Volume 30, Number 1, May 2012

Pages 1-16
Review
Hailin Zheng, Tamar Amit, Orit Bar-Am, Mati Fridkin, Moussa B.H. Youdim, Silvia A Mandel
From Anti-Parkinson’s Drug Rasagiline to Novel Multitarget Iron Chelators with Acetylcholinesterase and Monoamine Oxidase Inhibitory and Neuroprotective Properties for Alzheimer's Disease
Abstract: Alzheimer’s disease (AD) is a multifactorial syndrome involving a complex array of different, while related, factors in its progression. Accordingly, novel approaches that can simultaneously modulate several disease-related targets hold great promise for the effective treatment of AD. This review describes the development of novel hybrid molecules with multimodal activity, including: i) M30, the brain permeable selective monoamine oxidase (MAO)-A and -B inhibitor with chelating and neuroprotective activity; ii) HLA20, a brain permeable metal chelator with neuroprotective activity; iii) HLA20A, an acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity; iv) M30D, an AChE and MAO-A and -B inhibitor with site-activated chelating and neuroprotective activity; and v) analogs of the neuroprotective aminoacid peptide, NAPVSIPQ. HLA20A and M30D act as pro-chelators and can be activated to liberate their respective active chelators HLA20 and M30 through pseudo inhibition of AChE. We first discuss the knowledge and structure-based strategy for the rational design of these novel compounds. Then, we review our recent studies on these drug candidates, regarding their wide range in vitro and in vivo activities, with emphasis on antioxidant-chelating potency and AchE and MAO-A and -B inhibitory activity, as well as neuroprotective/neurorescue effects. Finally, we discuss the diverse molecular mechanisms of action of these compounds with relevance to AD, including modulation of amyloid-β and amyloid-β protein precursor expression/processing; induction of cell cycle arrest; inhibition of neuronal death markers; and upregulation of neurotrophic factors, as well as activation of protein kinase signaling pathways.

Pages 17-26
Review
Jean-Marie Serot, Jadwiga Zmudka, Pierre Jouanny
A Possible Role for CSF Turnover and Choroid Plexus in the Pathogenesis of Late Onset Alzheimer’s Disease
Abstract: According to the amyloid theory, the appearance of amyloid-β (Aβ) deposits represents a pivotal event in late onset Alzheimer’s disease (LOAD). Physiologically, Aβ42 monomers are cleaned by capillary resorption, enzymatic catabolism, and cerebrospinal fluid (CSF) transport. Factors that promote the oligomerization of Aβ42 must be specified. In vitro, these monomers spontaneously form neurotoxic oligomers whose rate increases with time suggesting that the stasis of CSF favors the oligomerization. In animals, experimental hydrocephalus generates CSF stasis followed by the appearance of amyloid deposits. In normal pressure hydrocephalus, amyloid deposits are common, especially in elderly patients, and the turnover decline has the same order of magnitude as in AD. In this disease, the effects of CSF stasis are potentiated by the decline in the ability of CSF to inhibit the formation of oligomers. CSF originates from choroid plexus (CP). In LOAD, the functions of secretion, synthesis, and transport of CP are impaired and this is related to morphological modifications. These impairments favor the decrease of CSF turnover, the diminished levels of transthyretin, a sequestering protein synthesized by CP, and the oligomerization of Aβ42. They are potentiated by a reduced enzymatic catabolism and a decreased capillary reabsorption of Aβ42, both alterations being related to age.

Pages 27-33
Hypothesis
Thomas B. Shea, Eugene Rogers, Ruth Remington
Nutrition and Dementia: Are We Asking the Right Questions?
Abstract: Alzheimer’s disease (AD) has no cure or nullifying pharmacological interventions. Nutritional supplementation represents a systemic approach that in some studies has provided benefit and has augmented pharmacological approaches. However, additional studies report no benefit of supplementation. We review herein how studies of nutrition on dementia, including those combining nutrition and dementia, are inherently compromised. We also review studies with mice, which demonstrate that nutritional supplementation can alleviate multiple genetic risk factors for AD. An individual diagnosed with AD has by definition undergone considerable cognitive decline; anticipating restoration/maintenance of cognitive performance following nutritional supplementation alone may be misdirected. Nutrition declines in aging, and even more so in AD. While optimization of nutrition should ideally be initiated well before any cognitive decline, we present evidence that the systemic benefit alone of nutritional supplementation at the very minimum warrants initiation along with pharmacological intervention.

