Volume 25, Number 2, July 2011

Pages 179-185
Review
Miryam Carecchio, Cristoforo Comi (Handling Associate Editor: Daniela Galimberti)
The Role of Osteopontin in Neurodegenerative Diseases
Abstract: Osteopontin (OPN) was shown to be involved in inflammatory and degenerative processes of the nervous system. In multiple sclerosis, the role of OPN has been studied in the inflammatory phase, where it was shown that the protein levels increase during disease relapses. Moreover, it was shown that subjects who carry a genotype associated with decreased protein levels tend to display a benign course. Taken altogether, these findings suggest that OPN may play a detrimental role in multiple sclerosis, at least in the inflammatory phase. In common neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease, OPN seems to act as a double-edged sword triggering neuronal toxicity and death in some contexts and functioning as a neuroprotectant in others. The involvement of OPN in several biological pathways and networks calls for more extensive research in order to unravel its role in the different disease phases and its potential as a therapeutic target.

Pages 187-208
Review
Silvia A. Mandel, Tamar Amit, Orly Weinreb and Moussa B.H. Youdim
Understanding the Broad-Spectrum Neuroprotective Action Profile of Green Tea Polyphenols in Aging and Neurodegenerative Diseases
Abstract: During the last century, the world population has shown a staggering increase in its proportion of elderly members and thus, neurodegenerative diseases like Alzheimer’s (AD) and Parkinson’s diseases (PD) are becoming an increasing burden. Brain aging and neurodegenerative diseases of the elderly are characterized by oxidative damage, dysregulation of redox metals homeostasis and inflammation, supporting a therapeutic use of antioxidants. Natural plant polyphenols (flavonoids and non-flavonoids) are the most abundant antioxidants in the diet and as such, are ideal nutraceuticals for neutralizing stress-induced free radicals and inflammation. Human epidemiological and new animal data suggest that green and black tea drinking (enriched in a class of flavonoids named catechins) may help protecting the aging brain and reduce the incidence of dementia, AD, and PD. Mechanistic studies on the neuroprotective/neuroregenerative effects of green tea catechins revealed that they act not only as antioxidants metal chelators,  but also as modulators of intracellular neuronal signaling and metabolism, cell survival/death genes, and mitochondrial function. Thus, these dietary compounds are receiving significant attention as therapeutic multifunctional cytoprotective agents that simultaneously manipulate various brain targets. The scope of this review is to assess and put into perspective salient features of the beneficial brain action of natural, non-toxic green tea catechins in aging-impaired cognition and neurodegenerative diseases and to discuss a scenario concerning their potential, in drug combination, to target distinct pathologies, in the quest for a disease modifying therapy.

Pages 209-212
Hypothesis
Harry S. Goldsmith
A New Approach to the Treatment of Alzheimer’s Disease: The Need for a Controlled Study
Abstract: It has been widely believed that decreased cerebral blood flow (CBF), known to occur in Alzheimer’s disease (AD), is the result of neuronal degeneration that causes a decrease in the need for adequate CBF.  There is new interest in the idea, however, that it is not neuronal degeneration that leads to decreased CBF to critical neurons, but it is the decrease in CBF which is the cause of the neuronal deterioration seen in AD patients.  In order to increase CBF to the AD brain, an operation called omental transposition has been developed in which an intact elongated omental pedicle, when placed directly on the brain, provides additional CBF and other biological nutrients to the brain.  It is understandable that AD patients are awaiting a method to control their disease, but this may take years to become available.  Placing the omentum on the AD brain has demonstrated increased CBF which may be the reason that several studies have shown that omental transposition to the brain can improve the cognitive ability of AD patients who have undergone the operation.  What is needed is a prospective controlled study that could scientifically establish the benefit of the procedure.

