Journal of Alzheimer's Disease - Volume 6, issue s6

Authors: Refolo, L.M. | Fillit, H.M.

Article Type: Editorial

DOI: 10.3233/JAD-2004-6S609

Citation: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S1-S2, 2004

Authors: Bredesen, Dale E.

Article Type: Research Article

DOI: 10.3233/JAD-2004-6S613

Citation: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S3-S6, 2004

Authors: Chao, Moses V. | Lee, Francis S.

Article Type: Research Article

DOI: 10.3233/JAD-2004-6S611

Citation: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S7-S11, 2004

Authors: Longo, Frank M. | Massa, Stephen M.

Article Type: Research Article

Abstract: Neurotrophins activate a number of signaling pathways relevant to neuroprotection; however, their poor pharmacological properties and their pleiotropic effects resulting from interaction with the p75NTR -Trk-sortilin three-receptor signaling system limit therapeutic application. While local application of neurotrophin proteins addresses some of the pharmacological challenges, selective targeting of neurotrophin receptors might allow for more selective application of neurotrophin receptor signaling modulation. Recent studies have supported the feasibility of developing non-peptidyl small molecules that mimic specific domains of neurotrophins and modulate signaling of specific neurotrophin receptors. The expression of p75NTR by populations of neurons most vulnerable in Alzheimer's disease and the …linkage of p75NTR signaling to aberrant signaling mechanisms occurring in this disorder, point to potential applications for p75NTR -based small molecule strategies. Small molecules targeted to p75NTR in the settings of neurodegenerative disease and other forms of neural injury might serve to inhibit death signaling, block proNGF-mediated degenerative signaling and minimize deleterious effects promoted by pharmacologically upregulated Trk signaling. Show more

DOI: 10.3233/JAD-2004-6S606

Citation: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S13-S17, 2004

Authors: Kelleher-Andersson, J.

Article Type: Research Article

DOI: 10.3233/JAD-2004-6S601

Citation: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S19-S25, 2004

Authors: Brinton, Roberta Diaz

Article Type: Research Article

Abstract: Our goal is to develop therapeutic agents that prevent age-associated neurodegenerative disease such as Alzheimer's. To achieve this goal, we are building on extensive knowledge regarding mechanisms of estrogen action in brain and the epidemiological human data indicating that estrogen/hormone therapy reduces the risk of developing Alzheimer's disease when administered at the time of the menopause and continued over several to many years. The mechanisms of estrogen action in neurons provides a systematic mechanistic rationale for determining why estrogen therapy is efficacious for prevention of Alzheimer's disease and why it is not efficacious for long-term treatment of the disease. Our …preclinical research plan is a hybrid of both discovery and translational research to develop a brain selective estrogen receptor modulator (SERM). We have termed such molecules NeuroSERMs to denote their preferential selectivity for activating estrogen mechanisms in brain. Our strategy to develop NeuroSERMs is threefold: (1) determine the target of estrogen action in brain, specifically the estrogen receptor in hippocampal and cortical neurons required for the neurotrophic and neuroprotective actions of estrogen; (2) develop NeuroSERM candidate molecules using three in silico discovery and design strategies and (3) determine the neurotrophic and neuroprotective efficacy of candidate molecules using neuronal responses predictive of clinical efficacy. Using an academic translational research model, a team of scientists with expertise in molecular biology, computational chemistry, synthetic chemistry, proteomics, neurobiology and mitochondrial function have been assembled along with state of the art technologies required to develop candidate NeuroSERM molecules. Show more