Pages 35-39
Short Communication
Laura J. Sharpe*, Jenny Wong*, Brett Garner, Glenda M. Halliday, Andrew J. Brown *These authors contributed equally to this work.
Is Seladin-1 Really a Selective Alzheimer’s Disease Indicator?
Abstract: Selective Alzheimer’s Disease Indicator-1 (Seladin-1) was originally identified by its down-regulation in the brains of Alzheimer’s disease (AD) patients. Here, we re-examine existing data and present new gene expression data that refutes its role as a selective AD indicator. Furthermore, we caution against the use of the name “Seladin-1” and instead recommend adoption of the approved nomenclature, 3β-hydroxysterol Δ24-reductase (or DHCR24), which describes its catalytic function in cholesterol synthesis. Further work is required to determine what link, if any, exists between DHCR24 and AD.

Pages 41-51
Silvia Alasia, Patrizia Aimar, Adalberto Merighi, Laura Lossi
Context-Dependent Toxicity of Amyloid-β Peptides on Mouse Cerebellar Cells
Abstract: Alzheimer’s disease (AD) is the major cause of dementia in old people. AD pathology is characterized by amyloid-β (Aβ) deposits in several regions of the brain, and links have been hypothesized between Aβ toxicity and apoptosis. Cerebellar granule cells (CGCs) have been widely used as in vitro tools for molecular studies correlating apoptosis with AD, although the cerebellum is a relatively spared area of the brain in vivo. We have used mixed neuronal-glial cerebellar cultures (NGCCs) and organotypic cerebellar cultures (OCCs) obtained from postnatal mice to assess the toxic effect of the Aβ oligomer 1-40 (Aβ1-40) after propidium iodide uptake in vitro. Our results demonstrate that NGCCs, which are primarily composed of CGCs, are resistant to Aβ1-40 challenge (5-10 µM) when cultured in physiological (5 mM) extracellular KCl ([K+]e) concentrations, i.e., in a condition in which CGCs undergo full maturation. Conversely, when 10 µM Aβ1-40 is given to NGCCs cultured in elevated (25 mM) [K+]e (and thus maintained in an immature state), there is a statistically significant increase in cell death. Cell death is by apoptosis, as demonstrated by ultrastructural examination. OCCs are resistant to Aβ challenge in any of the conditions tested (variation of [K+]e, presence or absence of serum, or addition of the neprilysin blocker phosphoramidon). Altogether these observations lead us to conclude that cerebellar cells in an organotypic context may be less susceptible to damage by Aβ, raising the question whether isolated CGCs are a reliable assay in drug discovery studies of AD.

Pages 53-61
Timothy M. Hughes, Lewis H. Kuller, Oscar L. Lopez, James T. Becker, Rhobert W. Evans, Kim Sutton-Tyrrell, Caterina Rosano (Handling Associate Editor: Cecília M. P. Rodrigues)
Markers of Cholesterol Metabolism in the Brain Show Stronger Associations with Cerebrovascular Disease than Alzheimer’s Disease
Abstract: Cholesterol metabolism is believed to play a role in the development of Alzheimer’s disease (AD). Oxysterol metabolites of cholesterol, 24S-hydroxycholesterol (24-OHC, a brain-derived oxysterol) and 27-hydroxycholesterol (27-OHC, a peripherally derived oxysterol) cross the blood brain barrier and have been associated with AD. We investigated whether oxysterols were associated with markers of cerebrovascular disease prior to the onset of cognitive impairment. Oxysterols were quantified in 105 participants (average age: 80±4 years) from the Pittsburgh Cardiovascular Health Study Cognition Study who remained cognitively normal at blood draw in 2002, had MRI in 1992 and 1998, and annual cognitive assessment for incident AD and mild cognitive impairment made by consensus conference between 1998 and 2010. Higher plasma levels of 24-OHC were associated with age, gender, the presence of high grade white matter hyperintensities, and brain infarcts on prior MRI. Participants with higher plasma 24-OHC and a greater ratio of 24-OHC/27-OHC were also more likely to develop incident cognitive impairment over 8 years of follow-up. Higher levels of 24-OHC suggest increased cholesterol metabolism occurring in the brains of participants with cerebrovascular disease prior to the onset of cognitive impairment. Measurement of oxysterols may provide information about cholesterol metabolism and brain disease over the cognitive impairment process.

