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