Alzheimer Disease: Illinois

Lal R, Lin H, Quist AP. · Center for Nanomedicine, University of Chicago, 5841 S. Maryland Ave., MC 6076, Chicago, IL 60637, USA. · Biochim Biophys Acta. · Pubmed #17553456 links to  free full text

Abstract: Alzheimer's disease (AD) is a protein misfolding disease. Early hypothesis of AD pathology posits that 39-43 AA long misfolded amyloid beta (Abeta) peptide forms a fibrillar structure and induces pathophysiological response by destabilizing cellular ionic homeostasis. Loss of cell ionic homeostasis is believed to be either indirectly due to amyloid beta-induced oxidative stress or directly by its interaction with the cell membrane and/or activating pathways for ion exchange. Significantly though, no Abeta specific cell membrane receptors are known and oxidative stress mediated pathology is only partial and indirect. Most importantly, recent studies strongly indicate that amyloid fibrils may not by themselves cause AD pathology. Subsequently, a competing hypothesis has been proposed wherein amyloid derived diffusible ligands (ADDLs) that are large Abeta oligomers (approximately >60 kDa), mediate AD pathology. No structural details, however, of these large globular units exist nor is there any known suitable mechanism by which they would induce AD pathology. Experimental data indicate that they alter cell viability by non-specifically changing the plasma membrane stability and increasing the overall ionic leakiness. The relevance of this non-specific mechanism for AD-specific pathology seems limited. Here, we provide a viable new paradigm: AD pathology mediated by amyloid ion channels made of small Abeta oligomers (trimers to octamers). This review is focused to 3D structural analysis of the Abeta channel. The presence of amyloid channels is consistent with electrophysiological and cell biology studies summarized in companion reviews in this special issue. They show ion channel-like activity and channel-mediated cell toxicity. Amyloid ion channels with defined gating and pharmacological agents would provide a tangible target for designing therapeutics for AD pathology.

Vassar R. · Department of Cell and Molecular Biology, Northwestern University, The Feinberg School of Medicine, Chicago, IL 60611-3006, USA. · Neuron. · Pubmed #17553417 No free full text.

Abstract: BACE initiates the production of beta-amyloid (Abeta), the likely cause of Alzheimer's disease (AD). In this issue of Neuron, Tesco et al. show that during apoptosis caspase-3 cleaves the adaptor protein GGA3, which is required for BACE lysosomal degradation, consequently stabilizing BACE and elevating Abeta generation.

Reynolds MR, Berry RW, Binder LI. · Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. · Biochemistry. · Pubmed #17542619 No free full text.

Abstract: Recent literature has ushered in a new awareness of the diverse post-translational events that can influence protein folding and function. Among these modifications, protein nitration is thought to play a critical role in the onset and progression of several neurodegenerative diseases. While previously considered a late-stage epiphenomenon, nitration of protein tyrosine residues appears to be an early event in the lesions of amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. The advent of highly specific biochemical and immunological detection methods reveals that nitration occurs in vivo with biological selectively and site specificity. In fact, nitration of only a single Tyr residue is often sufficient to induce profound changes in the activity of catalytic proteins and the three-dimensional conformation of structural proteins. Presumably, nitration modifies protein function by altering the hydrophobicity, hydrogen bonding, and electrostatic properties within the targeted protein. Most importantly, however, nitrative injury may represent a unifying mechanism that explains how genetic and environmental causes of neurological disease manifest a singular phenotype. In this review and synthesis, we first examine the pathways of protein nitration in biological systems and the factors that influence site-directed nitration. Subsequently, we turn our attention to the structural implications of site-specific nitration and how it affects the function of several neurodegeneration-related proteins. These proteins include Mn superoxide dismutase and neurofilament light subunit in amyotrophic lateral sclerosis, alpha-synuclein and tyrosine hydroxylase in Parkinson's disease, and tau in Alzheimer's disease.

Disterhoft JF, Oh MM. · Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-3008, USA. · Aging Cell. · Pubmed #17517042 No free full text.