Supplementary Data for Hughes et al. article (PDF)

Pages 63-73
Janelle N. Fawver*, Hayley E. Schall*, Rachel D. Petrofes-Chapa, Xiongwei Zhu, Ian V.J. Murray (Handling Associate Editor: Debomoy Lahiri) *These authors contributed equally to the manuscript.
Amyloid-β Metabolite Sensing: Biochemical Linking of Glycation Modification and Misfolding
Abstract: Glycation is the reaction of a reducing sugar with proteins and lipids, resulting in myriads of glycation products, protein modifications, cross-linking, and oxidative stress. Glycation reactions are also elevated during metabolic dysfunction such as in Alzheimer’s disease (AD) and Down’s syndrome. These reactions increase the misfolding of the proteins such as tau and amyloid-β (Aβ), and colocalize with amyloid plaques in AD. Thus, glycation links metabolic dysfunction and AD and may have a causal role in AD. We have characterized the reaction of Aβ with reactive metabolites that are elevated during metabolic dysfunction. One metabolite, glyceraldehyde-3-phosphate, is a normal product of glycolysis, while the others are associated with pathology. Our novel data demonstrates that lipid oxidation products malondialdehyde, hydroxynonenal, and glycation metabolites (methylglyoxal, glyceraldehyde, and glyceraldehyde-3-phosphate) modify Aβ42 and increase misfolding. Using mass spectrometry, modifications primarily occurred at the amino terminus. However, the metabolite methylglyoxal modified Arg5 in the Aβ sequence. 4-Hydroxy-2-nonenal modifications were similar to our previous publication. To place such modifications into an in vivo context, we stained AD brain tissue for endproducts of glycation, or advanced glycation endproducts (AGE). Similar to previous findings, AGE colocalized with amyloid plaques. In summary, we demonstrate the glycation of Aβ and plaques by metabolic compounds. Thus, glycation potentially links metabolic dysfunction and Aβ misfolding in AD, and may contribute to the AD pathogenesis. This association can further be expanded to raise the tantalizing concept that such Aβ modification and misfolding can function as a sensor of metabolic dysfunction.

Pages 75-82
Mirjam I. Geerlings, Adam M. Brickman, Nicole Schupf, Dev P. Devanand, José A. Luchsinger, Richard Mayeux, Scott A. Small
Depressive Symptoms, Antidepressant Use, and Brain Volumes on MRI in a Population-Based Cohort of Old Persons without Dementia
Abstract: We examined whether late-life depression, including depressive symptoms and antidepressant use, was associated with smaller total brain volume, smaller hippocampal volume, and larger white matter hyperintensity (WMH) volume in a large community-based cohort of old persons without dementia. Within the Washington/Hamilton Height-Inwood Columbia Aging Project (WHICAP), a community-based cohort study in northern Manhattan, 630 persons without dementia (mean age 80 years, SD=5) had volumetric measures of the total brain, hippocampus, and WMH at 1.5Tesla MRI and data on current depression, defined as a score of 4 or higher on the 10-item Center for Epidemiologic Studies-Depression (CES-D) scale, or use of antidepressants. Multiple linear regression analyses adjusted for age, gender, ethnicity, education, cardiovascular disease history, and MRI parameters showed that subjects with current depression had smaller relative total brain volume (B=-0.86%; 95%CI -1.68 to -0.05%; p<0.05), smaller relative hippocampal volume (B=-0.07 ml; 95%CI -0.14 to 0.00 ml; p=0.05), and larger relative WMH volume (natural logtransformed B=0.19 ml; 95%CI 0.02 to 0.35 ml; p<0.05). When examined separately, antidepressant use was significantly associated with smaller total brain, smaller hippocampal, and larger WMH volume, while high CES-D scores were not significantly associated with any of the brain measures, although the direction of association was similar as for antidepressant use. With the caveat that analyses were cross-sectional and we had no formal diagnosis of depression, our findings suggest that in this community-based sample of old persons without dementia, late-life depression is associated with more brain atrophy and more white matter lesions, which was mainly driven by antidepressant use.

