Alzheimer Disease: Florida

Koren J, Jinwal UK, Lee DC, Jones JR, Shults CL, Johnson AG, Anderson LJ, Dickey CA. · Johnnie B. Byrd Sr. Alzheimer's Center and Research Institute, Department of Molecular Medicine, University of South Florida, Tampa, USA. · J Cell Mol Med. · Pubmed #19449461 No free full text.

Abstract: Molecular chaperones and heat shock proteins (Hsp) have emerged as critical regulators of proteins associated with neurodegenerative disease pathologies. The very nature of the chaperone system, which is to maintain protein quality control, means that most nascent proteins come in contact with chaperone proteins. Thus, amyloid precursor protein (APP), members of the gamma-secretase complex (presenilin 1 [PS1] collectively), the microtubule-associated protein tau (MAPT) as well as a number of neuroinflammatory components are all in contact with chaperones from the moment of their production. Chaperones are often grouped together as one machine presenting abnormal or mutant proteins to the proteasome for degradation, but this is not at all the case. In fact, the chaperone family consists of more than 100 proteins in mammalian cells, and the primary role for most of these proteins is to protect clients following synthesis and during stress; only as a last resort do they facilitate protein degradation. To the best of our current knowledge, the chaperone system in eukaryotic cells revolves around the ATPase activities of Hsp70 and Hsp90, the two primary chaperone scaffolds. Other chaperones and co-chaperones manipulate the ATPase activities of Hsp70 and Hsp90, facilitating either folding of the client or its degradation. In the case of Alzheimer's disease (AD), a number of studies have recently emerged describing the impact that these chaperones have on the proteotoxic effects of tau and amyloid- beta accumulation. Here, we present the current understandings of chaperone biology and examine the literature investigating these proteins in the context of AD.

Golde TE, Das P, Levites Y. · Mayo Clinic, College of Medicine, Department of Neuroscience, Mayo Clinic Florida, 4500 San Pablo Rd., Jacksonville, FL 32224, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19275635 No free full text.

Abstract: There is substantial and compelling evidence that aggregation and accumulation of amyloid beta protein (Abeta) plays a pivotal role in the development of Alzheimer's disease (AD); thus, numerous strategies to prevent Abeta aggregation and accumulation or to facilitate removal of preexisting deposits of Abeta are being evaluated as ways to treat or prevent AD. Pre-clinical studies in mice demonstrate the therapeutic potential of altering Abeta deposition by inducing a humoral immune response to fibrillar Abeta42 (fAbeta42) or passively administering anti-Abeta antibodies (Abs), and both passive and active anti-Abeta immunotherapeutic approaches are now being tested in humans. Although a variety of mechanisms have been postulated regarding how Abeta immunotherapy might work to attenuate or in some circumstances clear Abeta from the brain, no mechanism has been definitively proven or disproven. Herein, we will review the various mechanisms that have been postulated. In addition we will discuss how a more thorough understanding of the pharmacokinetics of anti-Abeta Abs and their effects on Abeta levels and turnover provides insight into both the therapeutic potential and limitation of Abeta immunotherapy. We will conclude with a discussion of additional experimentation required to better understand the mechanism of action of anti-Abeta Abs in AD and optimize antibody (Ab) mediated therapy for AD.

Morgan D. · Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL 33612, USA. · CNS Neurol Disord Drug Targets. · Pubmed #19275633 No free full text.

Abstract: Immunotherapy has emerged as a leading new approach to the reduction of amyloid deposits in the brains of Alzheimer patients. At least 4 distinct actions of anti-Abeta antibodies have been proposed as contributing to the inhibition of amyloid deposition and its clearance. Critically, each of these proposed mechanisms may be acting simultaneously, and it is feasible that different antibodies may utilize each mechanism to a different extent. One of these proposed mechanisms involves the activation of microglia and the phagocytosis of Abeta peptide. In general this is assumed to proceed through the Fcgamma-receptor binding by antibody opsonized Abeta aggregates, however modifying the microglial phenotype into one with a greater propensity for phagocytosing Abeta is also feasible, as microglia avidly phagocytose Abeta in vitro without antibody present. Evidence is presented supporting arguments that microglial activation does play a role in amyloid removal, particularly compacted amyloid deposits, under certain conditions. In addition to the specific antibody used, other considerations in comparing different reports of antibody action in APP mice include the age of the mice, the extent of pre-existing amyloid when therapy is initiated, the time point when the effects of the therapy are examined and the route of antibody administration. Future questions will consider the source of the activated microglia near the plaques after antibody administration (resident or peripheral) and the extent to which shifts in the microglial phenotype mediate some of the amyloid lowering actions of immunotherapy.