Keywords: therapeutics, estrogen, Alzheimer's disease, neuroprotection, neurons

DOI: 10.3233/JAD-2004-6S607

Citation: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S27-S35, 2004

Authors: Gozes, Illana | Divinski, Inna

Article Type: Research Article

Abstract: Activity-dependent neuroprotective protein (ADNP), a gene product essential for brain formation, contains a short octapeptide sequence NAPVSIPQ (NAP) that protects neurons against a wide variety of insults. At the pico-molar concentration range, NAP provides neuroprotection by direct interaction with neurons. At the femtomolar concentration range, NAP requires the presence of glial cells to provide neuroprotection. To further understand the mechanism of neuroprotection afforded by NAP, specific binding proteins were searched for. Tubulin, the major subunit protein of microtubules, was identified as a NAP binding molecule. NAP structure allows membrane penetration, followed by tubulin binding and facilitation of microtubule assembly toward …cellular protection in astrocytes. NAP (10-15 M) promoted microtubule assembly in vitro and protected astrocytes against zinc intoxication which is associated with microtubule disruption. A two hour incubation period of astrocytes with femtomolar concentrations of NAP resulted in microtubule re-organization and transient increases in immunoreactive non-phosphorylated tau. Microtubules are the key component of the neuronal and glial cytoskeleton that regulates cell division, differentiation and protection, while tau pathology is a major contributor to Alzheimer's disease and other dementias. The findings described here may open up new horizons in research and development of neuroprotective compounds. Show more

DOI: 10.3233/JAD-2004-6S605

Citation: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S37-S41, 2004

Authors: Henricksen, L.A. | Federoff, H.J.

Article Type: Research Article

Abstract: Herein a case is made for the development of novel cytoprotective approaches based upon molecular mechanisms thought to underlie the caloric restriction phenomenon. This analysis leads to the prediction that molecular genetic perturbations affecting the metabolism of nuclear NAD+ and metabolites will be neuroprotective.

DOI: 10.3233/JAD-2004-6S608

Citation: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S43-S46, 2004

Authors: Andersen, Julie K.

Article Type: Research Article

Abstract: We have recently demonstrated that chelation of in vivo brain iron in a form which is not available to participate in oxidative events protects against a toxin-induced form of Parkinsonism in rodents, the well-established MPTP model [32]. These data strongly suggest that iron elevations observed in the Parkinsonian substantia nigra (SN), the brain region which undergoes selective neurodegeneration in the disease, are actively involved in subsequent neurodegenerative events. However the mechanism(s) by which iron levels become elevated in the Parkinsonian SN are still unclear. We hypothesize that increased oxidative stress associated with the disease may result in dysregulation of iron …homeostasis in midbrain dopaminergic neurons via alterations in binding of iron regulatory proteins (IRPs). This would mechanistically explain the noted increase in cellular iron levels in the Parkinsonian SN which appear to contribute to subsequent neurodegeneration. Show more

Keywords: Parkinson's disease, iron, oxidative stress, iron-regulatory proteins

DOI: 10.3233/JAD-2004-6S602

Citation: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S47-S52, 2004

Authors: Bartzokis, George | Lu, Po H. | Mintz, Jim

Article Type: Research Article

Abstract: Myelin plays an essential role in brain structure and function and the human brain is uniquely dependent on the elaboration of this late invention of evolution. Our brain has the most extensive and protracted process of myelination that extends to approximately age 50 in cortical regions that have the highest risk for developing Alzheimer's disease (AD) pathology. This myelin-centered model of the human brain asserts that unique vulnerabilities of myelin, especially late-developed myelin, and the oligodendrocytes that produce it are directly pertinent to many uniquely human neuropsychiatric diseases including late-life neurodegenerative disorders such as AD. Magnetic resonance imaging …(MRI) technology permits the in vivo assessment of the roughly quadratic (inverted U) lifelong trajectory of human myelin development and its subsequent breakdown. There is close agreement between neuropsychology, neuropathology, and imaging measures suggesting that the process of myelin breakdown begins in adulthood, accelerates as aging progresses, and underlies both age-related cognitive declines and the most powerful risk factor of dementia-causing disorders such as AD: age. This myelin-centered model together with the technology that makes it possible to measure the trajectory of myelin breakdown provide a framework for developing novel treatments, as well as assessing efficacy of currently available treatments, intended to slow or reverse the breakdown process in both clinically healthy as well as symptomatic populations. Such treatments can be expected to have a wide spectrum of efficacy and impact multiple human disease processes including potentially slowing brain aging and thus provide opportunities for primary prevention of age-related degenerative disorders such as AD. Show more