Pages 83-90
Ricardo Taipa, Assunção Tuna, Joana Damásio, Pedro S. Pinto, Sara Cavaco, Sonia Pereira, Gabriel Milterberger-Miltenyi, Daniela Galimberti, Manuel Melo Pires (Handling Associate Editor: Beatrice Arosio)
Clinical, Neuropathological, and Genetic Characteristics of the Novel IVS9+1delG GRN Mutation in a Patient with Frontotemporal Dementia
Abstract: Frontotemporal lobar degeneration (FTLD) refers to a clinically, pathologically, and genetically heterogeneous group of dementias that arises from the degeneration of the frontal and temporal lobes. Mutations in the progranulin gene (GRN) are a major cause of FTLD with TDP-43 inclusions. Herein, we describe the clinical, neuropathological, and genetic findings in a case of autosomal dominant behavioral variant of frontotemporal dementia (bvFTD) with asymmetrical parkinsonism and prominent visuospatial deficits that carries a novel GRN mutation. This case highlights important clinical characteristics that seem to be common in FTLD GRN-associated patients, such as asymmetrical parkinsonism and parietal symptoms, and that are correlated to the pathological involvement of striatum (rather than substantia nigra in our case) and parietal lobe. We also emphasize that plasma progranulin level can be useful to infer about the pathogenicity of new GRN mutations.

Pages 91-100
Abderazzak Mouiha, Simon Duchesne, and the Alzheimer’s Disease Neuroimaging Initiative
Toward a Dynamic Biomarker Model in Alzheimer’s Disease
Abstract: Biomarkers, both biological and imaging, are indicators of specific changes that characterize Alzheimer’s disease (AD) progression in vivo. Knowing the precise relationship between biomarkers and disease severity would allow for accurate disease staging and possible forecasting of decline. Jack et al. suggested as an initial hypothesis that this relationship be sigmoidal; the objective of this article is to determine, using large-scale population data from ADNI, the precise shape of this association. We considered six different models (linear; quadratic; robust quadratic; local quadratic regression; penalized B-spline; and sigmoid) and used the Akaike Information Criterion to gauge how well these models compare in conforming to the data. We included 576 subjects (229 controls, 193 AD, and 154 mild cognitive impairment subjects who converted to AD) from the ADNI study, for whom baseline data on cerebrospinal fluid amyloid-β (Aβ)42, phosphorylated tau (p-tau), and total-tau (t-tau), hippocampal volumes, and FDG-PET were available. Analysis of this cross-sectional dataset showed that a local quadratic regression model was 42% more likely than a sigmoid to be the best model for Aβ42. This ratio augments to 22% and 73% for Penalized B-Spline in the case of p-tau and t-tau, respectively; to 3500% for the linear model for FDG-PET; and to 6700% for the Penalized B-Spline for hippocampal volumes. Preliminary, cross-sectional evidence therefore indicates that the shape of the association with disease severity is non-linear and differs between biomarkers.