Abstract: Normal aging subjects, including humans, have difficulty learning hippocampus-dependent tasks. For example, at least 50% of normal aging rabbits and rats fail to meet a learning criterion in trace eyeblink conditioning. Many factors may contribute to this age-related learning impairment. An important cause is the reduced intrinsic excitability observed in hippocampal pyramidal neurons from normal aging subjects, as reflected by an enlarged postburst afterhyperpolarization (AHP) and an increased spike-frequency adaptation (accommodation). In this review, we will focus on the alterations in the AHP and accommodation during learning and normal aging. We propose that age-related increases in the postburst AHP and accommodation in hippocampal pyramidal neurons play an integral role in the learning impairment observed in normal aging subjects.

Ma Q, Cornelli U, Hanin I, Jeske WP, Linhardt RJ, Walenga JM, Fareed J, Lee JM. · Department of Pharmacology and Experimental Therapeutics, Stritch School ofMedicine, Loyola University Chicago, Maywood, IL 60153, USA. · Curr Pharm Des. · Pubmed #17504153 No free full text.

Abstract: Heparin is a glycosaminoglycan mixture currently used in prophylaxis and treatment of thrombosis. Heparin possesses non-anticoagulant properties, including modulation of various proteases, interactions with fibroblast growth factors, and anti-inflammatory actions. Senile dementia of Alzheimer's type is accompanied by inflammatory responses contributing to irreversible changes in neuronal viability and brain function. Vascular factors are also involved in the pathogenesis of senile dementia. Inflammation, endogenous proteoglycans, and assembly of senile plagues and neurofibrillary tangles contribute directly and indirectly to further neuronal damage. Neuron salvage can be achieved by anti-inflammation and the competitive inhibition of proteoglycans accumulation. The complexity of the pathology of senile dementia provides numerous potential targets for therapeutic interventions designed to modulate inflammation and proteoglycan assembly. Heparin and related oligosaccharides are known to exhibit anti-inflammatory effects as well as inhibitory effects on proteoglycan assembly and may prove useful as neuroprotective agents.

Desai BS, Monahan AJ, Carvey PM, Hendey B. · Department of Pharmacology, Rush University Medical Center, Chicago, IL 60612, USA. · Cell Transplant. · Pubmed #17503739 No free full text.

Abstract: The blood-brain barrier (BBB) is a tightly regulated barrier in the central nervous system. Though the BBB is thought to be intact during neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD), recent evidence argues otherwise. Dysfunction of the BBB may be involved in disease progression, eliciting of peripheral immune response, and, most importantly, altered drug efficacy. In this review, we will give a brief overview of the BBB, its components, and their functions. We will critically evaluate the current literature in AD and PD BBB pathology resulting from insult, neuroinflammation, and neurodegeneration. Specifically, we will discuss alterations in tight junction, transport and endothelial cell surface proteins, and vascular density changes, all of which result in altered permeability. Finally, we will discuss the implications of BBB dysfunction in current and future therapeutics. Developing a better appreciation of BBB dysfunction in AD and PD may not only provide novel strategies in treatment, but will prove an interesting milestone in understanding neurodegenerative disease etiology and progression.

Muma NA. · Department of Pharmacology, Loyola University Medical Center, Maywood, Illinois, USA. · J Neuropathol Exp Neurol. · Pubmed #17413316 No free full text.

