. One such gonadotropin, luteinizing hormone (LH), is significantly elevated in both the sera and brain tissue of patients with AD and leads to an increased production of amyloid-beta. Importantly, a key role in disease pathogenesis is further supported by the fact that the distribution of neuronal receptors for LH parallels those populations of neurons that degenerate during the course of the disease. That gonadotropins, not estrogen nor testosterone, mediate disease pathogenesis has led to a paradigm shift, not only for the treatment of AD but a wide variety of other age-related diseases. Therefore, the effects of agents that abolish LH, such as leuprolide acetate, which are currently being evaluated in Phase II clinical trials for the treatment of AD, are eagerly anticipated.

Zhu X, Webber KM, Casadesus G, Raina AK, Lee HG, Marlatt M, Hartzler A, Atwood CS, Perry G, Smith MA. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, Ohio 44106, USA. · Curr Drug Targets. · Pubmed #15270202 No free full text.

Abstract: In this review, we discuss the role of cell cycle dysfunction in the pathogenesis of Alzheimer disease and propose that such mitotic catastrophe, as one of the earliest events in neuronal degeneration, may, in fact, be sufficient to initiate the neurodegenerative cascade. The question as to what molecule initiates cell cycle dysfunction is now beginning to become understood and, in this regard, the gender-predication, age-related penetrance and regional susceptibility of specific neuronal populations led us to consider luteinizing hormone as a key mediator of the abnormal mitotic process. As such, agents targeted toward luteinizing hormone or downstream sequelae may be of great therapeutic value in the treatment of Alzheimer disease.

Lee HG, Casadesus G, Zhu X, Takeda A, Perry G, Smith MA. · Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · Ann N Y Acad Sci. · Pubmed #15246983 No free full text.

Abstract: Ever since their initial description over a century ago, senile plaques and their major protein component, amyloid-beta, have been considered key contributors to the pathogenesis of Alzheimer disease. However, counter to the popular view that amyloid-beta represents an initiator of disease pathogenesis, we herein challenge dogma and propose that amyloid-beta occurs secondary to neuronal stress and, rather than causing cell death, functions as a protective adaptation to the disease. By analogy, individuals suffering from altitude sickness nearly always have elevated levels of hemoglobin. However, while hemoglobin is toxic to cells in culture and increased erythropoiesis at sea level can be deadly, it is clear that the increases in hemoglobin occurring at altitude are beneficial. Amyloid, like hemoglobin, may also be beneficial, in this case, following neuronal stress or disease. Although controversial, a protective function for amyloid-beta is supported by all of the available literature to date and also explains why many aged individuals, despite the presence of high numbers of senile plaques, show little or no cognitive decline. With this in mind, we suspect that current therapeutic efforts targeted toward lowering amyloid-beta production or removal of deposited amyloid-beta will only serve to exacerbate the disease process.