Volume 15, Number 1, September 2008

Pages 1-10
Valeria Drago, Paul S. Foster, Raffaele Ferri, Debora Arico, Bartolo Lanuzza and Kenneth M. Heilman
Distractibility and Alzheimer Disease: The “Neglected” Phenomenon
Abstract: Patients with Alzheimer’s disease (AD) might have bilateral attentional disorders, such as a reduced spatial attentional window, due to pathological changes in regions important for mediating spatial attention. AD patients may also be highly distractible with the presentation of unilateral novel stimuli or be impaired at disengaging and reallocating their attention with imperative stimuli. This study sought to test these hypotheses by asking AD patients and normal control subjects to bisect 72 horizontal lines of 3 different lengths in three conditions: no lateral stimuli, novel right or left lateral stimuli (‘bottom-up’), and imperative left or right lateral stimuli (‘top-down’). Regarding the bottom-up condition, no group differences emerged, but the AD patients had a greater rightward bias with short lines and a leftward bias with long lines, independent of distracting stimuli. In the top-down condition, when the patients with AD, versus controls, were presented with imperative stimuli on their left side, they demonstrated a greater attentional bias than when presented with right-sided stimuli. Thus AD patients have a reduced spatial attentional window and while they are not highly distracted by novel stimuli, after allocating their attention to left sided stimuli, they have a reduced capacity to spatially re-allocate their attention.

Pages 11-28
Laura Mandolesi, Paola De Bartolo, Francesca Foti, Francesca Gelfo, Francesca Federico, Maria Giuseppa Leggio, Laura Petrosini (Communicated by Sigfrido Scarpa)
Environmental enrichment provides a cognitive reserve to be spent in the case of brain lesion
Abstract: To experimentally verify the reserve hypothesis, the influence of rearing conditions on the cognitive performances and on dendritic spines following basal forebrain lesions was analyzed. Adult rats reared in enriched or standard conditions were depleted of the cholinergic projection to the neocortex by 192 IgG-saporin injection into Ch4 region of basal forebrain. Their performance in spatial tasks was compared with that of intact animals reared in analogous conditions. Furthermore, number and density of dendritic spines of the layer-III parietal pyramidal neurons were analyzed. Cholinergic depletion of forebrain cortex resulted in impaired performances in most behavioral tasks in animals reared in standard conditions. Conversely, the enriched lesioned animals did not exhibit most deficits evoked by cholinergic lesion, even if some deficits, such as perseverative behaviors, were still present. The pyramidal neurons exhibited an increased spine number and density in the lesioned animals reared in standard conditions. In the enriched lesioned animals, the enhancement of spine number and density elicited by the rearing condition was fully maintained but not further increased in the presence of the lesion. Thus, rearing in an enriched environment results in the development of brain and cognitive reserves that reduce the cognitive impairment following forebrain lesions.

Pages 29-44
Natalie Moroz, Ming Tong, Lisa Longato, Haiyan Xu, Suzanne M. de la Monte
Limited Alzheimer-Type Neurodegeneration in Experimental Obesity and Type 2 Diabetes Mellitus
Abstract: Alzheimer’s disease (AD) is associated with brain insulin resistance and insulin deficiency, whereas Type 2 diabetes mellitus (T2DM) is associated with peripheral insulin resistance. This study assesses the degree to which T2DM causes AD-type neurodegeneration. In a C57BL/6 mouse model of obesity and T2DM, we characterized the histopathology, gene expression, and insulin and insulin-like growth factor (IGF)-receptor binding in temporal lobe. High fat diet (HFD) feeding for 16 weeks doubled mean body weight, caused T2DM, and marginally reduced mean brain weight. These effects were associated with significantly increased levels of tau, IGF-I receptor, insulin receptor substrate-1 (IRS-1), IRS-4, ubiquitin, glial fibrillary acidic protein, and 4-hydroxynonenol, and decreased expression of β-actin. HFD feeding also caused brain insulin resistance manifested by reduced BMAX for insulin receptor binding, and modestly increased brain insulin gene expression. However, HFD-fed mouse brains did not exhibit AD histopathology, increases in amyloid-β or phospho-tau, or impairments in IGF signaling or acetylcholine homeostasis. Obesity and T2DM cause brain atrophy with insulin resistance, oxidative stress, and cytoskeleton degradation, but the absence of many features that typify AD suggests that T2DM/obesity may contribute to, but are not sufficient to cause AD.