Abstract: Transglutaminase catalyzes a covalent bond between peptide-bound glutamine residues and either lysine-bound peptide residues or mono- or polyamines. Multiple lines of evidence suggest that transglutaminase is involved in neurodegenerative diseases including Alzheimer disease, progressive supranuclear palsy, Huntington disease (HD), and Parkinson disease. In all of the neurodegenerative diseases examined to date, transglutaminase enzyme activity is upregulated in selectively vulnerable brain regions, transglutaminase proteins are associated with inclusion bodies characteristic of the diseases, and prominent proteins in the inclusion bodies are modified by transglutaminase enzymes. These prominent proteins in the inclusion bodies, including tau, alpha-synuclein, and huntingtin protein, are modified by transglutaminase in vitro and alpha-synuclein and huntingtin protein are modified in cells in culture. Similar changes in transglutaminase and transglutaminase-modified proteins are replicated in transgenic mouse models of the neurodegenerative diseases, including Huntington disease and progressive supranuclear palsy. Lastly, inhibition of transglutaminase either via drug treatments or molecular approaches is beneficial for the treatment of HD transgenic mice but has yet to be explored for the other neurodegenerative diseases. Further research is needed to determine the specific role(s) that transglutaminase plays in the pathophysiology of neurodegenerative diseases with possible implications for transglutaminase as a therapeutic target.

Ohno M. · Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. · Rev Neurosci. · Pubmed #17139843 No free full text.

Abstract: Alzheimer's disease (AD) is a dementing neurodegenerative disorder for which effective disease-modifying therapeutic treatments have not yet been developed. Genetic and molecular biological studies provide accumulating evidence supporting the hypothesis that the production of amyloid-beta (Abeta) peptides, especially neurotoxic Abeta42, is central to the pathophysiology of AD--the 'amyloid cascade' hypothesis. Abeta is proteolytically generated from a type I integral membrane amyloid precursor protein by the sequential action of two enzymes, called beta- and gamma-secretase, in reference to their cleavage sites at the N- and C-terminals, respectively. Given the strong association between Abeta and AD, the strategies to inhibit the production of Abeta, the first step of the amyloid cascade, should prove beneficial as truly disease-modifying therapeutic approaches for the treatment of AD. Recent advances in genetic strategies including knockouts, transgenics and virus-delivered small interfering RNAs and the development of potent and specific small-molecule inhibitors have opened a new window to test the impacts of beta- and gamma-secretase inhibition in vivo. Since cognitive deficits are at the heart of AD, one of the most important challenges is to determine the therapeutic potential of secretase-inhibiting approaches for AD-related memory deficits, linking perspectives through the prism of molecular/pathological events and those through behavioral and neurophysiological manifestations. I review recent progress in this field, with special focus on the functional consequences of beta- and gamma-secretase inhibition and altered amyloid neuropathology in mouse models of AD memory deficits.

Grutzendler J, Gan WB. · Northwestern University, 303 East Chicago Avenue, Ward Building 10-132, Chicago, IL 60611, USA. · NeuroRx. · Pubmed #17012063 No free full text.

Abstract: Two-photon microscopy (TPM) has become an increasingly important tool for imaging the structure and function of brain cells in living animals. TPM imaging studies of neuronal structures over intervals ranging from seconds to years have begun to provide important insights into the structural plasticity of synapses and the modulating effects of experience in the intact brain. TPM has also started to reveal how neuronal connections are altered in animal models of neurodegeneration, acute brain injury, and cerebrovascular disease. Here, we review some of these studies with special emphasis on the degree of structural dynamism of postsynaptic dendritic spines in the adult mouse brain as well as synaptic pathology in mouse models of Alzheimer's disease and cerebral ischemia. We also discuss technical considerations that are critical for the acquisition and interpretation of data from TPM in vivo.

Morris MC, Schneider JA, Tangney CC. · Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, IL 60612, USA. · J Alzheimers Dis. · Pubmed #16917152 No free full text.

Abstract: The B-vitamins, including vitamins B12, B6, B1, B2, niacin (B3) and folate (B9), have been implicated as protective risk factors against cognitive decline and Alzheimer's disease. This commentary reviews the evidence to support protective relations of these vitamins, including consideration of known vitamin deficiency syndromes, theories of underlying biologic mechanisms, and the epidemiologic evidence. We also comment on the potential benefits and harms of vitamin supplementation as well as make recommendations for the direction of future studies.