Pages 213-217
Short Communication
Francesca Gelfo, Paola Tirassa, Paola De Bartolo, Carlo Caltagirone, Laura Petrosini, Francesco Angelucci (Handling Associate Editor: Sigfrido Scarpa)
Brain and Serum Levels of Nerve Growth Factor in a Rat Model of Alzheimer’s Disease
Abstract: Different Alzheimer’s disease (AD) stages may be characterized by different directions in nerve growth factor (NGF) changes, suggesting that NGF may serve as peripheral marker of AD. To characterize the time course of NGF changes in an AD animal model, we measured NGF brain and serum levels at 3, 7, and 15 days from cholinergic depletion. NGF levels increased in the frontal cortex and hippocampus at 3 and 7 days and decreased in the serum at 7 days from lesion, suggesting that opposite changes in brain and serum occur at early stages of cholinergic depletion. When compared to human data, these findings further elucidate the role of NGF in early and late AD disease stages.

Pages 219-229
Eugene O’Hare, David I.C. Scopes, J. Mark Treherne, John Monaghan, Philip M. Palmer, Hozefa Amijee, Eun-Mee Kim
Novel Anti-Inflammatory Compound SEN1176 Alleviates Behavioral Deficits Induced Following Bilateral Intrahippocampal Injection of Aggregated Amyloid-β1-42
Abstract: Behavioral effects of a novel anti-inflammatory SEN1176 were investigated. This pyrrolo[3,2-e][1,2,4]triazolo[1,5-a]pyrimidine suppresses amyloid-β (Aβ)1-42-induced macrophage production of nitric oxide, TNF-α, IL-1β, and IL-6 in a dose-dependent fashion, an activity profile consistent with SEN1176 being a neuroinflammation inhibitor. Using male Sprague-Dawley rats, SEN1176 was examined relative to detrimental behavioral effects induced following bilateral intrahippocampal (IH) injections of aggregated Aβ1-42. The rats were trained to respond under an alternating-lever cyclic-ratio (ALCR) schedule of food reinforcement, enabling measurement of parameters of operant performance that reflect aspects of learning and memory. Under the ALCR schedule, orally administered SEN1176 at 5, 20, or 30 mg/kg was effective in reducing the behavioral deficit caused by bilateral IH aggregated Aβ1-42 injections in a dose-related manner over a 90-day treatment period. SEN1176 at 20 and 30 mg/kg significantly reduced lever switching errors and, at doses of 5, 10, and 30 mg/kg, significantly reduced incorrect lever perseverations, indicating a reduction of the behavioral deficit induced as a result of inflammation following IH Aβ1-42 injections. When treatment with SEN1176 was instigated 30 days after IH Aβ1-42 injections, it resulted in progressive protection, and withdrawal of SEN1176 treatment 60 days after IH Aβ1-42 injections revealed partial retention of the protective effect. SEN1176 also significantly reduced numbers of activated astrocytes adjacent to the aggregated Aβ1-42 injection sites. These results indicate the potential of SEN1176 for alleviating chronic neuroinflammatory processes related to brain Aβ deposition that affect learning and memory in Alzheimer’s disease.

Pages 231-243
Daniel Havas, Birgit Hutter-Paier, Kiren Ubhi, Edward Rockenstein, Karl Crailsheim, Eliezer Masliah, Manfred Windisch
A Longitudinal Study of Behavioral Deficits in an AβPP Transgenic Mouse Model of Alzheimer’s Disease
Abstract: Elucidating the age-dependent alterations in transgenic (Tg) mice overexpressing amyloid-β protein precursor (AβPP) is important for understanding the pathogenesis of Alzheimer’s disease (AD) and designing experimental therapies. Cross-studies have previously characterized some time-dependent behavioral and pathological alterations in AβPP Tg mice, however, a more comprehensive longitudinal study is needed to fully examine the progressive nature of behavioral deficits in these mice. In order to better understand the age- and gender-dependent progression of behavioral alterations, we performed a longitudinal study wherein Tg mice overexpressing human AβPP751 with the London (V717I) and Swedish (K670M/N671L) mutations under the regulatory control of the neuron specific murine (m)Thy-1 promoter (mThy1-hAβPP751) were behaviorally analyzed at 3 months and then re-tested at 6 and 9 months of age. The results show that there was an age-associated impairment in learning in the water maze task and habituation in the hole-board task. Motor coordination of the mThy1-hAβPP751 Tg mice was well-preserved throughout the investigated life span however, gender-specific deficits were observed in spontaneous activity and thigmotaxis. Neuropathologically, mThy1-hAβPP751 Tg mice displayed a progressive increase in the number of Aβ plaques and mean plaque size in the cortex and hippocampus from 3 to 6 and from 6 to 9 months of age. Taken together, these results indicate that the mThy1-hAβPP751 Tg mice model AD from the early onset of the disease through to later stages, allowing them to be utilized at numerous points during the timeline for drug test designs.