Keywords: myelin, oligodendrocyte, white matter, degeneration, dementia, development, aging, Alzheimer's disease, amyloid, beta, tau, MRI, relaxation rate, cholesterol, iron, metal, chelation, nicotine, MCI, AAMI, cognitive, memory, impairment, medications, treatment, brain, neurons

DOI: 10.3233/JAD-2004-6S604

Citation: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S53-S59, 2004

Authors: Lipton, Stuart A.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common form of dementia, as least in western countries. It has been estimated that the cost to society for caring for AD patients will consume the entire gross national product of the U.S.A. by the middle of this century if left unabated. Until recently, the only available drugs for this condition were cholinergic treatments, which symptomatically enhance cognitive state to some degree, but they were not neuroprotective. In fact, many potential neuroprotective drugs tested in clinical trials failed because they were poorly tolerated. However, after our discovery of its clinically-tolerated mechanism of action, one …neuroprotective drug, memantine, was recently approved by the European Union and the U.S. Food and Drug Administration (FDA) for the treatment of Alzheimer's disease. Recent phase 3 clinical trials have shown that memantine is effective in the treatment of moderate-to-severe Alzheimer's disease and possibly vascular dementia (multi-infarct dementia). Here we review the molecular mechanism of memantine's action and also the basis for the drug's use in these neurological diseases, which are mediated at least in part by excitotoxicity. Excitotoxicity is defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, leading to neuronal injury or death. Excitotoxic neuronal cell death is mediated in part by overactivation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, which results in excessive Ca2+ influx through the receptor's associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function. This means that potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many previous NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of neurodegenerative disorders. In contrast, studies in our laboratory have shown that the adamantane derivative, memantine, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an uncompetitive, low-affinity, open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Clinical use has corroborated the prediction that memantine is thus well tolerated. Besides Alzheimer's disease, memantine is currently in trials for additional neurological disorders, including other forms of dementia, depression, glaucoma, and severe neuropathic pain. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites in addition to its ion channel that potentially could also be used for safe but effective clinical intervention. Show more

DOI: 10.3233/JAD-2004-6S610

Citation: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S61-S74, 2004

Authors: Thatcher, Gregory R.J. | Bennett, Brian M. | Dringenberg, Hans. C. | Reynolds, James N.

Article Type: Research Article

Abstract: GT 1061 is a novel therapeutic agent that is in Phase 1 clinical studies for Alzheimer's disease. GT 1061 is one of a family of novel nitrates that have demonstrated neuroprotective properties and cognition- and memory-enhancing properties in animal models. The prototype of this family, GT 715, has been reported effectively to dissociate the neuromodulatory and the systemic hypotensive effects of nitrates, the latter seriously limiting the therapeutic use of classical nitrates. Further data on the novel nitrates, GT 715 and GT 061, are presented in (a) the malonate-lesion rat model of excitotoxic neurodegeneration, and (b) the reversal of a …scopolamine-induced cognition deficit in the Morris water task which tests spatial memory. These data exemplify and reinforce the combined neuroprotective and cognition enhancing properties observed in this family of NO mimetic therapeutic agents. NO mimetics, that mimic the biological activity of NO, will bypass cholinergic receptor activation and are anticipated to provide multiple pathways of treating and circumventing dementia. NO mimetic activation of soluble guanylyl cyclase and cGMP formation in the brain represents one element of an effective neuroprotective strategy. 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, providing a combined neuroprotective and cognition-enabling approach to anti-neurodegenerative therapy. Show more

Keywords: cognition, dementia, nitric oxide, cGMP, nitrate, Alzheimer's, neurodegeneration