Thatcher GR, Bennett BM, Reynolds JN. · Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612-7231, USA. · Curr Alzheimer Res. · Pubmed #16842101 No free full text.

Abstract: NO is an important messenger molecule in the brain, playing an important role in learning and memory, in particular via the ERK/CREB signaling pathway. NO is also a neuroprotective agent; multiple mechanisms having been demonstrated that can contribute to cell survival as levels of antioxidants and trophic factors are reduced with aging. Small molecules that mimic the biological activity of NO, including NO donors, may thus ameliorate cognition and provide neuroprotection. Several lines of evidence have linked the neurodegeneration and dementia characteristic of Alzheimer's disease with the action of beta-amyloid protein at the alpha7-nicotinic acetylcholine receptor. The interplay of Abeta with alpha7-nicotinic ACh receptors operating via the ERK signaling cascade links the amyloid cascade and the cholinergic hypothesis in pathways that impact synaptic plasticity and memory. This interplay also provides linkages to disruption of NO/cGMP signaling in AD, and in addition, recent direct evidence has been found demonstrating that Abeta downregulates the NO/cGMP/CREB pathway. Activation of soluble guanylyl cyclase elevating cGMP in the brain represents the central element of a therapeutic approach to the treatment of AD and other neurodegenerative diseases, furthermore, evidence suggests that NO may display cGMP-independent activity and may operate via multiple biochemical signaling pathways to ensure the survival of neurons subjected to stress. GT 1061 is an NO chimera, an NO mimetic compound that contains an ancillary, synergistic pharmacophore, currently in clinical trials for Alzheimer's. NO chimeras and hybrid nitrates hold promise as therapeutics for AD with multiple sites of action.

Struble RG, Nathan BP, Cady C, Cheng X, McAsey M. · Department of Neurology and Center for Alzheimer Disease, Southern Illinois University School of Medicine, Springfield, IL 62794, USA. · Exp Gerontol. · Pubmed #16837159 No free full text.

Abstract: The effects of ovarian hormone on neuronal growth and function are well known. However, equally important, but often neglected, are ovarian hormone effects on glia. Our in vivo and in vitro studies show that estradiol modifies both neuronal growth and glial activity and these effects are tightly linked. Estradiol stimulates neurite growth and the release of the glial apolipoprotein E (apoE) in culture studies. Estradiol-stimulated neurite growth in these cultures requires apoE. Estradiol replacement in ovariectomized mice transiently increases the expression of apoE, the low density lipoprotein receptor related protein (LRP) and synaptophysin throughout the brain. Continuous estradiol replacement over two months loses effect on apoE, LRP, and synaptophysin and suppresses reactive gliosis. Estrous cycle variation of glial activation (GFAP) and apoE are not identical. We propose that estradiol (and other ovarian hormones) functions as a zeitgeber to co-ordinate neuronal-glial interactions. Co-ordination assures temporally appropriate excitatory and inhibitory interactions between glia and neurons. With aging and the loss of ovarian cyclicity, some of this co-ordination must be diminished. These observations present significant clinical implications. Approaches to hormone therapy (HT), for diminishing the risk of chronic neurological diseases, need to consider the temporal nature of ovarian hormones in brain repair and plasticity. Moreover, approaches must consider apoE genotype. The neuroprotective effects of HT in numerous chronic age-related diseases may represent effective co-ordination of repair processes rather than direct disease-specific actions. Moreover, the role of glial-derived proteins in neuroprotection should not be ignored.

