Volume 5, Number 3, June 2003

Pages 171-177
Shawn G. Anthony, Hyman M. Schipper, Rosemarie Tavares, Virginia Hovenesian, Selina C. Cortez, Edward G. Stopa, Conrad E. Johanson
Stress Protein Expression in the Alzheimer-diseased Choroid Plexus
Abstract: Abnormal patterns of stress protein expression are found in the cerebral cortex and hippocampus of Alzheimer (AD) subjects. In this study, expression of various stress proteins in the Alzheimer-diseased choroid plexus (CP) was assessed immunohistochemically. We observed decreased HO-1 immunoreactivity in the AD CP, commensurate with our earlier report of suppressed HO-1 protein levels in AD cerebrospinal fluid (Schipper et al., Neurology 54:1297-1304, 2000). Heat shock proteins (HSPs) 60 and 90 were markedly up-regulated in the AD CP relative to controls. Induction of HSP60, a mitochondrial stress protein, is compatible with mitochondrial pathology recently documented in AD CP. Up-regulation of HSP90, a steroid receptor chaperone, in the AD CP may indicate abnormal hormone receptor expression in this secretory tissue. Glucose-regulated protein (GRP) 78 and 94 immunostaining was diminished in AD CP, implicating possible derangements in glucose or calcium homeostasis. Oxidative stress, per se, is probably not responsible for our observations because: i) there were no noticeable differences in the expression of HSP 70, ubiquitin, and alpha-B crystallin in the AD CP; and ii) augmentation, rather than the noted suppression, of HO-1 immunoreactivity would have been expected.

Pages 179-188
Anthony P. James, Sebely Pal, Hanni C. Gennat, Donna F. Vine, and John C.L. Mamo (Communicated by Ralph Martins)
The incorporation and metabolism of amyloid-ß into chylomicron-like lipid emulsions
Abstract: The aggregation and deposition of amyloid-ß (Aß) in the brain is thought to be an early event in the pathology of Alzheimer's disease (AD). Many studies have reported the association of Aß with lipoproteins from plasma suggesting an involvement of lipoprotein particles in Aß transport. Chylomicron-like lipid emulsions, resembling chylomicrons in composition, size and metabolism were prepared in the presence of [125I]Aß1-40. Aß was found to associate significantly with these lipid emulsions during their preparation. The chylomicron-like emulsions containing Aß were then injected into a lateral ear vein of conscious rabbits and blood sampled at regular intervals up to 30 mins. It was observed that there was no difference in the plasma clearance of [125I]Aß and that of the 3H-cholesteryl ester, a marker of the emulsion particles, demonstrating that Aß remains associated with these particles throughout both their lipolysis and tissue uptake. Our results show that Aß can be metabolised in association with triglyceride rich lipoproteins (TRLs). In addition we report the presence of specific markers of TRLs of hepatic and intestinal origin in human CSF thus suggesting a potential means of cerebral Aß delivery.

Pages 189-195
Michael E. Godfrey, Damian P. Wojcik, Cheryl A. Krone (Communicated by Ralph Martins)
Apolipoprotein E genotyping as a potential biomarker for mercury neurotoxicity
Abstract: Apolipoprotein-E (apo-E) genotyping has been investigated as an indicator of susceptibility to heavy metal (i.e., lead) neurotoxicity. Moreover, the apo-E epsilon (e)4 allele is a major risk factor for neurodegenerative conditions, including Alzheimer's disease (AD). A theoretical biochemical basis for this risk factor is discussed herein, supported by data from 400 patients with presumptive mercury-related neuro-psychiatric symptoms and in whom apo-E determinations were made. A statistically relevant shift toward the at-risk apo-E e4 groups was found in the patients (p<0.001). The patients possessed a mean of 13.7 dental amalgam fillings and 31.5 amalgam surfaces. This far exceeds the number capable of producing the maximum identified tolerable daily intake of mercury from amalgam. The clinical diagnosis and proof of chronic low-level mercury toxicity has been difficult due to the non-specific nature of the symptoms and signs. Dental amalgam is the greatest source of mercury in the general population and brain, blood and urine mercury levels increase correspondingly with the number of amalgams and amalgam surfaces in the mouth. Confirmation of an elevated body burden of mercury can be made by measuring urinary mercury, after provocation with 2,3,-dimercapto-propane sulfonate (DMPS) and this was measured in 150 patients. Apo-E genotyping warrants investigation as a clinically useful biomarker for those at increased risk of neuropathology, including AD, when subjected to long-term mercury exposures. Additionally, when clinical findings suggest adverse effects of chronic mercury exposure, a DMPS urine mercury challenge appears to be a simple, inexpensive procedure that provides objective confirmatory evidence. An opportunity could now exist for primary health practitioners to help identify those at greater risk and possibly forestall subsequent neurological deterioration.

Pages 197-208
J.A. Joseph, D.R. Fisher
Muscarinic receptor subtype determines vulnerability to amyloid ß toxicity in transfected COS-7 cells
Abstract: Research has suggested that there are age-related increases in neuronal sensitivity to insult from oxidative stress (OS) and that the CNS alterations seen in Alzheimer disease (AD) and vascular dementia (VaD) are superimposed upon declining nervous and vascular systems. Since muscarinic receptors (mAChR) may be important in regional sensitivity, regulation of micro- circulation, and in various aspects of both neuronal (APP processing) and vascular functioning, we postulated that the various mAChR subtypes may show differential sensitivity to OS. Indeed, recent findings indicated that M1, M2, or M4 AChR-transfected COS-7 cells showed greater OS sensitivity [as reflected in Ca2+ buffering (i.e., the ability to extrude or sequester Ca2+ following oxotremorine-induced depolarization)] than those transfected with M3 or M5 AChR when exposed to dopamine. Interestingly, the results from the present study indicate that similar findings were also observed when the cells were exposed to Aß 25-35 and Aß 1-40 showed similar effects on M1 and M3 AChR. No effects were seen with Aß 35-25 or Aß 40-1. Thus, cells transfected with M1, M2 or M4 AChR showed greater disruptions in calcium regulation (as assessed via fluorescent imaging analysis prior to and following 750 µM oxotremorine) than those transfected with M3 or M5 AChR. We also examined the effects of calcium channel antagonists (e.g., Nifedipine) or antioxidants (vitamin E) in protecting against the deleterious effects of Aß. Results are discussed in terms of differences in MAChR structure that could lead to selective Aß effects and the possible implications on memory and APP processing.