Supplementary Data for Mouiha and Duchesne article (PDF)

Pages 101-108
Lieke L. Smits, Yolande A.L. Pijnenburg, Esther L.G.E. Koedam, Annelies E. van der Vlies, Ilona E.W. Reuling, Teddy Koene, Charlotte E. Teunissen, Philip Scheltens, Wiesje M. van der Flier
Early Onset Alzheimer’s Disease is Associated with a Distinct Neuropsychological Profile
Abstract: Alzheimer’s disease (AD) in younger patients is associated with a higher prevalence of atypical symptoms. We examined neuropsychological performance according to age-at-onset. We assessed cognition in 172 patients with AD (81 early and 91 late onset) in five cognitive domains (memory, language, visuo-spatial functioning, executive functioning, attention). Dementia severity was assessed using the Mini-Mental Status Examination (MMSE) and global cognitive decline using Cambridge Cognitive Examination (CAMCOG). Analyses of variance were performed with age-at-onset as between-subjects factor, and gender and education as covariates. Analysis was repeated after stratification for dementia severity (based on median MMSE). In early onset AD, age (mean±SD) was 60±4 years; 44 (54%) were female. In late onset AD, age was 72±5 years; 47 (52%) were female. Dementia severity and global cognitive decline did not differ between groups (early onset: MMSE: 20±5, CAMCOG: 69±15, late onset: MMSE: 21±5, CAMCOG: 70±15; p>0.05). Early onset patients performed worse than late onset patients on visuo-spatial functioning (p<0.01), executive functioning (p<0.001), and attention (p<0.01). Late onset patients performed worse on memory, although not significantly (p=0.11). Stratification for dementia severity showed that in mildly demented early onset patients, memory function was remarkably preserved compared to late onset patients (p<0.01). In moderate AD, differences in memory function disappeared, but early onset patients performed worse on visuo-spatial functioning (p<0.01), executive functioning (p<0.001), and attention (p<0.01) than late onset patients. Adjustment for APOE left results unchanged. In conclusion, early onset AD presents with a different cognitive profile and the disease course seems different. Relative sparing of memory function in early stages stresses the need to adequately test other cognitive domains.

Pages 109-120
Montserrat Alegret, Gemma Cuberas-Borrós, Georgina Vinyes-Junqué, Ana Espinosa, Sergi Valero, Isabel Hernández, Isabel Roca, Agustín Ruíz, Maitée Rosende-Roca, Ana Mauleón, James T. Becker, Joan Castell-Conesa, Lluís Tárraga, Mercè Boada
A Two-Year Follow-Up of Cognitive Deficits and Brain Perfusion in Mild Cognitive Impairment and Mild Alzheimer’s Disease
Abstract: The 15-Objects Test (15-OT) provides useful gradation of visuoperceptual impairment from normal aging through Alzheimer’s disease (AD) and correlates with temporo-parietal perfusion. The objectives of this study were to analyze progression of 15-OT performance in mild cognitive impairment (MCI) and AD, and its correlates with cognition and single photon emission computerized tomography (SPECT), as well as to examine neuropsychological and SPECT differences between the MCI patients who developed AD and those who did not. From the initial 126 participants (42/group), 38 AD, 39 MCI, and 38 elderly controls (EC) were reassessed (SPECT: 35 AD, 33 MCI, 35 EC) after two years. The progression of cognitive and SPECT scores during this period was compared between groups, and baseline data between converters and non-converters. The 15-OT was the only measure of progression that differed between the three groups; worsening scores on 15-OT were associated with worsening in verbal and visual retention, and decreased perfusion on left postsubicular area. In the MCI patients, cerebral perfusion fell over the two years in medial-posterior cingulate and fronto-temporo-parietal regions; AD showed extensive changes involving almost all cerebral regions. No SPECT changes were detected in controls. At baseline, the MCI patients who developed AD differed from non-converters in verbal recognition memory, but not in SPECT perfusion. In conclusion, SPECT and 15-OT appear to provide a potential measure to differentiate between normal aging, MCI, and AD. Worsening on 15-OT was related to decreased perfusion in postsubicular area; but further longitudinal studies are needed to determine the contribution of 15-OT as a predictor of AD from MCI.