Parihar MS, Brewer GJ. · Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62794-9626, USA. · Am J Physiol Cell Physiol. · Pubmed #16807300 links to  free full text

Abstract: Brain cells are highly energy dependent for maintaining ion homeostasis during high metabolic activity. During active periods, full mitochondrial function is essential to generate ATP from electrons that originate with the oxidation of NADH. Decreasing brain metabolism is a significant cause of cognitive abnormalities of Alzheimer disease (AD), but it remains uncertain whether this is the cause of further pathology or whether synaptic loss results in a lower energy demand. Synapses are the first to show pathological symptoms in AD before the onset of clinical symptoms. Because synaptic function has high energy demands, interruption in mitochondrial energy supply could be the major factor in synaptic failure in AD. A newly discovered age-related decline in neuronal NADH and redox ratio may jeopardize this function. Mitochondrial dehydrogenases and several mutations affecting energy transfer are frequently altered in aging and AD. Thus, with the accumulation of genetic defects in mitochondria at the level of energy transfer, the issue of neuronal susceptibility to damage as a function of age and age-related disease becomes important. In an aging rat neuron model, mitochondria are both chronically depolarized and produce more reactive oxygen species with age. These concepts suggest that multiple treatment targets may be needed to reverse this multifactorial disease. This review summarizes new insights based on the interaction of mitoenergetic failure, glutamate excitotoxicity, and amyloid toxicity in the exacerbation of AD.

Briones TL. · Department of Medical-Surgical Nursing, University of Illinois, Chicago, IL 60612, USA. · Curr Alzheimer Res. · Pubmed #16472203 No free full text.

Abstract: Age is the biggest risk factor for the development of neurodegenerative diseases. Consequently, as the population ages it becomes more critical to find ways to avoid the debilitating cost of neurodegenerative diseases such as Alzheimer's. Some of the non-invasive strategies that can potentially slow down the mental decline associated with aging are exercise and use of multi-sensory environmental stimulation. The beneficial effects of both exercise and multi-sensory environmental stimulation have been well-documented, thus it is possible that these strategies can either provide neuroprotection or increase resistance to the development of age-related cognitive problems.

Disterhoft JF, Oh MM. · Department of Physiology and Institute for Neuroscience, Feinberg School of Medicine, Northwestern University, 303 E Chicago Avenue, Chicago, IL 60611-3008, USA. · J Physiol Paris. · Pubmed #16458491 No free full text.

Abstract: When animals learn hippocampus-dependent associative and spatial tasks such as trace eyeblink conditioning and the water maze, CA1 hippocampal neurons become more excitable as a result of reductions in the post-burst, slow afterhyperpolarization. The calcium-activated potassium current that mediates this afterhyperpolarization is activated by the calcium influx that occurs when a series of action potentials fire and serves as a modulator of neuronal firing frequency. As a result, spike frequency accommodation is also reduced after learning. Neuronal calcium buffering processes change and/or voltage-dependent calcium currents increase during aging; leading to enhancements in the slow afterhyperpolarization, increased spike frequency accommodation and age-associated impairments in learning. We describe a series of studies done to characterize this learning-specific enhancement in intrinsic neuronal excitability and its converse in aging brain. We have also combined behavioral pharmacology and biophysics in experiments demonstrating that compounds that increase neuronal excitability in CA1 pyramidal neurons also enhance learning rate of hippocampus-dependent tasks, especially in aging animals. The studies reviewed here include those using nimodipine, an L-type calcium current blocker that tends to cross the blood-brain barrier; metrifonate, a cholinesterase inhibitor; CI1017, a muscarinic cholinergic agonist; and galantamine, a combined cholinesterase inhibitor and nicotinic agonist. Since aging is the chief risk factor for Alzheimer's disease, a disease that targets the hippocampus and associated brain regions and markedly impairs hippocampus-dependent learning, these compounds have potential use as treatments for this disease. Galantamine has been approved by the USDA for this purpose. Finally, we have extended our studies to the TG2576 transgenic mouse model of Alzheimer's disease (AD), that overproduces amyloid precursor protein (APP) and increases levels of toxic beta-amyloid in the brain. Not only do these mice show deficits in hippocampus-dependent learning as they age, but their hippocampal neurons show a reduced capacity to increase their levels of intrinsic excitability with reductions in the slow afterhyperpolarization after application of the muscarinic agonist carbachol. These TG2576 APP overproducing mice were crossed with BACE1 knockout mice, that do not produce beta-amyloid because cleavage of APP by the beta-site APP cleaving enzyme 1 (BACE1) is a critical step in its formation. Not only was hippocampus-dependent learning rescued in the bigenic TG2576-BACE1 mice, but the capacity of hippocampal neurons to show normal enhancements of intrinsic excitability was restored. The series of studies reviewed here support our hypothesis that enhancement in intrinsic excitability by reductions in calcium-activated potassium currents in hippocampal neurons is an important cellular mechanism for hippocampus-dependent learning.