Sanchez-Ramos J, Song S, Cao C, Arendash G. · Department of Neurology, University of South Florida, Tampa, FL 33612, USA. · BMC Neurosci. · Pubmed #19090991 links to  free full text

Abstract: There are no effective interventions that significantly forestall or reverse neurodegeneration and cognitive decline in Alzheimer's disease. In the past decade, the generation of new neurons has been recognized to continue throughout adult life in the brain's neurogenic zones. A major challenge has been to find ways to harness the potential of the brain's own neural stem cells to repair or replace injured and dying neurons. The administration of hematopoietic growth factors or cytokines has been shown to promote brain repair by a number of mechanisms, including increased neurogenesis, anti-apoptosis and increased mobilization of bone marrow-derived microglia into brain. In this light, cytokine treatments may provide a new therapeutic approach for many brain disorders, including neurodegenerative diseases like Alzheimer's disease. In addition, neuronal hematopoietic growth factor receptors provide novel targets for the discovery of peptide-mimetic drugs that can forestall or reverse the pathological progression of Alzheimer's disease.

Giunta B, Fernandez F, Nikolic WV, Obregon D, Rrapo E, Town T, Tan J. · Neuroimmunology Laboratory, Department of Psychiatry, Behavioral Medicine, Institute for Research in Psychiatry, University of South Florida, College of Medicine, Tampa, FL 33613, USA. · J Neuroinflammation. · Pubmed #19014446 links to  free full text

Abstract: Recently, the term "inflammaging" was coined by Franceshci and colleagues to characterize a widely accepted paradigm that ageing is accompanied by a low-grade chronic up-regulation of certain pro-inflammatory responses. Inflammaging differs significantly from the traditional five cardinal features of acute inflammation in that it is characterized by a relative decline in adaptive immunity and T-helper 2 responses and is associated with increased innate immunity by cells of the mononuclear phagocyte lineage. While the over-active innate immunity characteristic of inflammaging may remain subclinical in many elderly individuals, a portion of individuals (postulated to have a "high responder inflammatory genotype") may shift from a state of "normal" or "subclinical" inflammaging to one or more of a number of age-associated diseases. We and others have found that IFN-gamma and other pro-inflammatory cytokines interact with processing and production of Abeta peptide, the pathological hallmark feature of Alzheimer's disease (AD), suggesting that inflammaging may be a "prodrome" to AD. Although conditions of enhanced innate immune response with overproduction of pro-inflammatory proteins are associated with both healthy aging and AD, it is suggested that those who age "well" demonstrate anti-inflammaging mechanisms and biomarkers that likely counteract the adverse immune response of inflammaging. Thus, opposing the features of inflammaging may prevent or treat the symptoms of AD. In this review, we fully characterize the aging immune system. In addition, we explain how three novel treatments, (1) human umbilical cord blood cells (HUCBC), (2) flavanoids, and (3) Abeta vaccination oppose the forces of inflammaging and AD-like pathology in various mouse models.

Sugaya K, Merchant S. · Biomolecular Science Center, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 4000 Central Florida Blvd., BMS building, Room 223, Orlando, FL 32816-2364, USA. · J Alzheimers Dis. · Pubmed #18953112 No free full text.

Abstract: The use of stem cells for neuroreplacement therapy is no longer science fiction - it is science fact. We have succeeded in producing neural cells in the brain using both neural and mesenchymal stem cell transplantation and even systemic injection using a small molecular compound. We have seen the improvement of cognitive function in animal models following the application of these stem cell technologies. These results may promise a bright future for stem cell based neuroreplacement therapies for neurodegenerative diseases including Alzheimer's disease (AD). However, we have to consider the pathophysiological environments of individual diseases before clinical applications can be introduced. We must find the factors in the pathology that may affect stem cell biology and overcome the negative effects on neuroreplacement. Here, we discuss not only the potential for therapeutic applications of stem cell strategies in neuropathological conditions, but also how to overcome the adverse effects on the biology of stem cells due to the factors that are altered under AD pathology.

