Journal of Alzheimer's Disease - Volume 24, issue s2

Authors: Kawamata, Jun | Shimohama, Shun

Article Type: Research Article

Abstract: Both of the two most common neurodegenerative disorders, namely Alzheimer's disease (AD) and Parkinson's disease (PD), have multiple lines of evidence from molecular and cellular to epidemiological, that nicotinic transmission is implicated in their pathogenesis. This review article presents evidence of nicotinic acetylcholine receptor (nAChR)-mediated protection against neurotoxicity induced by amyloid-β (Aβ), glutamate, rotenone, and 6-hydroxydopamine (6-OHDA) and the signal transduction involved in this mechanism. Our studies clarified that survival signal transduction, α7 nAChR-Src family-PI3 K-AKT pathway, and subsequent upregulation of Bcl-2 and Bcl-x, would lead to neuroprotection. In addition to the PI3 K-AKT pathway, two other survival pathways, JAK2/STAT3 …and MEK/ERK, are proposed by other groups. These three survival pathways are related to each other through intracellular signal transductions in neurons. The JAK2/STAT3 pathway is cholinergic anti-inflammation pathway mediated by α7 nAChR on macrophage and microglia as well as neuron. Recently analyzing the properties of galantamine, we clarify the 4th independent neuroprotective pathway, which is mediated by enhancement of microglial α7 nAChR resulting in upregulation of Aβ phagocytosis. Galantamine sensitizes microglial α7 nAChRs to choline and induce Ca2+ influx into microglia. The Ca2+ -induced intracellular signaling cascades may then stimulate Aβ phagocytosis through actin reorganization. The discovery of the 4th pathway would facilitate further investigation of possible nAChRs enhancing drugs targeting not only neuronal but also microglial nAChRs. Show more

Keywords: Alzheimer's disease, amyloid-β, glutamate, nAChR, nicotine, Parkinson's disease, phagocytosis

DOI: 10.3233/JAD-2011-110173

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 95-109, 2011

Authors: Ienco, Elena Caldarazzo | LoGerfo, Annalisa | Carlesi, Cecilia | Orsucci, Daniele | Ricci, Giulia | Mancuso, Michelangelo | Siciliano, Gabriele

Article Type: Review Article

Abstract: Oxidative stress is a metabolic condition arising from imbalance between the production of potentially reactive oxygen species and the scavenging activities. Mitochondria are the main providers but also the main scavengers of cell oxidative stress. The role of mitochondrial dysfunction and oxidative stress in the pathogenesis of neurodegenerative diseases is well documented. Therefore, therapeutic approaches targeting mitochondrial dysfunction and oxidative damage hold great promise in neurodegenerative diseases. Despite this evidence, human experience with antioxidant neuroprotectants has generally been negative with regards to the clinical progress of disease, with unclear results in biochemical assays. Here we review the antioxidant approaches performed …so far in neurodegenerative diseases and the future challenges in modern medicine. Show more

Keywords: Antioxidants, clinical trial, neurodegenerative diseases, oxidative stress

DOI: 10.3233/JAD-2011-110164

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 111-126, 2011

Authors: Barten, Donna M. | Cadelina, Gregory W. | Hoque, Nina | DeCarr, Lynn B. | Guss, Valerie L. | Yang, Ling | Sankaranarayanan, Sethu | Wes, Paul D. | Flynn, Marianne E. | Meredith, Jere E. | Ahlijanian, Michael K. | Albright, Charles F.

Article Type: Research Article

Abstract: Levels of tau in cerebrospinal fluid (CSF) are elevated in Alzheimer's disease (AD) patients. It is believed this elevation is related to the tau pathology and neurodegeneration observed in AD, but not all tauopathies have increased CSF tau. There has been little pre-clinical work to investigate mechanisms of increased CSF tau due to the difficulty in collecting CSF samples from mice, the most commonly used pre-clinical models. We developed methods to collect CSF from mice without contamination from tau in brain tissue, which is approximately 50,000 fold more abundant in brain than CSF. Using these methods, we measured CSF tau …from 3xTg, Tg4510, and Tau Alone transgenic mice. All three lines of mice showed age-dependent increases in CSF tau. They varied in phenotype from undetectable to severe tau pathology and neurodegeneration, suggesting that degenerating neurons are unlikely to be the only source of pathologic CSF tau. Overall, CSF tau levels mirrored expression levels and changes of tau in the brain, but they did not always correlate exactly. CSF tau was often more sensitive to changes in brain transgene expression and pathology. In addition, we also developed ELISA assays specific to different regions of the tau protein. We used these assays to provide evidence that CSF tau exists as fragments, with little intact C-terminus and partial loss of the N-terminus. Taken together, these assays and mouse models may be used to facilitate a deeper understanding of CSF tau in neurodegenerative disease. Show more