Vetrivel KS, Thinakaran G. · Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, IL 60637, USA. · Neurology. · Pubmed #16432149 No free full text.

Abstract: Trafficking and proteolytic processing of amyloid precursor protein (APP) have been the focus of numerous investigations in the past two decades, since the identification of Abeta as the principal component of brain senile plaques and the cloning of APP cDNA. Tremendous progress has been made in the recent past toward the characterization of beta- and gamma-secretases. Here, we review the salient features of Alzheimer disease amyloidogenesis, and discuss the current knowledge on APP trafficking and amyloidogenic processing of APP in intracellular membrane compartments and microdomains.

Cole SL, Vassar R. · Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611, USA. · Neurobiol Dis. · Pubmed #16406223 No free full text.

Abstract: Cholesterol metabolism has been linked to Alzheimer's disease (AD) neuropathology, which is characterized by amyloid plaques, neurofibrillary tangles and neuroinflammation. Indeed, the use of statins, which inhibit cholesterol and isoprenoid biosynthesis, as potential AD therapeutics is under investigation. Whether statins offer benefit for AD will be determined by the outcome of large, placebo-controlled, randomized clinical trials. However, their use as pharmacological tools has delineated novel roles for isoprenoids in AD. Protein isoprenylation regulates multiple cellular and molecular events and here we review the complex roles of isoprenoids in AD-relevant processes and carefully evaluate isoprenoid pathways as potential AD therapeutic targets.

Chauhan NB. · Research and Development, Jesse Brown VA Medical Center Chicago, 820 South Damen Avenue, Chicago, IL 60612, USA. · J Nutr Health Aging. · Pubmed #16395514 No free full text.

Abstract: The epidemiological, clinical and laboratory data have shown that garlic contains many biologically active compounds which are beneficial to human health in general. Among all, one garlic-preparation called aged garlic extract, is proven to be safer. Although additional studies are warranted in humans, compelling evidence supports the health effects attributed to aged garlic extract and its implications in preventing or reducing the risk of cardiovascular ailments, stroke and cancer. Recently, the beneficial effects of garlic and its constituents on neuronal physiology and brain functions are beginning to emerge. However, this field is still in infancy and not yet fully explored. This review encompasses multiple health effects of garlic and its constituents with reference to neuroprotection. Possible potential of dietary garlic as an alternative herbal pharmacotherapy for Alzheimer's disease is discussed.

Wu C, Pike VW, Wang Y. · Department of Medicinal Chemistry, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA. · Curr Top Dev Biol. · Pubmed #16338342 No free full text.