Edwards TM, Myers JP. · Department of Zoology, University of Florida, Gainesville, FL 32611, USA. · Cien Saude Colet. · Pubmed #18813540 links to  free full text

Abstract: Health or disease is shaped for all individuals by interactions between their genes and environment. Exactly how the environment changes gene expression and how this can lead to disease are being explored in a fruitful new approach to environmental health research, representative studies of which are reviewed here. We searched Web of Science and references of relevant publications to understand the diversity of gene regulatory mechanisms affected by environmental exposures with disease implications. Pharmaceuticals, pesticides, air pollutants, industrial chemicals, heavy metals, hormones, nutrition, and behavior can change gene expression through a broad array of gene regulatory mechanisms. Furthermore, chemically induced changes in gene regulation are associated with serious and complex human diseases, including cancer, diabetes and obesity, infertility, respiratory diseases, allergies, and neurodegenerative disorders such as Parkinson and Alzheimer diseases. The reviewed studies indicate that genetic predisposition for disease is best predicted in the context of environmental exposures. And the genetic mechanisms investigated in these studies offer new avenues for risk assessment research. Finally, we are likely to witness dramatic improvements in human health, and reductions in medical costs, if environmental pollution is decreased.

Leissring MA. · Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA. · J Biol Chem. · Pubmed #18723506 No free full text.

Abstract: The amyloid beta-protein (Abeta), which accumulates abnormally in Alzheimer disease (AD), is degraded by a diverse set of proteolytic enzymes. Abeta-cleaving proteases, largely ignored until only recently, are now known to play a pivotal role in the regulation of cerebral Abeta levels and amyloid plaque formation in animal models, and accumulating evidence suggests that defective Abeta proteolysis may be operative in many AD cases. This review summarizes the growing body of evidence supporting the involvement of specific Abeta-cleaving proteases in the etiology and potential treatment of AD. Recognition of the importance of Abeta degradation to the overall economy of Abeta has revised our thinking about the mechanistic basis of AD pathogenesis and identified a novel class of enzymes that may serve as both therapeutic targets and therapeutic agents.

Streit WJ, Miller KR, Lopes KO, Njie E. · Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA. · Front Biosci. · Pubmed #18508444 No free full text.

Abstract: We have long promulgated the idea that microglial cells serve an entirely beneficial role in the central nervous system (CNS), not only as immunological sentinels to fend off potentially dangerous infections, but also as constitutively neuroprotective glia that help sustain neuronal function in the normal and especially in the injured CNS when microglia become activated. In recent years, we have reported on the presence of degenerating microglial cells, which are prominent in the brains of aged humans and humans with neurodegenerative diseases, and this has led us to propose a hypothesis stating that loss of microglia and microglial neuroprotective functions could, at least in part, account for aging-related neurodegeneration. In the current review, we sum up the many aspects that characterize microglial activation and compare them to those that characterize microglial senescence and degeneration. We also consider the possible role of oxidative stress as a cause of microglial degeneration. We finish up by discussing the role microglial cells play in terms of amyloid clearance and degradation with the underlying idea that removal of amyloid constitutes a microglial neuroprotective function, which may become compromised during aging.

Fukui H, Moraes CT. · Neuroscience Program, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. · Trends Neurosci. · Pubmed #18403030 No free full text.

Abstract: Aging is the most important risk factor for common neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Aging in the central nervous system has been associated with elevated mutation load in mitochondrial DNA, defects in mitochondrial respiration and increased oxidative damage. These observations support a 'vicious cycle' theory which states that there is a feedback mechanism connecting these events in aging and age-associated neurodegeneration. Despite being an extremely attractive hypothesis, the bulk of the evidence supporting the mitochondrial vicious cycle model comes from pharmacological experiments in which the modes of mitochondrial enzyme inhibition are far from those observed in real life. Furthermore, recent in vivo evidence does not support this model. In this review, we focus on the relationship among the components of the putative vicious cycle, with particular emphasis on the role of mitochondrial defects on oxidative stress.

Altmann LJ, McClung JS. · Department of Communication Sciences and Disorders, University of Florida, Gainesville, FL 32611-7420, USA. · Semin Speech Lang. · Pubmed #18348089 No free full text.