Pages 45-59
Gigliola Ramírez, Sergio Rey, Rommy von Bernhardi
Proinflammatory Stimuli are Needed for Induction of Microglial Cell-Mediated AβPP244-C and Aβ-Neurotoxicity in Hippocampal Cultures
Abstract: Amyloid-β plaques and neurodegeneration are hallmarks of Alzheimer’s disease, where glial cells are responsible for sustained neuroinflammation. Here we show that hippocampal-microglia co-cultures exposed to proinflammatory mediators, amyloid-β amyloid-β protein precursor construct-conjugated beads increased their production of nitrites. In contrast, inflammation was unable to significantly induce cell death by itself, whereas inflammation plus amyloid-β or amyloid-β protein precursor induced a significant increment of cell death and a 6-fold increase of production of Interleukin 1β. Those effects were not observed in the absence of microglia or when hippocampal cells were co-cultured with microglia for one day. In contrast, a 2-fold increase of transforming growth factor β1 was observed in hippocampal cultures exposed to inflammatory stimuli for 4 days, whereas induction of transforming growth factor β1 by inflammation plus amyloid-β and amyloid-β protein precursor was nearly abolished by microglia. Our results indicate that neurotoxicity induced by amyloid-β or amyloid-β protein precursor was a slow process depending on activated microglia and additional stimuli. The observed cytotoxicity could be consequence of a vicious cycle in which elevated concentrations of Interleukin 1β and radical species along with decreased secretion of neuroprotective cytokines such as transforming growth factor β1 support persistent activation of glial cells and cell damage.

Pages 61-70
Arianna Cozza, Erika Melissari, Paola Iacopetti, Veronica Mariotti, Andrea Tedde, Benedetta Nacmias, Angela Conte, Sandro Sorbi, Silvia Pellegrini (Communicated by Alessandro Serretti)
SNPs in Neurotrophin System Genes and Alzheimer’s Disease in an Italian Population
Abstract: Increasing evidence suggests a role for nerve growth factor (NGFB), brain-derived neurotrophic factor (BDNF), and their receptors, nerve growth factor receptor (NGFR), and neurotrophin tyrosine kinase receptors 1 and 2 (NTRK1 and NTRK2), in Alzheimer’s disease (AD). However, genetic association between the neurotrophin system genes and AD has been poorly investigated. We genotyped 21 single nucleotide polymorphisms (SNPs) within these genes in a population of Italian AD patients and healthy controls. We found an allele-wise association of rs2072446 on NGFR with familial AD (fAD, p = 0.047), and a genotype-wise association of rs2289656 on NTRK2 with sporadic AD (sAD, p = 0.0036). rs6336 on NTRK1 resulted associated to early-onset sAD in both allele-wise (p = 0.028) and genotype-wise (p = 0.014) analysis, while rs1048218 on BDNF showed allele-wise association with late-onset sAD (p = 0.047). A trend to association with sAD and/or fAD was observed for other SNPs. Our results suggest that genetic variants of neurotrophin system genes might confer susceptibility to AD.

Pages 71-82
Nune Darbinian, Jianqi Cui, Anna Basile, Luis Del Valle, Jessica Otte, Judith Miklossy, Bassel E. Sawaya, Shohreh Amini, Kamel Khalili, Jennifer Gordon
Negative regulation of AβPP gene expression by Pur-alpha
Abstract: The nucleic acid binding protein, Pur-alpha, is best characterized as a transcription factor with affinity to single stranded G/C rich regions. Pur-alpha exhibits developmental and tissue-specific regulation and plays a critical role in neuronal development and differentiation. Similar to Pur-alpha, the amyloid-β protein precursor (AβPP) is a developmentally regulated protein which promotes neuronal survival. Both the human and mouse AβPP promoters contain multiple G/C rich sequences which regulate AβPP at the transcriptional and translational levels. Using an in vitro reporter assay, we confirmed that Pur-alpha consensus binding sites within the human AβPP promoter down-regulate AβPP transcription. Electrophoretic mobility shift and chromatin immunoprecipitation assays (ChIP) showed direct binding of Pur-alpha to the AβPP promoter. Down regulation of AβPP went beyond the transcriptional level as overexpression of Pur-alpha in glial and fibroblast cell lines decreased basal levels of AβPP while siRNA targeting Pur-alpha increased basal levels of AβPP. Similar findings were observed in brain tissue and fibroblasts from mice with targeted deletion of Pur-alpha. These data point to a novel mechanism of controlling AβPP levels by the transcriptional regulatory protein, Pur-alpha, and suggest that Pur-alpha may be involved in the dysregulation of AβPP seen in Alzheimer's disease.