Pages 245-262
Siva Sundara Kumar Durairajan, Liang-Feng Liu, Jia-Hong Lu, Irene Koo, Kei Maruyama, Sookja K. Chung, Jian-Dong Huang, Min Li
Stimulation of Non-Amyloidogenic Processing of Amyloid-β Protein Precursor by Cryptotanshinone Involves Activation and Translocation of ADAM10 and PKC-α
Abstract: Cerebral deposition of amyloid-β peptide (Aβ) plaques is now considered the central feature of Alzheimer’s disease. Recent studies suggest that cryptotanshinone (CTS) extracted from the root of Salvia miltiorrhiza Bunge could be used for the prevention and treatment of Alzheimer’s disease. In this study, we investigated the role of CTS on non-amyloidogenic processing of amyloid-β protein precursor (AβPP) as well as its regulation by protein kinase C (PKC). Treatment with CTS dose-dependently and significantly reduced both intracellular and secreted levels of Aβ40 and Aβ42 in N2a mouse neuroblastoma cells stably expressing human SwedishAβPP (N2a-SwedAβPP). Using N2a-SwedAβPP and human neuroblastoma SHSY5Y cells, it was demonstrated that CTS significantly and dose-dependently increased the production of sAβPPα and C-terminal fragment-α (CTF-α) from AβPP. At the same time, CTS specifically increased the maturation of “a disintegrin and metalloproteinase-10” (ADAM10), an α-secretase candidate. The increase of sAβPPα secretion by CTS was blocked by the hydroxamate-based inhibitors GI254023X and GW280264X, and by the PKC-α inhibitor GÖ6976, suggesting involvement of the ADAM10 and PKC-α in CTS-induced α-secretase cleavage. In other experiments, CTS induced the phosphorylation of PKC-α indicating that PKC-α is involved in CTS-induced sAβPPα secretion. Furthermore, treatment of neuroblastoma cells with CTS induced the co-translocation of ADAM10 and PKC-a to the cell membrane, the site at which AβPP was cleaved, and this translocation was significantly reduced by GÖ6976. These results suggest that CTS-induced sAβPPα secretion is regulated by a PKC-α and ADAM10 cascade in neuroblastoma cells and may be involved in the lowering of Aβ production.

Supplementary Data for Kumar Durairajan et al. article (PDF)

Pages 263-277
Dang Thanh Nam, Madeleine Arseneault, Charles Ramassamy (Handling Associate Editor: Othman Ghribi)
Regulation of Redox-Sensitive Signaling Pathways in Rat Primary Astrocytes Following Acrolein Exposure
Abstract: Lipid peroxidation leads to the formation of a number of by-products including acrolein. In brain from patients with Alzheimer’s disease (AD), acrolein was found to be elevated in vulnerable regions. Astrocytes contribute to a variety of neuronal functions but the toxicity of acrolein in astroglial cells remains unknown. Using the rat primary astroglial cells, our results show that acrolein is toxic from 15 μM. Acrolein induced a biphasic effect on glutathione (GSH) levels with a depletion after 30 min of treatment followed by a progressive increase 24 h after exposure while the expression of γ-glutamyl-cysteine-synthase (γ-GCS) was induced. Protein carbonyls levels were significantly higher with all tested concentrations of acrolein. We have further investigated the effect of acrolein on the regulation of different redox-sensitive signaling pathways. A treatment with 20 µM of acrolein for 30 min activated NF-κB, Nrf2, and heme oxygenase-1 while after 24 h of exposure, their induction was observed with the subtoxic and toxic concentrations of acrolein except for NF-κB. Sirt-1 was also up-regulated after 24 h of exposure with acrolein. Acrolein also induced the phosphorylation of p66shc and of ERK1/2 after 30 min of treatment. Our results provide evidence that acrolein is a potent inducer of redox-sensitive pathways in astrocytes with a differential regulation after a short or a long term period of exposure to overcome cell death. Considering the crucial role of astrocytes in the brain, these results demonstrated that acrolein could disrupt neuronal functions and synaptic homeostasis by provoking dysfunctional or loss of astrocytes.