Keywords: Alzheimer's disease, cerebrospinal fluid, ELISA, FTDP-17 protein, human, MAPT, mice, tau proteins, tauopathy, transgenic

DOI: 10.3233/JAD-2011-110161

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 127-141, 2011

Authors: Halima, Saoussen Ben | Rajendran, Lawrence

Article Type: Review Article

Abstract: β-secretase, a key enzyme involved in amyloid-β generation, is an attractive candidate for Alzheimer's disease therapy. Transition-state inhibitors of β-secretase are designed to achieve specificity. However, these inhibitors bind only to the active conformation of the enzyme and as the active β-secretase is sequestered in subcellular compartments, new strategies have to be implemented. We propose that membrane-anchoring of β-secretase inhibitors would render them endocytosis-competent thereby enabling the inhibitors to reach these compartments that harbor active β-secretase. By choosing cholesterol as a membrane anchor, we also enrich the inhibitor in lipid rafts where much of the β-secretase is present. In addition, …membrane-anchoring of soluble inhibitors reduces the dimensionality of the inhibitor and consequently increases the inhibitor concentration at the target membrane plane. Such inhibitors have great potential in terms of substrate selectivity and reduced side effects. Not only for β-secretase, this strategy could be applied for many membrane targets that are localized either at the plasma membrane or in the endocytic compartments. Show more

Keywords: Alzheimer's disease, amyloid, BACE1, β-secretase, drug design, endocytosis, inhibitor, lipid rafts, membrane anchoring, targeting

DOI: 10.3233/JAD-2011-110269

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 143-152, 2011

Authors: Britton, Gabrielle B. | Rao, K.S.J.

Article Type: Review Article

Abstract: Despite the profound burden of Alzheimer's disease (AD) on public health, research to understand its underlying pathology has not yet produced new therapeutic approaches to improve symptoms or halt disease progression. AD is characterized by early cognitive deficits, particularly in short-term memory, followed by a gradual decline in other cognitive functions. Functional imaging studies indicate that hippocampal and medial temporal lobe cortices are the sites of early pathology underlying the initial memory impairments. Behaviors that rely on hippocampal integrity have been the focus of extensive research using animal models and represent useful functional endpoints in pre-clinical AD research. In this …review, we argue that relevant information can be derived from studying normal, aging animals performing hippocampal-sensitive tasks. Because age is the greatest risk factor for developing clinical AD, the aspects of cognitive decline occurring in normal, aging animals that resemble those seen in aging humans are reliable endpoints that can be applied to improving human therapies. Ultimately, pre-clinical studies that employ tasks sensitive to hippocampal function can be applied toward novel hypotheses in AD intervention and could provide important insights for developing early detection devices for AD patients. Show more

Keywords: Aging, Alzheimer's disease, behavior, cognition, hippocampus

DOI: 10.3233/JAD-2011-110239

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 153-159, 2011

Authors: Marques, Sueli | Batalha, Vânia L. | Lopes, Luísa Vaqueiro | Outeiro, Tiago Fleming

Article Type: Research Article

Abstract: Aging is the best-known risk factor for many disorders, including neurodegenerative diseases such as Alzheimer's disease (AD). The effect of epigenetic modulation of gene expression on normal aging and in pathological conditions is still unclear, but it is likely it may explain some of the complexity that is characteristic of these processes. Caffeine is a widely consumed psychoactive drug, which is emerging as a protective agent against AD progression and in aging associated deficits. This occurs mainly through the blockade of adenosine A2A receptors, whose expression and function become aberrant throughout aging and in age-related pathologies. Here, we discuss …the data supporting the effects of caffeine in AD, focusing on adenosine A2A receptors and epigenetic modulation of gene expression. In addition, we speculate on the potential of caffeine as an epigenetic modulator and the consequences it might have for preventive and therapeutic applications of caffeine in AD. Show more