Pages 83-95
Christoph Laske, Konstantinos Stellos, Gerhard W. Eschweiler, Thomas Leyhe, Meinrad Gawaz (Communicated by Milan Fiala)
Decreased CXCL12 (SDF-1) Plasma Levels in Early Alzheimer’s Disease: A Contribution to a Deficient Hematopoietic Brain Support?
Abstract: The chemokine CXCL12 (also known as stromal cell-derived factor 1, SDF-1) controls many aspects of bone marrow-derived stem cell functions and has been associated with neurogenesis as well with recruitment of brain resident and non-resident circulating cells towards sites of lesion in the central nervous system (CNS). Disrupting this line of chemokine-mediated intercellular communication may contribute to the pathogenesis of Alzheimer’s disease (AD). In this study, decreased CXCL12 plasma levels in patients with early AD (p=0.003) were found, which significantly inversely correlated with CSF tau protein levels (r=-0.373; p=0.042) and positively with CXCL12 CSF levels (r=0.429; p=0.018) and with changes of cognitive functions over the time period of 15 months (r=0.583; p=0.009). Our findings indicate a lack of chemotactic activity in early AD and support the view of a deficient regenerative hematopoietic brain support in early AD with putative pathogenic and therapeutic relevance.

Pages 97-107
Kelly L. Janis, Ryan T. Brennan, Robert E. Drolet, Bahareh Behrouz, Sarah K. Kaufman, Keith J. Lookingland, John L. Goudreau
Effects of Sildenafil on Nigrostriatal Dopamine Neurons in a Murine Model of Parkinson’s Disease
Abstract: The objective of this study was to determine if the phosphodiesterase 5 (PDE-5) inhibitor, sildenafil, could be used as a neuroprotective agent in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) murine model of Parkinson’s disease. The underlying hypothesis of these studies is that blockade of PDE-5 catabolism of cGMP will attenuate the loss of nigrostriatal dopamine (NSDA) neurons following chronic neurotoxin exposure. Chronic MPTP-treated mice were administered sildenafil using three different regimens. Animals were: 1) treated with sildenafil and then exposed to chronic MPTP; 2) treated concurrently with sildenafil and MPTP; and 3) first exposed to MPTP and subsequently treated with sildenafil. End points of neurotoxicity included dopamine (DA) and tyrosine hydroxylase (TH) concentrations in NSDA axon terminals in the striatum, and stereological cell counts of TH immunoreactive neurons in the substantia nigra. Results reveal that sildenafil did not prevent neurotoxicity produced by chronic MPTP exposure regardless of the treatment paradigms employed. On the other hand, sildenafil did not produce any deleterious effect on NSDA neuron function nor did it potentiate the neurotoxic effects of MPTP. These results suggest that sildenafil would not accelerate DA cell loss when used as a treatment for erectile dysfunction in men diagnosed with Parkinson’s disease.

Pages 109-115
Gang Wang, Qi Cheng, Shi Zhang, Li Bai, Jie Zeng, Pei-jing Cui, Ting Zhang, Zhi-kun Sun, Ru-jing Ren, Yu-lei Deng, Wei Xu, Ying Wang, Sheng-Di Chen
Economic Impact of Dementia in Developing Countries: An Evaluation of Alzheimer-Type Dementia in Shanghai, China
Abstract: The main objective of this study was to assess the economic cost of Alzheimer’s disease (AD) in Shanghai, China, as a pilot study for future evaluations. Sixty-seven patients with AD were interviewed, and the information of the AD-related cost and resources used was collected from October 2005 to September 2006. By retrospective analysis, annual costs were calculated and expressed in Chinese renminbi (RMB). Direct cost per patient per year averaged approximately 8,432 RMB (1,058 USD), indirect cost per patient per year was 10,568 RMB (1,326 USD), and annual costs were 19,001 RMB (2,384 USD) per patient per year in this investigation. Total cost was significantly associated with the degree of severity including cognitive function (MMSE) and activity of daily living (ADL). With the increase in the number of persons at risk for developing AD, the economic burden of AD patients in China is significantly heavy.