Pages 279-293
Angela Marie Floden and Colin Kelly Combs (Handling Associate Editor: Othman Ghribi)
Microglia Demonstrate Age-Dependent Interaction with Amyloid-β Fibrils
Abstract: Alzheimer’s disease (AD) is an age-associated disease characterized by increased accumulation of extracellular amyloid-β (Aβ) plaques within the brain. Histological examination has also revealed profound microglial activation in diseased brains often in association with these fibrillar peptide aggregates. The paradoxical presence of increased, reactive microglia yet accumulating extracellular debris suggests that these cells may be phagocytically compromised during disease. Prior work has demonstrated that primary microglia from adult mice are unable to phagocytose fibrillar Aβ1-42 in vitro when compared to microglia cultured from early postnatal animals. These data suggest that microglia undergo an age-associated decrease in microglial ability to interact with Aβ fibrils. In order to better define a temporal profile of microglia-Aβ interaction, acutely isolated, rather than cultured, microglia from 2 month, 6 month, and postnatal day 0 C57BL/6 mice were compared.  Postnatal day 0 microglia demonstrated a CD47 dependent ability to phagocytose Aβ fibrils that was lost by 6 months. This corresponded with the ability of postnatal day 0 but not adult microglia to decrease Aβ immunoreactive plaque load from AD sections in vitro. In spite of limited Aβ uptake ability, adult microglia had functional phagocytic uptake of bacterial bioparticles and demonstrated the ability to adhere to both Aβ plaques and in vitro fibrillized Aβ. These data demonstrate a temporal profile of specifically Aβ-microglia interaction with a critical developmental period at 6 months in which cells remain able to interact with Aβ fibrils but lose their ability to phagocytose it.

Pages 295-307
Jin Yu, Marco Gattoni-Celli, Hong Zhu, Narayan R. Bhat, Kumar Sambamurti, Sebastiano Gattoni-Celli, Mark S. Kindy
Vitamin D3-Enriched Diet Correlates with a Decrease of Amyloid Plaques in the Brain of AβPP Transgenic Mice
Abstract: In addition to its function in calcium and bone metabolism, vitamin D is neuroprotective and important for mitigating inflammation. Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system, characterized by neuronal loss in many areas of the brain, and the formation of senile (neuritic) plaques, which increase in number and size over time. The goal of this project was to investigate whether vitamin D3 supplementation would affect amyloid plaque formation in amyloid-β protein precursor (AβPP) transgenic mice that spontaneously develop amyloid plaques within 3-4 months of birth. AβPP mice were fed control, vitamin D3-deficient or vitamin D3-enriched diets for five months, starting immediately after weaning. At the end of the study, the animals were subjected to behavioral studies, sacrificed, and examined for bone changes and brain amyloid load, amyloid-β (Aβ) peptide levels, inflammatory changes, and nerve growth factor (NGF) content. The results obtained indicate that a vitamin D3-enriched diet correlates with a decrease in the number of amyloid plaques, a decrease in Aβ peptides, a decrease in inflammation, and an increase in NGF in the brains of AβPP mice. These observations suggest that a vitamin D3-enriched diet may benefit AD patients.

Pages 309-321
Susanne Neufang, Atae Akhrif, Valentin Riedl, Hans Förstl, Alexander Kurz, Claus Zimmer, Christian Sorg, Afra M Wohlschläger (Handling Associate Editor: Rex Cannon)
Disconnection of Frontal and Parietal Areas Contributes to Impaired Attention in Very Early Alzheimer’s Disease
Abstract: In Alzheimer’s disease (AD), the loss of cerebral connectivity has been evidenced by numerous studies. There is growing evidence of attention related failures already in prodromal stages of AD; however, connectivity changes within attention networks have been rarely reported. Here we focused on effective connectivity of top-down attention control in patients with prodromal Alzheimer’s disease (pAD). We scanned 15 pAD patients and 16 healthy elderly using the Attentional Network Task and determined effective connectivity within a cingulo-fronto-parietal network using Dynamic Causal Modeling. We related connectivity parameters to structural and behavioral parameters (gray matter volume as well as reaction time) to examine the relation between affected domains. Our analyses revealed that effective connectivity from the right middle frontal gyrus to the left superior parietal cortex as well as from the right to the left superior parietal gyrus was reduced in pAD patients. Furthermore, we found that, effective connectivity varied as a function of GM volume in the patient group: right middle frontal gray matter volume significantly correlated with connectivity from the right parietal cortex to the right middle frontal gyrus as well as from the middle frontal gyrus to the anterior cingulate cortex. In addition, inter-parietal connectivity was correlated to right and left parietal gray matter volume. We conclude that, at very early stages of AD, the reduction of effective connectivity in fronto-parietal circuits is related to regional gray matter volume and contributes to impairments in top-down attentional control.