Abstract: Many studies present apparently conflicting results and conclusions about the effects of Alzheimer's disease (AD) on language use. This review attempts to reconcile these apparently conflicting results regarding the language impairments in AD by discussing how the slow deterioration of the semantic system at the feature level interacts with the task demands of tests used to evaluate performance. In particular, performance is impaired on tasks that require relatively complete, elaborate semantic representations but is preserved when the task requires only partial semantic representations consisting largely of shared features. The variety of language impairments reported in complex, multiword tasks are likely attributable to a combination of the deterioration of semantic representations and reduced working memory resources. The few available treatment studies for language impairments in AD suggest that treatments designed for adults with other language impairments, such as aphasia, may also be effective in AD.

Sugaya K. · Burnett College of Biomedical Sciences, University of Central Florida, Orlando, Fla. 32816-2364, USA. · Neurodegener Dis. · Pubmed #18322381 No free full text.

Abstract: BACKGROUND: We found that human neural progenitor cells (HNPCs) exposed to high concentrations of amyloid precursor protein (APP) or transplanted into APP transgenic mice (APP23) primarily differentiated into astrocytes, suggesting that pathological alterations of APP processing in Alzheimer's disease (AD) may prevent neuronal differentiation of HNPCs. OBJECTIVES: To investigate the mechanism of APP-induced glial differentiation of HNPCs. METHODS: We treat HNPCs with APP and analyze the expression and phosphorylation of signaling molecules using PCR and Western blots. To confirm the involvement of the factors, RNA interference of the signaling molecule is conducted. RESULTS: APP treatment caused inductions of CNTF, gp130 and JAK1 gene expressions, and STAT3 phosphorylation, while silencing of these genes by RNA interference suppressed the glial differentiation of the cells, indicating involvement of the IL-6/gp130 pathway. APP also increased the generation of notch intracellular domain and gene expression of Hes1, indicating that glial differentiation of HNPCs may be mediated by the notch signaling. CONCLUSION: These results indicate that APP may regulate HNPC differentiation through activation of both the IL-6/gp130 and notch signaling pathway. Although the importance of adult neurogenesis is not clear, glial differentiation of HNPCs may cause problems in maintaining normal brain function and may contribute to the AD pathology.

Wider C, Wszolek ZK. · Department of Neurology, Mayo Clinic, Jacksonville, Fla. 32224, USA. · Neurodegener Dis. · Pubmed #18322368 No free full text.

Abstract: Genetic studies have led to major discoveries in the pathogenesis of various neurodegenerative diseases. Ubiquitin-positive familial frontotemporal dementia was recently found to be caused by mutations in the progranulin gene (PGRN), and the major constituent of the inclusions, TDP-43, was subsequently identified. The tau gene (MAPT) causes frontotemporal dementia with parkinsonism linked to chromosome 17. In Parkinson disease, LRRK2 mutations have emerged as a major cause of both familial and sporadic forms, adding to the previously known genes SNCA,PRKN,DJ1 and PINK1. Several genes have been implicated in Alzheimer disease, including the APP gene and the PSEN genes. Recently, variants in the sortilin-related receptor 1 gene, SORL1, were associated with Alzheimer disease.

Daiello LA. · Pharmacotherapy Solutions, 2115 Ivanhoe Rd, Orlando, FL 32804, USA. · Am J Manag Care. · Pubmed #18095783 links to  free full text

Abstract: Diagnosis and treatment of dementia in nursing homes and assisted living facilities remains challenging since response to treatment and disease course varies for the common degenerative dementias. Four cholinesterase inhibitors and an N-methyl-D-aspartate glutamate receptor antagonist are approved by the US Food and Drug Administration for the treatment of Alzheimer's disease (AD). Treatment with AD medications is clinically efficacious and associated with reduced caregiver burden. Some controlled trials have reported that cholinesterase inhibitors and memantine ameliorate dementia-related behavioral symptoms. Antipsychotic therapy is often used for intractable behavioral symptoms or psychosis not responding to nonpharmacologic interventions and antidementia medications; however, the risk/benefit ratio for each patient should be critically evaluated, because treatment with atypical antipsychotics has been associated with serious adverse events, including increased risk for death in older adults with dementia.

Goodman IJ. · Department of Neurology, University of Florida School of Medicine, FL, USA. · Expert Rev Mol Diagn. · Pubmed #18088227 No free full text.