Abstract: Tremendous efforts have been made in the search for a cure or effective treatment of Alzheimer's disease (AD) to develop therapies aimed at halting or reversing amyloid plaque deposition in the brain. This necessitates in vivo detection and quantification of amyloid plaques in the brain for efficacy evaluation of anti-amyloid therapies. For this purpose, a wide array of amyloid-imaging probes has been developed, mainly for in vivo studies based on positron emission tomography and single photon emission computed tomography. This review provides a full account of the development of amyloid-imaging agents. The in vitro binding properties and in vivo pharmacokinetic profiles of all amyloid-imaging agents so far reported are comprehensively and uniquely surveyed. Emphasis is placed on the development of small-molecule probes based on amyloid dyes, such as Congo red and thioflavin T. Compared to large biomolecules, these small-molecule probes have been systematically investigated through extensive structure activity relationship studies. Many of the probes show favorable properties for in vivo studies. As a result, three lead compounds, termed PIB (Pittsburgh-Compound B, [(11)C]6-OH-BTA-1), FDDNP (2-(1-[6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene)malononitrile), and SB-13 (4-N-methylamino-4'-hydroxystilbene), have been identified and evaluated in human subjects. Preliminary studies have indicated that these lead compounds exhibit a characteristic retention in AD subjects that is consistent with the AD pathology, thus proving the concept that amyloid deposits in the brain can be readily detected and quantified in vivo. The progress to date paves the way for further investigation in various aspects of AD research. Once developed, these amyloid-imaging agents could be used as biomarkers to aid in early and definitive diagnosis of AD, facilitate drug discovery and development, and allow pathophysiological studies of the disease mechanism. Furthermore, the success in the development of amyloid-imaging agents helps with the development of imaging agents for in vivo studies of other AD pathologies in particular and of neurodegenerative disorders in general.

Buracchio T, Arvanitakis Z, Gorbien M. · Rush Alzheimer's Disease Center, Department of Neurological Sciences, Rush University Medical Center, Chicago, Ill 6012, USA. · Dement Geriatr Cogn Disord. · Pubmed #16174977 No free full text.

Abstract: As life expectancy continues to increase over time, dementia is becoming an increasingly more common problem and a major cause of disability in older persons. It is now more important than ever to identify and manage common causes of dementia given variations in disease course, treatments and the possibility for modification of risk factors. Dementia with Lewy bodies (DLB) is a dementia syndrome characterized by progressive cognitive decline, with fluctuating cognition, recurrent detailed and well-formed hallucinations, and parkinsonism. This article aims to provide an overview of current concepts of DLB, including a description of the key clinical features and neuropathology, neurochemistry, and genetics of DLB, then a discussion of the relationship of DLB with Alzheimer's disease and Parkinson's disease, and, finally, a summary of current management strategies available for this disorder.

Thatcher GR, Bennett BM, Reynolds JN. · Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St. Chicago, IL 60612-7231, USA. · Curr Alzheimer Res. · Pubmed #15974915 No free full text.

Abstract: Nitric oxide is multifunctional messenger molecule in the brain, playing important roles including in learning and memory and in regulating the expression of trophic factors that may be reduced with aging. Small molecules that mimic the biological activity of NO, NO mimetics, will bypass cholinergic receptor activation and are anticipated to provide multiple pathways of treating and circumventing dementia in Alzheimer's disease. Activation of soluble guanylyl cyclase and cGMP formation in the brain represents one element of effective neuroprotective pathways mediated by NO. Substantial evidence suggests that NO mimetics may display cGMP-dependent and cGMP-independent activity and may operate via multiple biochemical signaling pathways, both to ensure the survival of neurons subjected to stress and also to provide cognition-enabling pathways to circumvent dementia. GT 1061 is an NO mimetic compound currently in clinical trials for Alzheimer's. A survey of current research indicates that NO mimetics will provide a combined neuroprotective and cognition-enabling approach to anti-neurodegenerative therapy.

Mufson EJ, Counts SE, Perez SE, Binder L. · Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, Suite 300, Chicago, IL 60612, USA. · Neuropeptides. · Pubmed #15893372 No free full text.