Keywords: Adenosine A2A receptors, aging, Alzheimer's disease, caffeine, epigenetics

DOI: 10.3233/JAD-2011-110032

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 161-171, 2011

Authors: Gong, Qi-Hai | Shi, Xue-Ru | Hong, Zhen-Yi | Pan, Li-Long | Liu, Xin-Hua | Zhu, Yi-Zhun

Article Type: Review Article

Abstract: For hundreds of years, hydrogen sulfide (H2 S) has been known solely as a toxic gas with the smell of rotten eggs. Nevertheless, the notoriety of H2 S as a toxic gas is experiencing a transformation, with an increasing amount of research showing that it regulates a range of physiological and pathological processes in mammals. Hence H2 S is a physiologically important molecule and has been referred to as the third gaseous mediator alongside nitric oxide and carbon monoxide. This past decade has seen an exponential growth of scientific interest in the physiological and pathological significance of H2 S. In …particular, in the central nervous system, H2 S facilitates long-term potentiation and regulates intracellular calcium concentration and pH level in brain cells. Interestingly, H2 S may exert antioxidant, anti-apoptotic, and anti-inflammatory effects which are related to neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and vascular dementia. Meanwhile, abnormal generation and metabolism of H2 S are involved in most of these neurodegenerative disorders. This review presents current knowledge of H2 S and its neuroprotective effects in neurodegenerative disorders, with a special emphasis on AD and PD. It is concluded that a H2 S-modulated agent will be a new hope for neurodegenerative disorders including AD and PD. Show more

Keywords: Alzheimer's disease, hydrogen sulfide, neurodegeneration, Parkinson's disease

DOI: 10.3233/JAD-2011-110128

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 173-182, 2011

Authors: Hegde, Muralidhar L. | Hegde, Pavana M. | Rao, K.S. | Mitra, Sankar

Article Type: Review Article

Abstract: The neurons in the central nervous system (CNS) with high O2 consumption and prolonged life span are chronically exposed to high levels of reactive oxygen species (ROS). Accumulation of ROS-induced genome damage in the form of oxidized bases and single-strand breaks (SSBs) as well as their defective or reduced repair in the brain has been implicated in the etiology of various neurological disorders including Alzheimer's/Parkinson's diseases (AD/PD). Although inactivating mutations in some DNA repair genes have been linked to hereditary neurodegenerative diseases, the underlying mechanisms of repair deficiencies for the sporadic diseases is not understood. The ROS-induced DNA damage …is predominantly repaired via the highly conserved and regulated base excision/SSB repair (BER/SSBR) pathway. We recently made an interesting discovery that the transition metals iron and copper, which accumulate excessively in the brains of AD, PD, and other neurodegenerative diseases, act as a ‘double-edged sword’ by inducing genotoxic ROS and inhibiting DNA damage repair at the same time. These metals inhibit the base excision activity of NEIL family DNA glycosylases by oxidizing them, changing their structure, and inhibiting their binding to downstream repair proteins. Metal chelators and reducing agents partially reverse the inhibition, while curcumin with both chelating and reducing activities reverses the inhibition nearly completely. In this review, we have discussed the possible etiological linkage of BER/SSBR defects to neurodegenerative diseases and the therapeutic potential of metal chelators in restoring DNA repair capacity. Show more

Keywords: Alzheimer's disease, base excision repair, curcumin, metal chelators, metal toxicity, neurodegenerative diseases, oxidative genome damage, Parkinson's disease

DOI: 10.3233/JAD-2011-110281

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 183-198, 2011

Authors: Plangár, Imola | Zádori, Dénes | Klivényi, Péter | Toldi, József | Vécsei, László

