Alzheimer Disease: Wenk GL

Marchalant Y, Brothers HM, Wenk GL. · Department of Psychology, The Ohio State University, Columbus, OH 43210, USA. · Biomed Pharmacother. · Pubmed #18400455 links to  free full text

Abstract: Aging often leads to cognitive decline due to neurodegenerative process in the brain. As people live longer, there exists a growing concern linked to long-term, slowly debilitating diseases, such as Alzheimer's disease for which a cure has not yet been found. Recently, the role of neuroinflammation has attracted attention due to its slow onset, chronic nature and its possible role in the development of many different neurodegenerative diseases. In the future, treatment of chronic neuroinflammation may help counteract aspects of neurodegenerative disease. Our recent studies have focused upon the endocannabinoid system for its unique effects on the expression of neuroinflammation. The basis for the manipulation of the endocannabinoid system in the brain in combination with existing treatments for Alzheimer's disease will be discussed in this review.

Wenk GL, Parsons CG, Danysz W. · Department Psychology & Neuroscience, Ohio State University, Ohio, USA. · Behav Pharmacol. · Pubmed #16940762 No free full text.

Abstract: Glutamatergic neurotransmission is critical to normal learning and memory and when the activity of glutamate neurons becomes excessive, or the normal function of its primary receptors becomes dysfunctional, this may lead to pathological changes associated with age-related neurodegenerative diseases. Anomalous glutamatergic activity associated with Alzheimer's disease may be due to a postsynaptic receptor and downstream defects that produce inappropriately timed or sustained glutamate activation of N-methyl-D-aspartate receptors, leading to neuronal injury and death and cognitive deficits associated with dementia. The mechanisms leading to the condition of chronically depolarized membranes on vulnerable neurons in the Alzheimer's disease brain are likely due to a complex interaction between oxidative stress, mitochondrial failure, chronic brain inflammation and the presence of amyloid-beta and hyperphosphorylated-tau; each of these factors are highly interrelated with each other and are discussed with an emphasis upon potential therapeutic mechanisms underlying the neuroprotective actions of memantine.

Wenk GL. · Department of Psychology, Ohio State University, Columbus, OH 43210, USA. · J Clin Psychiatry. · Pubmed #16649845 No free full text.

Abstract: The cognitive symptoms of Alzheimer's disease (AD) are believed to be caused not only by the loss of neurons in the cholinergic and glutamatergic neural systems but also by the irregular functioning of surviving neurons in these 2 systems. Aberrant cholinergic functioning in AD has been linked to deficits in the neurotransmitter acetylcholine, while AD-related abnormalities in glutamatergic signaling have been attributed to excitotoxicity caused by the persistent, low-level stimulation of glutamatergic neurons via the chronic influx of Ca(2+) ions through the N-methyl-D-aspartate (NMDA) receptor calcium channel. Glutamatergic abnormalities in AD can be corrected to some extent by the NMDA receptor antagonist memantine, an agent whose therapeutic efficacy is believed to be related to its low to moderate level of affinity for the NMDA receptor calcium channel, a characteristic that allows memantine to prevent excessive glutamatergic stimulation while still permitting normal glutamate-mediated neurotransmission to take place. Although the mechanism underlying the chronic stimulation of glutamatergic neurons in AD has yet to be elucidated, one hypothesis is that the characteristic neuropathologic features of AD -- beta-amyloid deposits and neurofibrillary tangles -- induce brain inflammation, which in turn impairs glutamatergic receptor function in such a way that the ability of these receptors to prevent the influx of Ca(2+) in the absence of an appropriate presynaptic signal is compromised. If this hypothesis is correct, and if it is correct that beta-amyloid deposits and neurofibrillary tangles arise long before the symptomatic onset of AD, then memantine, with its ability to alleviate glutamatergic receptor overstimulation, would be expected to provide therapeutic benefits beginning from the earliest stages of the disease.

Rogawski MA, Wenk GL. · Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-4457, USA. · CNS Drug Rev. · Pubmed #14530799 No free full text.