Pages 323-335
Chuanhai Cao, Li Wang, Xiaoyang Lin, Malgorzata Mamcarz, Chi Zhang, Ge Bai, Jasson Nong, Sam Sussman, Gary Arendash (Handling Associate Editor: Jonathan Geiger)
Caffeine Synergizes with Another Coffee Component to Increase Plasma GCSF: Linkage to Cognitive Benefits in Alzheimer’s Mice
Abstract: Retrospective and prospective epidemiologic studies suggest that enhanced coffee/caffeine intake during aging reduces risk of Alzheimer’s disease (AD).  Underscoring this premise, our studies in AD transgenic mice show that long-term caffeine administration protects against cognitive impairment and reduces brain amyloid-β levels/deposition through suppression of both β- and γ-secretase.  Because coffee contains many constituents in addition to caffeine that may provide cognitive benefits against AD, we examined effects of caffeinated and decaffeinated coffee on plasma cytokines, comparing their effects to caffeine alone.  In both AβPPsw+PS1 transgenic mice and non-transgenic littermates, acute i.p. treatment with caffeinated coffee greatly and specifically increased plasma levels of granulocyte-colony stimulating factor (GCSF), IL-10, and IL-6.  Neither caffeine solution alone (which provided high plasma caffeine levels) or decaffeinated coffee provided this effect, indicating that caffeine synergized with some as yet unidentified component of coffee to selectively elevate these three plasma cytokines.  The increase in GCSF is particularly important because long-term treatment with coffee (but not decaffeinated coffee) enhanced working memory in a fashion that was associated only with increased plasma GCSF levels among all cytokines.  Since we have previously reported that long-term GCSF treatment enhances cognitive performance in AD mice through three possible mechanisms (e.g., recruitment of microglia from bone marrow, synaptogenesis, and neurogenesis), the same mechanisms could be complimentary to caffeine’s established ability to suppress Aβ production.  We conclude that coffee may be the best source of caffeine to protect against AD because of a component in coffee that synergizes with caffeine to enhance plasma GCSF levels, resulting in multiple therapeutic actions against AD.

Pages 337-345
Gang Yin, Ling-Yun Li, Min Qu, Hong-Bin Luo, Jian-Zhi Wang, Xin-Wen Zhou
Upregulation of AKT Attenuates Amyloid-β-Induced Cell Apoptosis
Abstract: Overproduction and accumulation of amyloid-β (Aβ) have been proposed to be an initiating factor of neuron loss in Alzheimer’s disease (AD). AKT is a pivotal molecule in regulating neuronal survival; however, it is still not known whether upregulation of AKT can protect the cells from the Ab-induced apoptosis. By using cell viability assay and flow cytometry, we demonstrated in the present study that overexpression of AKT could significantly attenuate the cell apoptosis induced by Aβ1-42, whereas simultaneous inhibition of PI3K, the immediate upstream stimulator of AKT, abolished the protective effect of AKT in HEK293 cells. Upregulation of AKT restored the Ab-induced alterations of the mitochondria-related Bcl-2 family members (including Bcl-xL, Bcl-w, Bad, and Bax) and suppressed the activation of caspase-3 and JNK. Our data suggest that upregulation of AKT could be a promising therapeutic strategy for arresting Ab toxicity in AD patients.