Abstract: Urinary assay (Alzheimer's disease reaction titer [ADRT]) adds significant information in the diagnosis of Alzheimer's disease (AD), particularly for the nonspecialist. Clinical studies of ADRT in series of AD and non-AD patients have found sensitivity of 89-92.3%, specificity of 90-96.8%, positive predictive value (PPV) of 94.8-97.4% and negative predictive value (NPV) of 78.9-91.8%. The added information from the improvements of PPV and NPV are particularly helpful for the nonspecialist in the community. As a laboratory assay that requires a first-morning noncontaminated sample, ADRT is noninvasive, convenient and safe. ADRT is based on reagents derived from human AD brain cDNA. The pathophysiological roles of these genetic fragments and reagents are still under investigation. ADRT should have a positive impact on primary-care AD clinical practice.

Acevedo A, Loewenstein DA. · Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, and Wien Center for Alzheimer's Disease and Memory Disorders, Mount Sinai Medical Center, Miami Beach, Florida 33140, USA. · J Geriatr Psychiatry Neurol. · Pubmed #18004010 No free full text.

Abstract: There have been increasing efforts to develop cognitive interventions to ameliorate cognitive problems experienced by older adults. In healthy elderly populations, cognitive training has centered on the enhancement of memory and speed of processing, with the goal of maximizing current function and reducing the risk of cognitive decline. Among elderly persons with nonprogressive neurological conditions such as traumatic brain injury (TBI) and stroke, there has been an emphasis on rehabilitation to help restore function. Most recently, there has been increased attention on the development of new cognitive techniques to treat persons with progressive neurodegenerative conditions such as Alzheimer disease. The literature is reviewed on current approaches to cognitive interventions in elderly healthy populations, and a particular emphasis is placed on the most recent strides in progressive neurocognitive conditions, particularly Alzheimer disease. Important issues such as study design, the use of ecologically and functionally valid outcome measures, the need to examine heterogeneous populations and cross-cultural variables, and the incorporation of technologically based systems are examined. It is concluded that cognitive interventions in the elderly show considerable promise and deserve further study.

Sugaya K, Kwak YD, Ohmitsu O, Marutle A, Greig NH, Choumrina E. · Burnett College of Biomedical Sciences, University of Central Florida, Orlando, FL 32816. USA. · Curr Alzheimer Res. · Pubmed #17908039 No free full text.

Abstract: We have demonstrated that aged animals show significant improvements in cognitive function and neurogenesis after brain transplantation of human neural stem cells or of human adult mesenchymal stem cells that have been dedifferentiated by transfection of the embryonic stem cell gene. We have also demonstrated that peripheral administration of a pyrimidine derivative increased cognition, endogenous brain stem cell proliferation and neurogenesis. These results indicate a bright future for stem cell therapies in Alzheimer's disease (AD). Before this is realized, however, we need to consider the affect of AD pathology on stem cell biology to establish an effective stem cell therapy for this disease. Although amyloid-beta (Abeta) deposition is a hallmark of AD, an absence of a phenotype in the beta-amyloid precursor protein (APP) knockout mouse, might lead one to underestimate the potential physiological functions of APP and suggest that it is unessential or can be compensated for. We have found, however, that APP is needed for differentiation of neural stem cells (NSCs) in vitro, and that NSCs transplanted into a APP-knockout mouse did not migrate or differentiate -- indicating that APP plays an important role in differentiation or migration process of NSCs in the brain. Then again, treatment with high a concentration of APP or its over-expression increased glial differentiation of NSCs. Human NSCs transplanted into APP-transgenic mouse brain exhibited less neurogenesis and active gliosis around the plaque like formations. Treatment of such animals with the compound, (+)-phenserine, that is known to reduce APP protein levels, increased neurogenesis and suppressed gliosis. These results suggest APP levels can regulate NSC biology in the adult brain, that altered APP metabolism in Down syndrome or AD may have implications for the pathophysiology of these diseases, and that a combination of stem cell therapy and regulation of APP levels could provide a treatment strategy for these disorders.