Abstract: Memantine has been demonstrated to be safe and effective in the symptomatic treatment of Alzheimer's disease (AD). While the neurobiological basis for the therapeutic activity of memantine is not fully understood, the drug is not a cholinesterase inhibitor and, therefore, acts differently from current AD therapies. Memantine can interact with a variety of ligand-gated ion channels. However, NMDA receptors appear to be a key target of memantine at therapeutic concentrations. Memantine is an uncompetitive (channel blocking) NMDA receptor antagonist. Like other NMDA receptor antagonists, memantine at high concentrations can inhibit mechanisms of synaptic plasticity that are believed to underlie learning and memory. However, at lower, clinically relevant concentrations memantine can under some circumstances promote synaptic plasticity and preserve or enhance memory in animal models of AD. In addition, memantine can protect against the excitotoxic destruction of cholinergic neurons. Blockade of NMDA receptors by memantine could theoretically confer disease-modifying activity in AD by inhibiting the "weak" NMDA receptor-dependent excitotoxicity that has been hypothesized to play a role in the progressive neuronal loss that underlies the evolving dementia. Moreover, recent in vitro studies suggest that memantine abrogates beta-amyloid (Abeta) toxicity and possibly inhibits Abeta production. Considerable attention has focused on the investigation of theories to explain the better tolerability of memantine over other NMDA receptor antagonists, particularly those that act by a similar channel blocking mechanism such as dissociative anesthetic-like agents (phencyclidine, ketamine, MK-801). A variety of channel-level factors could be relevant, including fast channel-blocking kinetics and strong voltage-dependence (allowing rapid relief of block during synaptic activity), as well as reduced trapping (permitting egress from closed channels). These factors may allow memantine to block channel activity induced by low, tonic levels of glutamate--an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity--while sparing synaptic responses required for normal behavioral functioning, cognition and memory.

Wenk GL. · Division of Neural Systems, Memory & Aging, The University of Arizona, Tucson 85724, USA. · J Clin Psychiatry. · Pubmed #12934968 No free full text.

Abstract: Alzheimer's disease is characterized by degenerative changes in a variety of neurotransmitter systems. These include alterations in the function of the monoaminergic neural systems that release glutamate, norepinephrine, and serotonin as well as a few neuropeptide-containing systems. Alzheimer's disease is also characterized by degenerative changes in selected brain regions, including the temporal and parietal lobes and restricted regions within the frontal cortex and cingulate gyrus. The degeneration of these systems may underlie specific aspects of the dementia associated with Alzheimer's disease. A major problem in Alzheimer's disease research today is that none of the current hypothesized mechanisms are able to explain the cellular and regional distribution pattern that characterizes the neuropathology of Alzheimer's disease. This article summarizes the nature and extent of the changes associated with neural systems, possible treatment approaches, and a potential mechanism involving chronic neuroinflammation to explain the pattern of neuropathologic changes in Alzheimer's disease.

Marchalant Y, Rosi S, Wenk GL. · Arizona Research Laboratories, Division of Neural Systems Memory and Aging, University of Arizona, Tucson, AZ, USA. · Neuroscience. · Pubmed #17178196 links to  free full text

Abstract: Cannabinoid receptors (CBr) stimulation induces numerous central and peripheral effects. A growing interest in the beneficial properties of manipulating the endocannabinoid system has led to the possible involvement of CBr in the control of brain inflammation. In the present study we examined the effect of the CBr agonist, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo[1,2,3-de]-1,4benzoxazin-6-yl]-1-naphthalenyl-methanone mesylate (WIN-55212-2), on microglial activation and spatial memory performance, using a well-characterized animal model of chronic brain inflammation produced by the infusion of lipopolysaccharide (LPS, 250 ng/h for 3 weeks) into the fourth ventricle of young rats. WIN-55212-2 (0.5 or 1.0 mg/kg/day, i.p.) was administered for 3 weeks. During the third week of treatment, spatial memory ability was examined using the Morris water-maze task. We found that 0.5 and 1 mg/kg WIN-55212-2 reduced the number of LPS-activated microglia, while 1 mg/kg WIN-55212-2 potentiated the LPS-induced impairment of performance in the water maze task. Cannabinoid receptors 1 were not expressed by microglia and astrocytes, suggesting an indirect effect of WIN-55212-2 on microglia activation and memory impairment. Our results emphasize the potential use of CBr agonists in the regulation of inflammatory processes within the brain; this knowledge may lead to the use of CBr agonists in the treatment of neurodegenerative diseases associated with chronic neuroinflammation, such as Alzheimer disease.

Mohmmad Abdul H, Wenk GL, Gramling M, Hauss-Wegrzyniak B, Butterfield DA. · Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA. · Neurosci Lett. · Pubmed #15351438 No free full text.