DOI: 10.3233/JAD-2004-6S614

Citation: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S75-S84, 2004

Authors: Buccafusco, Jerry J. | Beach, J. Warren | Terry, Jr., Alvin V. | Doad, Gurbir S. | Sood, Ajay | Arias, Esperanza | Misawa, Hidemi | Masai, Manabu | Fujii, Takeshi | Kawashima, Koichiro

Article Type: Research Article

Abstract: The ability of choline to serve as a full, though low potency agonist for the α7 nicotinic receptor has provided the impetus to develop analogs that exhibit levels of potency and effectiveness suitable for use as therapeutic agents. Seven analogs of choline were synthesized based on previous work with the analog pyrrolidinecholine. The drugs were administered to differentiated PC-12 cells 24 hr prior to growth factor withdrawal which itself induced cytotoxicity in 30–40% of the cells. Three of 7 choline analogs exhibited potency and efficacy similar to that for nicotine as cytoprotective agents. Despite being tertiary amines, 4 of the …choline analogs were more potent than choline in inhibiting [3 H]choline uptake into cultured fibroblasts transfected with the high affinity, sodium-dependent choline transporter. One of the most effective analogs JAY 2-21-29 was shown to produce a potent (EC50 ∼ 30 nM) cytoprotective action that was blocked by pretreatment with the α7 nicotinic receptor selective antagonist methyllycaconitine, but not by theα2 subtype-preferring antagonist dihydro-β-erythroidin. These preliminary studies support the further neurochemical characterization of these compounds 1) as selectiveα7 nicotinic receptor agonists and, 2) based on their interaction with the choline transporter, as potential cholinergic false neurotransmitters as has been demonstrated for pyrrolidinecholine. Show more

Keywords: nicotinic receptor, choline analog, choline uptake, cytoprotection, PC-12 cells, structure-activity

DOI: 10.3233/JAD-2004-6S612

Citation: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S85-S92, 2004

Authors: Faden, Alan I. | Knoblach, Susan M. | Movsesyan, Vilen A. | Cernak, Ibolja

Article Type: Research Article

Abstract: The tripeptide thyrotropin-releasing hormone (TRH) and/or related analogues have shown neuroprotective activity across multiple animal trauma models as well as in a small clinical trial of spinal cord injury. The metabolic product of TRH (cyclo-his-pro) retains physiological activity. We have developed a number of novel cyclic dipeptides that are structurally similar to cyclo-his-pro, and have examined their neuroprotective activity across multiple in vitro models of neuronal injury and after traumatic brain injury (TBI) in rodents. Four such compounds were found to reduce cell death after trophic withdrawal or traumatic injury in primary neuronal cultures; two also protected against glutamate or …β-amyloid neurotoxicity. All compounds significantly improved motor and cognitive recovery after controlled cortical impact injury in mice, and markedly reduced lesion volumes as shown by high field magnetic resonance imaging. Further, compound 35b, which is being developed for clinical trials, also showed considerable neuroprotection after fluid percussion induced TBI in rats, and improved cognitive function after daily administration in chronically brain injured rats. At a mechanistic level, the drugs attenuate both apoptotic and necrotic cell death in primary neuronal cultures, markedly reduce intracellular calcium accumulation after injury, and limit changes in mitochondrial membrane potential and associated cytochrome c release. In addition, microarray studies show that 35b reduces transcriptional changes after injury for a number of genes (and proteins) that may be associated with secondary injury, including cell cycle genes, aquaporins and cathepsins. It also upregulates brain-derived neurotrophic factor (BDNF), heat shock proteins (HSP) and hypoxia inducible factor (HIF). Thus, these novel dipeptides have multipotential actions that make them candidates for the treatment of both acute and chronic neurodegeneration. Show more

DOI: 10.3233/JAD-2004-6S603

Citation: Journal of Alzheimer's Disease, vol. 6, no. s6, pp. S93-S97, 2004