Edwards TM, Myers JP. · Department of Zoology, University of Florida, Gainesville, Florida 32611, USA. · Environ Health Perspect. · Pubmed #17805414 links to  free full text

Abstract: OBJECTIVE: Health or disease is shaped for all individuals by interactions between their genes and environment. Exactly how the environment changes gene expression and how this can lead to disease are being explored in a fruitful new approach to environmental health research, representative studies of which are reviewed here. DATA SOURCES: We searched Web of Science and references of relevant publications to understand the diversity of gene regulatory mechanisms affected by environmental exposures with disease implications. DATA SYNTHESIS: Pharmaceuticals, pesticides, air pollutants, industrial chemicals, heavy metals, hormones, nutrition, and behavior can change gene expression through a broad array of gene regulatory mechanisms. Mechanisms include regulation of gene translocation, histone modifications, DNA methylation, DNA repair, transcription, RNA stability, alternative RNA splicing, protein degradation, gene copy number, and transposon activation. Furthermore, chemically induced changes in gene regulation are associated with serious and complex human diseases, including cancer, diabetes and obesity, infertility, respiratory diseases, allergies, and neurodegenerative disorders such as Parkinson and Alzheimer diseases. One of the best-studied areas of gene regulation is epigenetics, especially DNA methylation. Our examples of environmentally induced changes in DNA methylation are presented in the context of early development, when methylation patterns are initially laid down. This approach highlights the potential role for altered DNA methylation in fetal origins of adult disease and inheritance of acquired genetic change. CONCLUSIONS: The reviewed studies indicate that genetic predisposition for disease is best predicted in the context of environmental exposures. Second, the genetic mechanisms investigated in these studies offer new avenues for risk assessment research. Finally, we are likely to witness dramatic improvements in human health, and reductions in medical costs, if environmental pollution is decreased.

Klein TW, Newton CA. · University of South Florida, Department of Molecular Medicine, Tampa, FL, USA. · Adv Exp Med Biol. · Pubmed #17713029 No free full text.

Abstract: Cannabinoid-based drugs modeled on cannabinoids originally isolated from marijuana are now known to significantly impact the functioning of the endocannabinoid system of mammals. This system operates not only in the brain but also in organs and tissues in the periphery including the immune system. Natural and synthetic cannabinoids are tricyclic terpenes, whereas the endogenous physiological ligands are eicosanoids. Several receptors for these compounds have been extensively described, CB1 and CB2, and are G protein-coupled receptors; however, cannabinoid-based drugs are also demonstrated to function independently of these receptors. Cannabinoids regulate many physiological functions and their impact on immunity is generally antiinflammatory as powerful modulators of the cytokine cascade. This anti-inflammatory potency has led to the testing of these drugs in chronic inflammatory laboratory paradigms and even in some human diseases. Psychoactive and nonpsychoactive cannabinoid-based drugs such as Delta9-tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Furthermore, although clinical trials are not yet reported, preclinical data with cannabinoid-based drugs suggest efficacy in other inflammatory diseases such as inflammatory bowel disease, Alzheimer's disease, atherosclerosis, and osteoporosis.

Eckman CB, Eckman EA. · Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA. · Neurol Clin. · Pubmed #17659184 No free full text.

Abstract: Alzheimer's disease (AD) is a devastating neurodegenerative disease. To rationally develop novel therapeutic and/or preventative agents for AD, an understanding of the etiology and pathogenesis of this complex disease is necessary. This article examines the evidence for the amyloid hypothesis of AD pathogenesis and discusses how it relates to the neurological and neuropathological features of AD, the known genetic risk factors and causative mutations, and the heightened risk associated with advanced age.

Morgan D. · Alzheimer Research Laboratory, Department of Molecular Pharmacology and Physiology, School of Basic Biomedical Sciences, College of Medicine, 12901 BB Downs Blvd. MDC Box 9, University of South Florida, Tampa, FL 33612, USA. · Exp Neurol. · Pubmed #17445801 No free full text.

Abstract: Transgenic mouse models of amyloid deposition consistently demonstrate impaired performance on certain tasks of learning and memory. The article by Zhang et al. (2006) demonstrates reductions in dentate gyrus neurogenesis in a murine model of amyloid deposition which is linked to the deposition of amyloid and not overexpression of transgenes. Neurogenesis plays at least a facilitatory role in the formation of memory, the nature of which is only beginning to emerge. Thus, it seems reasonable to propose that the memory deficits found in the amyloid precursor protein transgenic mouse models of amyloid deposition result, at least in part, from reduced rates of hippocampal neurogenesis. The possible relationship to memory loss in Alzheimer's dementia is also discussed.