Abstract: Epidemiological and biochemical studies strongly implicate a role for cholesterol in the pathogenesis of Alzheimer's disease (AD). Mutation in the PS-1 and APP genes, which increases production of the highly amyloidogenic amyloid beta-peptide (Abeta42), is the major cause of familial AD. The AD brain is under significant oxidative stress, including protein oxidation and lipid peroxidation. In the present study, protein oxidation and lipid peroxidation were compared in the brain homogenates from knock-in mice expressing mutant human PS-1 and APP in relation to the intake of dietary cholesterol. The APP and PS-1 mice displayed increased oxidative stress as measured by protein oxidation and lipid peroxidation, independent of dietary cholesterol. These results are discussed with reference to proposed therapeutic strategies of AD.

Wenk GL, McGann-Gramling K, Hauss-Wegrzyniak B. · Division of Neural Systems, Memory and Aging, University of Arizona, 350 Life Sciences North Building, Tucson, AZ 85724, USA. · Neuroscience. · Pubmed #15099690 No free full text.

Abstract: Neuroinflammation, and elevated levels of inflammatory proteins, such as tumor necrosis factor-alpha, and the deposition of beta-amyloid may interact to contribute to the pathogenesis of Alzheimer's disease. We reproduced a component of the neuroinflammatory state within the basal forebrain cholinergic system, a region that is vulnerable to degeneration in Alzheimer's disease, of transgenic Tg2576 mice that express the Swedish double mutation of the human amyloid precursor protein (APPswe). We have previously shown that basal forebrain cholinergic neurons are selectively vulnerable to the consequences of neuroinflammation. In the current study, tumor necrosis factor-alpha was infused into the basal forebrain region of APPswe and nontransgenic control mice for 20 days with the expectation that the presence of the transgene would enhance the loss of cholinergic neurons. Chronic infusion of tumor necrosis factor-alpha significantly decreased cortical choline acetyltransferase activity, reduced the number of choline acetyltransferase-immunoreactive cells and increased the number of activated astrocytes and microglia within the basal forebrain. The presence of the APPswe gene did not enhance the vulnerability of forebrain cholinergic neurons to the chronic neuroinflammation. Furthermore, combined treatment of these mice with memantine demonstrated that the neurotoxic effects of tumor necrosis factor-alpha upon cholinergic cells did not require the activation of the N-methyl-d-aspartate receptors. In contrast, we have previously shown that memantine was able to provide neuroprotection to cholinergic forebrain neurons from the consequences of exposure to the inflammogen lipopolysaccharide. These results provide insight into the mechanism by which neuroinflammation may selectively target specific neural systems during the progression of Alzheimer's disease.

Wenk GL, McGann-Gramling K, Hauss-Wegrzyniak B, Ronchetti D, Maucci R, Rosi S, Gasparini L, Ongini E. · Division of Neural Systems, Memory and Aging, University of Arizona, Tucson, Arizona 85724, USA. · J Neurochem. · Pubmed #15056291 No free full text.

Abstract: Chronic neuroinflammation and oxidative stress contribute to the neurodegeneration associated with Alzheimer's disease and represent targets for therapy. Ferulic acid is a natural compound that expresses antioxidant and anti-inflammatory activities. Nitric oxide is also a key modulator of inflammatory responses. Grafting a nitric oxide-releasing moiety onto anti-inflammatory drugs results in enhanced anti-inflammatory activity. We compared the effectiveness of ferulic acid with a novel nitric oxide-releasing derivative of ferulic acid in an animal model of chronic neuroinflammation that reproduces many interesting features of Alzheimer's disease. Lipopolysaccharide was infused into the 4th ventricle of young rats for 14 days. Various doses of ferulic acid or its nitric oxide-releasing derivative were administered daily. Both drugs produced a dose-dependent reduction in microglia activation within the temporal lobe. However, the nitric oxide-releasing ferulic acid derivative was significantly more potent. If we delayed the initiation of therapy for 14 days, we found no reduction in microglial activation. In addition, both drugs demonstrated antioxidant and hydroxyl radical scavenging abilities in in vitro studies. Overall, our results predict that a treatment using nitric oxide-releasing ferulic acid may attenuate the processes that drive the pathology associated with Alzheimer's disease if the treatment is initiated before the neuroinflammatory processes can develop.

Wenk GL, McGann K, Hauss-Wegrzyniak B, Rosi S. · Arizona Research Laboratories, Division of Neural Systems, Memory and Aging, University of Arizona, Tucson, AZ 85724, USA. · Neuroscience. · Pubmed #14568031 No free full text.