Supplementary Data for Alegret et al. article (PDF)

Pages 121-129
Eva Mª Arroyo-Anlló, Pierre Ingrand, Roger Gil
Improvement of Semantic Categorization through Procedural Learning in Alzheimer's Disease
Abstract: This paper studies the procedural learning of semantic categorization in 20 patients with mild Alzheimer’s disease (AD). We investigated if the AD group was able to develop semantic skill using a cognitive procedural task, developed in our laboratory, by applying a manual and serial reaction time paradigm to semantic categorization. The AD group had markedly lower scores than the normal group on semantic categorization and had longer reaction times than the control subjects. Nevertheless, we observed an improvement of semantic categorization reaction times over time with practice, even with new verbal material to categorize, in both the AD and control groups. These results support the notion that AD patients are able to acquire semantic skill without awareness simply by repeated exposure, although their semantic accuracy will not reach normal levels.

Pages 131-143
Simone Verheij*, Danya Muilwijk*, Johan J.M. Pel, Tischa J.M. van der Cammen, Francesco U.S. Mattace-Raso, Johannes van der Steen *These authors contributed equally to this study.
Visuomotor Impairment in Early-Stage Alzheimer’s Disease: Changes in Relative Timing of Eye and Hand Movements
Abstract: Although memory complaints are one of the first clinical symptoms in patients with Alzheimer’s disease (AD), damage to the parietal lobe, a key structure in the visuomotor coordination network, was recently identified in early-stage AD. The aim of this study was to quantify visuomotor coordination in patients with probable AD and to compare their visuomotor performance with controls using five eye-hand coordination tasks of variable complexity.Eye and hand movements were measured in 16 AD patients and 18 controls. The measurement setup consisted of a touch screen, an eye-tracking device, and a motion capturing system. We investigated eye-hand coordination by quantifying absolute and relative latencies of eye and hand movements and by analyzing eye and hand kinematics. We found that AD patients need significantly more time to initiate and execute goal-directed hand movements. AD patients are also unable to suppress reflexive eye and, to a lesser extent, hand movements. Furthermore, AD patients use a stepwise approach of eye and hand movements to touch a sequence of stimuli, whereas controls more often show an anticipatory approach. The impairments in reflex suppression of eye and hand movements, and changes in relative timing of eye-hand coordination, in AD patients support the notion that cortical networks involving the posterior parietal cortex are affected at an early disease-stage. It also suggests that the problems of AD patients to perform daily activities that require eye-hand coordination are not only caused by cognitive decline, but also by degeneration of neural networks involved in visuomotor coordination.

Supplementary Data for Verheij et al. article (PDF)

Pages 145-153
Brice Flammang, Raphaëlle Pardossi-Piquard, Jean Sevalle, Delphine Debayle, Anne-Sophie Dabert-Gay, Aurélie Thévenet, Inger Lauritzen, Frédéric Checler (Handling Associate Editor: Othman Ghribi)
Evidence that the Amyloid-β Protein Precursor Intracellular Domain, AICD, Derives From β-Secretase-Generated C-Terminal Fragment
Abstract: One of the major pathological hallmarks of brains affected with Alzheimer’s disease (AD) is the senile plaque, an extracellular deposit mainly composed of a set of highly insoluble peptides of various lengths (39-43 amino acids) referred to as amyloid-β (Aβ) peptides. Aβ peptides are derived from combined proteolytic cleavages undergone on the amyloid-β protein precursor (AβPP) by a set of enzymes called secretases. Several lines of anatomical and biological evidence suggest that Aβ peptides would not account for all pathological stigmata and molecular dysfunctions taking place in AD. In amyloidogenic and non-amyloidogenic pathways, AβPP first undergoes β- or α-secretases-mediated cleavages yielding C99 and C83, respectively. These two membrane-embedded C-terminal fragments are both potential targets of subsequent γ-secretase-mediated proteolysis. The latter cleavage not only generates either p3 or Aβ peptides but similarly gives rise to an AβPP IntraCellular Domain (AICD fragment) that could modulate the transcription of several genes linked to AD pathology. It is therefore striking that AICD theoretically derives from both amyloidogenic and non-amyloidogenic AβPP processing pathways. Here we show that AICD predominantly derives from C99 by means of recombinant substrates and transiently transfected cells expressing C99. Our data suggest a preferred pathogenic pathway for AICD production and suggests that this fragment, in addition to C99 and Aβ peptides, could contribute to AD pathology.