Abstract: Galanin (GAL) is a biologically active 29 amino acid (30 in humans) which participates in the modulation of several ascending neurotransmitter systems including cholinergic basal forebrain (CBF) neurons, which undergo extensive degeneration in Alzheimer's disease (AD). GAL immunoreactive fibers within the CBF display hypertrophy and hyperinnervate surviving CBF neurons in late AD. Over the years, this unique neuronal plasticity response has been an active area of research for our group. We have examined tissue from a clinically well characterized cohort of retired elderly clergy to determine whether people with mild cognitive impairment display GAL hyperinnervation upon CBF neurons. We found that GAL hyperinnervation is a late stage event and that CBF neuron reduction is not correlated with GAL over expression during prodromal AD. Interestingly, findings from our laboratory using tau immunohistochemistry and single cell gene array technologies suggest that GAL remodeling may influence neurofibrillary tangle formation by altering tau phosphorylation events in CBF neurons in AD. Studies using GAL-tg mice suggest that GAL over expression reduces the cholinergic phenotype but does not produce a frank loss of CBF cells. This phenotypic down regulation of ChAT is reminiscent of the lack of a frank CBF neuron loss in prodromal AD. Moreover, studies using mice transgenic for both the amyloid precursor protein (APP) and presenilin-1 (PS1) bearing AD-related mutations (APPswe/PS1delta9) displayed increased GAL immunoreactive fibers, neurities and plaques in cortex and hippocampus. These fin'dings provide evidence for a mechanistic relationship between amyloidosis and GAL over expression in AD. Understanding GALs role in the clinical and pathological features of AD, may lead to novel drug treatments for this disease.

Counts SE, Mufson EJ. · Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA. · J Neuropathol Exp Neurol. · Pubmed #15835262 No free full text.

Abstract: Dysfunction of nerve growth factor (NGF) and its high (TrkA) and low (p75NTR) affinity receptors has been suggested to underlie the selective degeneration of the nucleus basalis (NB) cholinergic cortical projection neurons in end stage Alzheimer disease (AD). Whether the NGF system is dysfunctional during the prodromal stages of AD has only recently been evaluated. Surprisingly, the number of choline acetyltransferase-containing neurons remains stable despite a significant reduction in NGF receptor-positive cells in people with mild cognitive impairment (MCI), suggesting a phenotypic NGF receptor downregulation but not a frank loss of NB neurons during prodromal AD. Moreover, there is a loss of cortical TrkA in the face of stable p75NTR and increased proNGF levels, the precursor molecule of mature NGF, in early AD. Depending upon the cellular context these changes may result in increased pro-apoptotic signaling, cell survival, or a defect in retrograde transport mechanisms. Alterations in NGF and its receptors within the cholinotrophic NB system in early AD suggest that NGF-mediated cell signaling is required for the longterm survival of these neurons. Therapeutic neurotrophic intervention might delay or prevent NB neuron degeneration and preserve cholinergic cortical function during prodromal AD.

Gorelick PB. · Department of Neurology and Rehabilitation, University of Illinois College of Medicine at Chicago, Chicago, Ill 60612, USA. · Stroke. · Pubmed #15731466 links to  free full text

Abstract: BACKGROUND AND PURPOSE: Vascular risk factors are common in the elderly, and some such as hypertension may be important predictors of cognitive impairment. SUMMARY OF REVIEW: In this article, the role that vascular risk factors may play in the prevention of vascular and nonvascular forms of cognitive impairment is reviewed. CONCLUSIONS: Because vascular risk factors may have negative effects on brain structure and cognitive function, and because vascular risk factors may be present in midlife or possibly earlier, we may need to develop long-term intervention strategies to control or prevent vascular risk factors in an effort to preserve cognitive vitality as we age.

Maki PM. · Department of Psychiatry and Psychology, University of Illinois at Chicago, Chicago, Illinois 60612, USA. · Gynecol Endocrinol. · Pubmed #15724810 No free full text.

Abstract: Prospective observational studies suggest that hormone therapy (HT) might confer protection against the development of Alzheimer's disease. In contrast, recent findings from the Women's Health Initiative Memory Study (WHIMS) indicated a doubling of the risk of all-cause dementia in women randomized to receive HT after age 64. The discrepancy between findings from observational studies and the WHIMS is commonly attributed to the lack of treatment bias in the randomized trial. However, there are other potentially important dfferences between the WHIMS and the observational studies. These include timing of initiation of HT and type of HT regimen used. The present review focuses on the clinical and basic science studies bearing on these clinically important issues. Additional clinical studies are needed to understand the external generalizability of the WHIMS results to populations of women for whom HT remains an indication.