Abstract: Inflammation and reduced forebrain norepinephrine are features of Alzheimer's disease that may interact to contribute to the degeneration of specific neural systems. We reproduced these conditions within the basal forebrain cholinergic system, a region that is vulnerable to degeneration in Alzheimer's disease. Tumor necrosis factor-alpha was infused into the basal forebrain of young mice pretreated with a norepinephrine neuronal toxin, N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP4), with the expectation that the loss of noradrenergic input would enhance the loss of cholinergic neurons. The results indicate that chronic infusion of tumor necrosis factor-alpha alone significantly decreased cortical choline acetyltransferase activity and increased the number of activated microglia and astrocytes within the basal forebrain. The loss of forebrain norepinephrine following systemic treatment with DSP4 did not alter the level of cortical choline acetyltransferase activity or activate microglia but significantly activated astrocytes within the basal forebrain. Infusion of tumor necrosis factor-alpha into DSP4-pretreated mice also reduced cortical choline acetyltransferase activity on the side of the infusion; however, the decline was not significantly greater than that produced by the infusion of tumor necrosis factor-alpha alone. The neurodegeneration seen may be indirect since a double-immunofluorescence investigation did not find evidence for the co-existence of tumor necrosis factor-alpha type I receptors on choline acetyltransferase-positive cells in the basal forebrain. The results suggest that noradrenergic cell loss in Alzheimer's disease does not augment the consequences of the chronic neuroinflammation and does not enhance neurodegeneration of forebrain cholinergic neurons.

Gold PE, Cahill L, Wenk GL. · University of Illinois at Urbana-Champaign, USA. · Sci Am. · Pubmed #12661320 No free full text.

This publication has no abstract.

Jantzen PT, Connor KE, DiCarlo G, Wenk GL, Wallace JL, Rojiani AM, Coppola D, Morgan D, Gordon MN. · Department of Pharmacology, Alzheimer's Research Laboratory, University of South Florida, Tampa, Florida 33612, USA. · J Neurosci. · Pubmed #11896164 links to  free full text

Abstract: 3-4-(2-Fluoro-alpha-methyl-[1,1'-biphenyl]-4-acetyloxy)-3-methoxyphenyl]-2-propenoic acid 4-nitrooxy butyl ester (NCX-2216), a nitric oxide (NO)-releasing derivative of the cyclooxygenase-1-preferring nonsteroidal anti-inflammatory drug (NSAID) flurbiprofen, dramatically reduced both beta-amyloid (Abeta) loads and Congo red staining in doubly transgenic (Tg) amyloid precursor protein plus presenilin-1 mice when administered at 375 ppm in diet between 7 and 12 months of age. This reduction was associated with a dramatic increase in the number of microglia expressing major histocompatibility complex-II antigen, a marker for microglial activation. In contrast, ibuprofen at 375 ppm in diet caused modest reductions in Abeta load but not Congo red staining, suggesting that the effects of this nonselective NSAID were restricted primarily to nonfibrillar deposits. We detected no effects of the cyclooxygenase-2-selective NSAID celecoxib at 175 ppm on amyloid deposition. In short-term studies of 12-month-old Tg mice, we found that the microglia-activating properties of NCX-2216 (7.5 mg small middle dot kg(-1) small middle dot d(-1), s.c.) were present after 2 weeks of treatment. Microglia were not activated by NCX-2216 in non-Tg mice lacking Abeta deposits, nor were microglia activated in Tg animals by flurbiprofen (5 mg small middle dot kg(-1) small middle dot d(-1)) alone. These data are consistent with the argument that activated microglia can clear Abeta deposits. We conclude that the NO-generating component of NCX-2216 confers biological actions that go beyond those of typical NSAIDs. In conclusion, NCX-2216 is more efficacious than ibuprofen or celecoxib in clearing Abeta deposits from the brains of Tg mice, implying potential benefit in the treatment of Alzheimer's dementia.

Hauss-Wegrzyniak B, Galons JP, Wenk GL. · Arizona Research Laboratories Division of Neural Systems, University of Arizona, Tucson, Arizona 85724, USA. · Exp Neurol. · Pubmed #10993694 No free full text.

Abstract: Brain inflammation may have a pathogenic role in many neurodegenerative diseases, including Alzheimer's disease. In the present study, we investigated the effects of chronic neuroinflammation upon anatomical changes in two regions of interest in the temporal lobe using high-resolution magnetic resonance imaging techniques. We show that chronic infusion of lipopolysaccharide into the fourth ventricle for 4 consecutive weeks enlarged the lateral ventricles and significantly decreased the size of the hippocampal formation and the temporal lobe region. These changes are comparable to those observed in humans during the early stages of Alzheimer's disease.