Small BJ, Gagnon E, Robinson B. · School of Aging Studies, University of South Florida, Tampa, USA. · Geriatrics. · Pubmed #17408315 No free full text.

Abstract: With the projected dramatic increase in the number of people who will be diagnosed with Alzheimer's disease (AD) in the coming years, interest is growing in identifying and treating adults at high risk for developing the disorder. Recent research suggests that individuals who will go on to receive a diagnosis of AD exhibit deficits in cognitive performance years beforehand. Those with mild cognitive impairment (MCI), for example, have characteristic cognitive deficits, such as memory loss, and convert to a diagnosis of AD at a faster rate than cognitively healthy controls. MCI has thus become a focus of research because it may help identify high-risk individuals for whom prophylactic treatments designed to slow the progress toward AD can be prescribed. After describing the diagnostic criteria and dementia outcomes associated with MCI, this article discusses several challenges to the study of cognitive impairment before the diagnosis of AD.

Norenberg MD, Rao KV. · Veterans Affairs Medical Center, University of Miami Miller School of Medicine, Miami, FL 33101, USA. · Neurochem Int. · Pubmed #17397969 No free full text.

Abstract: Mitochondria, being the principal source of cellular energy, are vital for cell life. Yet, ironically, they are also major mediators of cell death, either by necrosis or apoptosis. One means by which these adverse effects occur is through the mitochondrial permeability transition (mPT) whereby the inner mitochondrial membrane suddenly becomes excessively permeable to ions and other solutes, resulting in a collapse of the inner membrane potential, ultimately leading to energy failure and cell necrosis. The mPT may also bring about the release of various factors known to cause apoptotic cell death. The principal factors leading to the mPT are elevated levels of intracellular Ca2+ and oxidative stress. Characteristically, the mPT is inhibited by cyclosporin A. This article will briefly discuss the concept of the mPT, its molecular composition, its inducers and regulators, agents that influence its activity and describe the consequences of its induction. Lastly, we will review its potential contribution to acute neurological disorders, including ischemia, trauma, and toxic-metabolic conditions, as well as its role in chronic neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.

Leissring MA. · Department of Biochemistry, The Scripps Research Institute, Scripps Florida, 5353 Parkside Dr., RE-2, Jupiter, FL 33458, USA. · Curr Alzheimer Res. · Pubmed #17168642 No free full text.

Abstract: Proteases have long played a central role in the molecular pathogenesis of Alzheimer's disease (AD), yet proteases that degrade the amyloid beta-protein (Abeta) itself were largely ignored until only quite recently. Today, we know that Abeta-degrading proteases are critical regulators of brain Abeta levels in vivo, with evidence accumulating that their dysfunction may play a role in the etiology of AD. This review explores the historical factors that obscured this important aspect of amyloidogenesis, and discusses the many fresh insights it offers into the causes of and potential treatments for AD.

Golde TE, Dickson D, Hutton M. · Mayo Clinic College of Medicine, Department of Neuroscience, Mayo Clinic Jacksonville 4500 San Pablo Rd., Jacksonville, Florida 32224, USA. · Curr Alzheimer Res. · Pubmed #17168641 No free full text.

Abstract: Advances in the understanding of Alzheimer's disease (AD) pathogenesis provide strong support for a modified version of the amyloid cascade hypothesis, which is now often referred to as the amyloid beta protein (Abeta) cascade hypothesis. The basic tenant of this modified hypothesis is that Abeta aggregates trigger a complex pathological cascade leading to neurodegeneration. Thus, as opposed to the original amyloid hypothesis, whose basic tenant was that amyloid deposits cause AD, the Abeta hypothesis is more inclusive in that it takes into account the possibility that several different Abeta assemblies might contribute to AD pathogenesis and not merely the detectable amyloid deposits within the brain. Significantly, the Abeta hypothesis has provided the rationale for a plethora of therapeutic interventions that target Abeta production, aggregation or clearance. Indeed, AD research is entering an exciting phase in which strategies derived from basic research will be tested in humans. Despite this progress, many aspects of AD pathogenesis, particularly those downstream of Abeta accumulation are not well understood. Herein, we explore several observations that serve to illustrate the more enigmatic aspects of the Abeta hypothesis, and discuss why further basic research may be critical in order to develop therapies designed to halt neurodegeneration and reverse cognitive decline in patients already suffering from AD dementia.