Article Type: Review Article

Abstract: Alzheimer's disease (AD) is a chronic neurodegenerative disorder associated with dementia as a main feature. Despite decades of thorough research in the field of AD, the pathomechanism is still not fully understood. The development of novel experimental models can help us in the discovery of both genetic and non-genetic components of disease pathogenesis. As currently available therapies in AD can provide merely moderate or only temporary symptomatic relief, there is a great demand for the development of new drugs with higher therapeutic potential. Some of the candidates would be those targeting the kynurenine pathway, the neuroactive metabolites of which are …surely involved in both neurodegeneration and neuroprotection, mainly in relation with glutamate excitotoxicity and oxidative stress. Both analogs of the neuroprotective kynurenic acid and small molecule enzyme inhibitors preventing the formation of neurotoxic compounds may have potential therapeutic significance. However, there is a great need for new strategies to improve efficacy, transport across the blood-brain barrier and bioavailability, naturally with simultaneous minimization of the adverse side-effects. Show more

Keywords: Alzheimer's disease, animal models, kynurenine pathway, therapy

DOI: 10.3233/JAD-2011-110131

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 199-209, 2011

Authors: Padmaraju, Vasudevaraju | Bhaskar, Jamuna J. | Prasada Rao, Ummiti J.S. | Salimath, Paramahans V. | Rao, K.S.

Article Type: Research Article

Abstract: Parkinson's disease (PD) is a neurodegenerative disease with multiple etiologies. Advanced glycation end products (AGEs) accumulate in the aging brain and could be one of the reasons for age-related diseases like PD. Oxidative stress also leads to the formation of AGEs and may be involved in neurodegeneration by altering the properties of proteins. α-Synuclein is involved in pathogenesis of PD and there are limited studies on the role of AGE-α-synuclein in neurodegeneration. We studied the aggregation and DNA binding ability of AGE-α-synuclein in vitro. α-Synuclein is glycated using methylglyoxal and formation of AGE-α-synuclein is characterized using fluorescence studies, intrinsic tyrosine …fluorescence, and fructosamine estimation. The results indicated that AGE-α-synuclein aggregates into smaller globular-like aggregates compared to fibrils formed with native α-synuclein. Further, it is found that AGE-α-synuclein induced conformational changes in scDNA from B-form to B-C-A mixed conformation. Additionally, AGE-α-synuclein altered DNA integrity as evidenced by the melting temperature, ethidium bromide, and DNAse I sensitivity studies. AGE-α-synuclein converted biphasic Tm to higher monophasic Tm . The Tm of AGE-α-synuclein-scDNA complex is more than that of native α-synuclein-scDNA complex, indicating that AGE-α-synuclein stabilized the uncoiled scDNA. AGE-α-synuclein could stabilize the uncoiled scDNA, as shown by the decrease in the number of ethidium bromide binding molecules per base pair of DNA. DNAse I sensitive studies indicated that both AGE-α-synuclein-scDNA and α-synuclein-scDNA are resistant to DNAse I digestion. The relevance of these findings to neuronal cell death is discussed. Show more

Keywords: AGEs, α-synuclein, DNA conformation, glycation, Parkinson's disease, protein aggregation

DOI: 10.3233/JAD-2011-101965

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 211-221, 2011

Authors: Gadad, Bharathi Shrikanth | Britton, Gabrielle B. | Rao, K.S.

Article Type: Review Article

Abstract: Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Prion disease, Huntington's disease, and amyotrophic lateral sclerosis are o increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation in selected brain regions. The aggregates usually consist of insoluble fibrillar aggregates containing misfolded protein with β-sheet conformation. The most probable explanation is that inclusions and the aggregates symbolize an end stage of a molecular cascade of several events, and that earlier event in the cascade may be more directly tied up to pathogenesis than the inclusions themselves. Small intermediates termed as ‘soluble oligomers’ in …the aggregation process might influence synaptic dysfunction, whereas large, insoluble deposits might function as reservoir of the bioactive oligomers. Compelling evidence suggests the role of misfolded proteins in the form of oligomers might lead to synaptic dysfunction, neuronal apoptosis and brain damage. However, the mechanism by which oligomers trigger neurodegeneration still remains mysterious. The aim of this article is to review the literature around the molecular mechanism and role of oligomers in neurodegeneration and leading approaches toward rational therapeutics. Show more

Keywords: Aggregation, neurodegeneration, oligomers, therapy, toxicity

DOI: 10.3233/JAD-2011-110182

Citation: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 223-232, 2011