Journal of Alzheimer's Disease - Volume 25, issue 2

Authors: Carecchio, Miryam | Comi, Cristoforo

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, Eta-1, multiple sclerosis, Parkinson's disease, SPP1

DOI: 10.3233/JAD-2011-102151

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 179-185, 2011

Authors: Mandel, Silvia A. | Amit, Tamar | Weinreb, Orly | Youdim, Moussa B.H.

Article Type: Review Article

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 and Parkinson's diseases (AD and PD, respectively) 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. Show more

Keywords: Alzheimer's disease, combination therapy, green tea polyphenols, hypoxia inducible factor, iron chelation, neuroprotection/neurorescue, Parkinson's disease

DOI: 10.3233/JAD-2011-101803

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 187-208, 2011

Authors: Goldsmith, Harry S.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, amyloid plaque, cerebral blood flow, omental transposition, omentum

DOI: 10.3233/JAD-2011-101935

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 209-212, 2011

Authors: Gelfo, Francesca | Tirassa, Paola | De Bartolo, Paola | Caltagirone, Carlo | Petrosini, Laura | Angelucci, Francesco

Article Type: Short Communication

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. Show more

Keywords: ChAT, cholinergic neurons, neurotrophins, Saporin

DOI: 10.3233/JAD-2011-110047

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 213-217, 2011

Authors: O'Hare, Eugene | Scopes, David I.C. | Treherne, J. Mark | Monaghan, John | Palmer, Philip M. | Amijee, Hozefa | Kim, Eun-Mee

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, amyloid-β, behavior, inflammation

DOI: 10.3233/JAD-2011-100044

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 219-229, 2011

Authors: Havas, Daniel | Hutter-Paier, Birgit | Ubhi, Kiren | Rockenstein, Edward | Crailsheim, Karl | Masliah, Eliezer | Windisch, Manfred

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, hole board task, memory, motor coordination, rodent, transgenic, water maze

DOI: 10.3233/JAD-2011-101866

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 231-243, 2011

Authors: Durairajan, Siva Sundara Kumar | Liu, Liang-Feng | Lu, Jia-Hong | Koo, Irene | Maruyama, Kei | Chung, Sookja K. | Huang, Jian-Dong | Li, Min

Article Type: Research Article

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-α 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. Show more

Keywords: ADAM10, Alzheimer's disease, amyloid-β, Chinese medicine, cryptotanshinone, neuroblastoma, PKC

DOI: 10.3233/JAD-2011-102085

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 245-262, 2011

Authors: Nam, Dang Thanh | Arseneault, Madeleine | Ramassamy, Charles

Article Type: Research Article

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 hrs 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 hrs 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 hrs 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. Show more

Keywords: Alzheimer's disease, glutathione, heme oxygenase-1, NF-κB, Nrf2, p66Shc, Sirt-1

DOI: 10.3233/JAD-2011-102094

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 263-277, 2011

Authors: Floden, Angela Marie | Combs, Colin Kelly

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, cytokine, inflammation, microglia, phagocytosis, receptor

DOI: 10.3233/JAD-2011-101014

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 279-293, 2011

Authors: Yu, Jin | Gattoni-Celli, Marco | Zhu, Hong | Bhat, Narayan R. | Sambamurti, Kumar | Gattoni-Celli, Sebastiano | Kindy, Mark S.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, amyloid-β, animal models, transgenic mice, vitamin D

DOI: 10.3233/JAD-2011-101986

Citation: Journal of Alzheimer's Disease, vol. 25, no. 2, pp. 295-307, 2011