Pages 209-228
Guo-Jun Chen, Julia Xu, Stephanie A. Lahousse, Niki L. Caggiano, and Suzanne M. de la Monte
Transient hypoxia causes Alzheimer-type molecular and biochemical abnormalities in cortical neurons: potential strategies for neuroprotection
Abstract: Familial Alzheimer’s Disease (AD) has been linked to amyloid ß protein precursor (AßPP) and presenilin gene mutations. In sporadic AD, which accounts for the vast majority of cases, the pathogenesis of neurodegeneration is unknown; however, recent evidence suggests a role for oxidative stress. The present study demonstrates that transient hypoxic injury to cortical neurons causes several of the molecular and biochemical abnormalities that occur in AD including, mitochondrial dysfunction, impaired membrane integrity, increased levels of DNA damage, reactive oxygen species, phospho-tau, phospho-MAP-1B, and ubiquitin immunoreactivity, and AßPP cleavage with accumulation of amyloid-ß-immunoreactive products. These abnormalities were associated with activation of kinases that phosphorylate tau, including glycogen synthase kinase 3ß (GSK-3ß), mitogen-activated protein kinase (MAPK), and cyclin-dependent kinase 5 (Cdk-5). Further studies showed that significant neuro-protection with sparing of mitochondrial function and membrane integrity could be achieved by pre-treating the cortical neurons with N-acetyl cysteine, glutathione, or inhibitors of GSK-3ß, MAP kinase, or AßPP gamma-secretase. Therefore, in the absence of underlying gene mutations, oxidative stress can cause AD-type abnormalities, including aberrant post-translational processing of neuronal cytoskeletal proteins and AßPP. Our results also suggest that pre-treatment with agents that block specific components of the AD neurodegeneration cascade may provide neuroprotection against oxidative stress-induced impairments in membrane integrity, mitochondrial function, and viability.

Pages 229-239
Mark A. Lovell, Chengsong Xie, Shuling Xiong, William R. Markesbery
Protection against amyloid beta peptide and iron/hydrogen peroxide toxicity by alpha lipoic acid
Abstract: Current evidence supports the role of oxidative stress in the pathogenesis of neuron degeneration in Alzheimer’s disease (AD). alpha-Lipoic acid (LA), an essential cofactor in mitochondrial dehydrogenase reactions, functions as an antioxidant and reduces oxidative stress in aged animals. Here, we describe the effects of LA and its reduced form, dihydrolipoic acid (DHLA), in neuron cultures treated with amyloid ß-peptide (Aß 25-35) and iron/hydrogen peroxide (Fe/H2O2). Pretreatment of dissociated primary hippocampal cultures with LA significantly protected against Aß and Fe/H2O2 toxicity. In contrast, concomitant treatment of cultures with LA and Fe/H2O2 significantly potentiated the toxicity. Decreased cell survival in cultures treated concomitantly with LA and Fe/H2O2 correlated with increased free radical production measured by dichlorofluorescein fluorescence. Treatment of cortical neurons with DHLA significantly protected glucose-transport against Fe/H2O2 or Aß-mediated decreases although treatment with LA did not provide protection. These data suggest that DHLA, the reduced form of LA, significantly protects against both Aß and Fe/H2O2 mediated toxicity. The data also suggest that concomitant exposure to LA and Fe/H2O2 significantly potentiates the oxidative stress. Overall, these data suggest that the oxidation state of LA is critical to its function and that in the absence of studies of LA/DHLA equilibria in human brain the use of LA as an antioxidant in disorders where there is increased Fe such as AD is of questionable efficacy.

Pages 241-245
Qunxing Ding, Jeffrey N. Keller
Does proteasome inhibition play a role in mediating neuropathology and neuron death in Alzheimer’s disease?
Abstract: An increasing number of studies have demonstrated evidence that inhibition of proteasome activity may play a causal role in mediating the neuropathology and neuron death observed in Alzheimer’s disease (AD). These reports have clearly demonstrated that proteasome inhibition occurs in the AD brain, with numerous in vitro and in vivo studies elucidating the ability of proteasome inhibitors to induce AD-like neuropathology and even neuron death. In spite of these clear and significant findings, several important questions regarding the role of proteasome inhibition in AD remain unanswered. We propose that chronic low-level proteasome inhibition, but not severe and acutely toxic levels of proteasome inhibition, likely plays a role in mediating specific aspects of AD neuropathology. Experimental evidence supporting this hypothesis, as well as the scientific implications of this hypothesis are discussed.

Pages 247-250
Kurt A. Jellinger
Letter to the Editor: Is Alzheimer’s disease a vascular disorder?

Pages 251-262
Transcript of Live Discussion held at the Alzheimer Research Forum
The Cell Cycle in Alzheimer's Disease: Let's Unite Around Division!

Pages 263-264
Book Review: Losing My Mind: An Intimate Look at Life with Alzheimer’s by Thomas DeBaggio. The Free Press/Simon & Schuster (New York), 2002, 207pp. Reviewed by Carlos Garcia.

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