Pages 155-166
Tuan Minh Do, Marie-Sophie Noel-Hudson, Sandy Ribes, Capucine Besengez, Maria Smirnova, Salvatore Cisternino, Marion Buyse, Frédéric Calon, Giovanna Chimini, Hélène Chacun, Jean-Michel Scherrmann, Robert Farinotti, Fanchon Bourasset (Handling Associate Editor: Othman Ghribi)
ABCG2 and ABCG4-Mediated Efflux of Amyloid-β Peptide 1-40 at the Mouse Blood-Brain Barrier
Abstract: The accumulation of amyloid-β peptide (Aβ) in the brain is a critical hallmark of Alzheimer’s disease. This high cerebral Aβ concentration may be partly caused by impaired clearance of Aβ across the blood-brain barrier (BBB). The low-density lipoprotein receptor-related protein-1 (LRP-1) and the ATP-binding cassette (ABC) protein ABCB1 (P-glycoprotein) are involved in the efflux of Aβ across the BBB. We hypothesized that other ABC proteins, such as members of the G subfamily, are also involved in the BBB clearance of Aβ. We therefore investigated the roles of ABCG2 (BCRP) and ABCG4 in the efflux of [3H]Aβ1-40 from HEK293 cells stably transfected with human ABCG2 or mouse abcg4. Weshowed that ABCG2 and Abcg4 mediate the cellular efflux of [3H]Aβ1-40. In addition, probucol fully inhibited the efflux of [3H]Aβ1-40 from HEK293-abcg4 cells. Using the in situ brain perfusion technique, we showed that GF120918 (dual inhibitor of Abcb1 and Abcg2) strongly enhanced the uptake (Clup, µl/g/s) of [3H]Aβ1-40 by the brains of Abcb1-deficient mice, but not by the brains of Abcb1/Abcg2-deficient mice, suggesting that Abcg2 is involved in the transport of Aβ at the mouse BBB. Perfusing the brains of Abcb1/Abcg2- and Abca1-deficient mice with [3H]Aβ1-40 plus probucol significantly increased the Clup of Aβ. This suggests that a probucol-sensitive transporter that is different from Abca1, Abcb1, and Abcg2 is involved in the brain efflux of Aβ. We suggest that this probucol-sensitive transporter is Abcg4. We conclude that Abcg4 acts in concert with Abcg2 to efflux Aβ from the brain across the BBB.

Pages 167-182
Jaya R.P. Prasanthi, Matthew Schrag, Bhanu Dasari, Gurdeep Marwarha, Wolff M. Kirsch, Othman Ghribi (Handling Associate Editor: Ashley Bush)
Deferiprone Reduces Amyloid-β and Tau Phosphorylation Levels but not Reactive Oxygen Species Generation in Hippocampus of Rabbits Fed a Cholesterol-Enriched Diet
Abstract: Accumulation of amyloid-β (Aβ) peptide and the hyperphosphorylation of tau protein are major hallmarks of Alzheimer’s disease (AD). The causes of AD are not well known but a number of environmental and dietary factors are suggested to increase the risk of developing AD. Additionally, altered metabolism of iron may have a role in the pathogenesis of AD. We have previously demonstrated that cholesterol-enriched diet causes AD-like pathology with iron deposition in rabbit brain. However, the extent to which chelation of iron protects against this pathology has not been determined. In this study, we administered the iron chelator deferiprone in drinking water to rabbits fed with a 2% cholesterol diet for 12 weeks. We found that deferiprone (both at 10 and 50 mg/kg/day) significantly decreased levels of Aβ40 and Aβ42 as well as BACE1, the enzyme that initiates cleavage of amyloid-β protein precursor to yield Aβ. Deferiprone also reduced the cholesterol diet-induced increase in phosphorylation of tau but failed to reduce reactive oxygen species generation. While deferiprone treatment was not associated with any change in brain iron levels, it was associated with a significant reduction in plasma iron and cholesterol levels. These results demonstrate that deferiprone confers important protection against hypercholesterolemia-induced AD pathology but the mechanism(s) may involve reduction in plasma iron and cholesterol levels rather than chelation of brain iron. We propose that adding an antioxidant therapy to deferiprone may be necessary to fully protect against cholesterol-enriched diet-induced AD-like pathology.