Pages 347-357
Sabine Derflinger*, Christian Sorg*, Christian Gaser, Nicholas Myers, Milan Arsic, Alexander Kurz, Claus Zimmer, Afra Wohlschläger, Mark Mühlau *These authors contributed equally to this work.
Grey-Matter Atrophy in Alzheimer's Disease is Asymmetric but not Lateralized
Abstract: In Alzheimer’s disease (AD), brain atrophy has been proposed to be left lateralized. Here, we reinvestigated the asymmetry and lateralization (i.e., asymmetry directed toward one hemisphere) of grey-matter (GM) distribution in 35 patients with AD, 24 patients with amnestic mild cognitive impairment (aMCI, a state of increased risk for AD), and 30 age-matched healthy controls (HC). We analyzed GM distribution by applying voxel-based morphometry (VBM) including analyses for asymmetry and lateralization. When comparing MCI with AD patients, VBM revealed GM loss in the entorhinal, temporoparietal, dorsofrontal, and occipital cortices as well as in the precuneus; when comparing HCs with MCI patients, we found similar differences, which were less pronounced especially within the temporoparietal cortex and precuneus. Analyses of regional asymmetry and regional lateralization as well as global lateralization did not yield significant results. However, lobar asymmetry of the temporal, parietal, and occipital lobes increased from HC to AD. Moreover, in aMCI and AD patients, performance of language-based neuropsychological tests correlated with lateralization of GM loss to the left hemisphere. We conclude that, in principle, brain atrophy in AD is asymmetric rather than lateralized. At the individual level however, asymmetry contributes to cognitive deficits.

Pages 359-372
Stephen B Wharton, Carol Brayne, George M Savva, Fiona E Matthews, Gill Forster, Julie Simpson, Gemma Lace, Paul G Ince, on behalf of the Medical Research Council Cognitive Function and Aging Study.
Epidemiological Neuropathology: The MRC Cognitive Function and Aging Study Experience
Abstract: We here describe the study-design major findings from the neuropathological component of the Medical Research Council Cognitive Function and Aging Study (MRC CFAS). MRC CFAS is a population-representative study of aging and health including more than 18000 participants at baseline.  More than 500 brain donations were accrued to date and have been subjected to comprehensive pathological assessment. This resource enables a thorough epidemiological description of the neuropathology associated with dementia in the UK. Results to date reveal a high prevalence of mixed Alzheimer and vascular pathology, a significant population who die with dementia but with a more limited pathological burden than is traditionally associated with dementia, and a group who die with a significant pathological burden yet remained cognitively intact until death. This dissociation between pathology and dementia increases with increasing age. Further studies have described the distribution and etiology of neurodegenerative disease in the population, and determined pathological correlates of cognitive impairment and dementia. Brain donation programs linked to epidemiological studies provide an invaluable resource for describing the pathological correlates of dementia in a way that is representative of the population, thereby identifying targets for and assessing the likely effect of therapeutic and preventive interventions.

Pages 373-381
Michael Ewers, Xin Cheng*, ZhenYu Zhong*, Hikmet F. Nural, Cathal Walsh, Thomas Meindl, Stefan J. Teipel, Katharina Buerger, He, Yong Shen, Harald Hampel *contributed equally to the study
Increased CSF- BACE1 Activity Associated with Decreased Hippocampus Volume in Alzheimer’s Disease
Abstract: The enzyme β-secretase (BACE1) is essentially involved in the production of cerebral amyloidogenic pathology in Alzheimer’s disease (AD). The measurement of BACE1 activity in cerebrospinal fluid (CSF) has been reported, which may render CSF measurement of BACE1 a potential biomarker candidate of AD. In order to investigate whether BACE1 protein activity is correlated with regional brain atrophy in AD, we investigated the association between CSF levels of BACE1 and MRI-assessed hippocampus volume in patients with AD (n = 30). An increase in CSF-BACE1 activity was associated with decreased left and right hippocampus volume corrected for global head volume in the AD patients. Boot-strapped regression analysis showed that increased CSF levels of BACE1 activity were associated with increased CSF concentration of total tau but not amyloid-β1-42 in AD. White matter hyperintensities did not influence the results. BACE1 activity and protein levels were significantly increased in AD compared to 19 elderly healthy controls. Thus, the CSF biomarker candidate of BACE1 activity was associated with hippocampus atrophy in AD in a robust manner and may reflect neurotoxic amyloid-β-related processes.

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