Pages 117-128
Inês Baldeiras, Isabel Santana, Maria Teresa Proença, Maria Helena Garrucho, Rui Pascoal, Ana Rodrigues, Diana Duro, Catarina Resende Oliveira
Peripheral Oxidative Damage in Mild Cognitive Impairment and Mild Alzheimer’s Disease
Abstract: Oxidative stress has been shown to be a triggering event in the pathogenesis of Alzheimer’s disease (AD). However, little evidence exists on the role of oxidative imbalance in Mild Cognitive Impairment (MCI), a group with a high risk of progression to AD. We therefore assessed the peripheral blood levels of a broad spectrum of non-enzymatic and enzymatic antioxidant defenses, as well as lipid and protein oxidation markers and nitrogen oxidative species in 85 MCI patients, 42 mild AD patients and 37 age-matched controls. In mild AD patients, the plasma levels of vitamin E were significantly decreased, while the plasma concentration of oxidized glutathione was increased in both MCI and mild AD patients. An increase in plasmatic and erythrocytes oxidative markers was also observed in MCI and mild AD patients as compared to controls. In both patients groups, increased levels of plasma antioxidants were found in females, whereas apolipoprotein E ε4 allele carriers showed higher indices of intracellular oxidative markers. Moreover, in MCI patients, cognitive function positively correlates with antioxidant levels. This study shows that most of the oxidative changes found in mild AD patients are already present in the MCI group, and that progression to AD might be accompanied by antioxidant depletion.

Pages 129-137
Eka J. Wahjoepramono, Linda K. Wijaya, Kevin Taddei, Georgia Martins, Matthew Howard, Karl deRuyck, Kristyn Bates, Satvinder S. Dhaliwal, Giuseppe Verdile, Malcolm Carruthers, Ralph N. Martins
Distinct Effects of Testosterone on Plasma and Cerebrospinal Fluid Amyloid-β Levels 
Abstract: The effect of testosterone on the levels of the Alzheimer’s disease amyloid-β peptide (Aβ) was investigated in guinea pigs. Castrated guinea pigs (GPX) were administered testosterone at two different dosages, following which plasma and cerebrospinal fluid (CSF) Aβ40 levels were measured. Plasma Aβ40 levels were reduced in GPX in the early stages of low-dose testosterone treatment, whereas CSF Aβ40 levels were only reduced by the time circulating testosterone had returned to untreated GPX levels. The supraphysiological testosterone dose did not reduce CSF Aβ40 levels significantly until circulating testosterone was back to uncastrated levels, whereas plasma Aβ40 levels significantly increased over time in these animals. These results indicate that the extent of testosterone-induced changes to Aβ40 levels and their response rates depend on both the tissue examined and testosterone dosage.

Pages 139-151
Geneviève Leuba, Armand Savioz, André Vernay, Béatrice Carnal, Rudolf Kraftsik, Eric Tardif, Irène Riederer, Béat Michel Riederer
Differential Changes in Synaptic Proteins in the Alzheimer Frontal Cortex with Marked Increase in PSD-95 Postsynaptic Protein
Abstract: We investigated how synaptic plasticity is related to the neurodegeneration process in the human dorsolateral prefrontal cortex. Pre- and postsynaptic proteins of Brodmann’s area 9 from patients with Alzheimer’s disease (AD) and age-matched controls were quantified by immunohistochemical methods and Western blots. The main finding was a significant increase in the expression of postsynaptic density protein PSD-95 in AD brains, revealed on both sections and immunoblots, while the expression of spinophilin, associated to spines, remained quantitatively unchanged despite qualitative changes with age and disease. Presynaptic protein α-synuclein indicated an increased immunohistochemical level, while synaptophysin remained unchanged. MAP2, a somatodendritic microtubule protein, as well as AD markers such as amyloid-β protein and phosphorylated protein tau showed an increased expression on immunosections in AD. Altogether these changes suggest neuritic and synaptic reorganization in the process of AD. In particular, the significant increase in PSD-95 expression suggests a change in NMDA receptors trafficking and may represent a novel marker of functional significance for the disease.

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