Pages 183-208
Aaron Clausen*, Xiaobo Xu*, Xiaoning Bi, Michel Baudry (Handling Associate Editor: D. Allan Butterfield) *These authors contributed equally to this work.
Effects of the Superoxide Dismutase/Catalase Mimetic EUK-207 in a Mouse Model of Alzheimer’s Disease: Protection Against and Interruption of Progression of Amyloid and Tau Pathology and Cognitive Decline
Abstract: Alzheimer’s disease (AD) is characterized by progressive cognitive deficits, accumulation of amyloid-β (Aβ) and intracellular neurofibrillary tangles, and neuronal death. Additionally, mitochondrial dysfunction and free radical damage are hallmarks of AD brain. Here we set out to define the role of oxidative stress in AD pathogenesis and progression by chronically treating 3xTg-AD mice with the superoxide dismutase (SOD)/catalase mimetic, EUK-207. Treatment started at 4 months before onset of pathology and cognitive deficits, and continued until 9 months, when the AD phenotype was established. Cognitive performance was assessed using fear conditioning, and brain oxidative stress, Aβ, and tau pathology were analyzed. At 9 months, 3xTg-AD mice exhibited a decline in performance in both contextual and cued fear conditioning, as compared to wild-type mice. EUK-207-treated 3xTg-AD mice did not display any deficit in fear conditioning and exhibited reduced Aβ, tau, and phosphorylated tau accumulation in amygdala and hippocampus, as well as brain levels of Aβ42, oxidized nucleic acids, and lipid peroxidation. The effects of a 3-month treatment after pathology onset at 9 months on cognitive performance, brain oxidative stress, Aβ, and tau pathology were also evaluated. EUK-207-treated 3xTg-AD mice did not display any deficit in fear conditioning and were protected against increases in brain levels of oxidized nucleic acids and lipid peroxidation; they also had reduced Aβ, tau, and hyperphosphorylated tau accumulation in amygdala and hippocampus. Our results confirm a critical role for oxidative stress in AD pathogenesis and progression and suggest the potential usefulness of EUK-207 in AD treatment.

Supplementary Data for Clausen et al. article (PDF)

Pages 209-219
Loren Mowszowski, Daniel F. Hermens, Keri Diamond, Louisa Norrie, Ian B. Hickie, Simon J.G. Lewis, Sharon L. Naismith (Handling Associate Editor: Michael Hornberger)
Reduced Mismatch Negativity in Mild Cognitive Impairment: Associations with Neuropsychological Performance
Abstract: Mild cognitive impairment (MCI) refers to a transitory state between healthy aging and dementia. Biomarkers are needed to facilitate early identification of MCI and predict progression to dementia. One potential neurophysiological biomarker, mismatch negativity (MMN), is an event-related potential reflecting fundamental, pre-attentive cognitive processes. MMN is reduced in normal aging and dementia and in neuropsychiatric samples and is associated with verbal memory deficits and poor executive functioning. This study aimed to investigate auditory MMN and its relationship to neuropsychological performance in MCI. Twenty-eight MCI participants and fourteen controls, aged ≥50 years, underwent neurophysiological and neuropsychological assessment, and completed questionnaires pertaining to disability. Relative to controls, the MCI group demonstrated reduced temporal MMN amplitude (p < 0.01). Reduced right temporal MMN was significantly associated with poorer verbal learning (r = 0.496; p < 0.01) and reduced left temporal MMN was significantly associated with increased self-reported disability (r = -0.419; p < 0.05). These results indicate that patients with MCI exhibit altered pre-attentive information processing, which in turn is associated with memory and psychosocial deficits. These findings overall suggest that MMN may be a viable neurophysiological biomarker of underlying disease in this ‘at risk’ group.

Page 221
Book Review: Memory Loss: A Practical Guide for Clinicians by Andrew E. Budson and Paul R. Solomon, Saunders, 2011, 320 pp. Reviewed by Peter Whitehouse.

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