Journal of Alzheimer's Disease - Volume 60, issue s1

Article Type: Editorial

DOI: 10.3233/JAD-170656

Citation: Journal of Alzheimer's Disease, vol. 60, no. s1, pp. S1-S2, 2017

Authors: Sathya, Mohan | Moorthi, Ponnusamy | Premkumar, Palanisamy | Kandasamy, Mahesh | Jayachandran, Kesavan Swaminathan | Anusuyadevi, Muthuswamy

Article Type: Research Article

Abstract: Deterioration of cholesterol metabolism has recently been a frontier subject of investigation in the field of Alzheimer’s disease (AD). Though amyloid-β protein precursor (AβPP) primes the pathological cascade, changes in cholesterol levels and its intermediates, geranyl geranyl pyrophosphate and farnesyl pyrophosphate, is expected to have a different consequence on AβPP processing and amyloid-β (Aβ) generation. However, the use of statins (HMG-COA reductase inhibitor) has been widely implicated in slowing down the pathogenic progression of AD, while the epidemiological reports on its biological effect remains controversial. Considering this fact, the choice of drug that could maintain cholesterol homeostasis without altering its …biosynthesis may yield a better therapeutic efficacy on AD. Thus, the present study focused on determining the influence of cholesterol and isoprenoids on amyloidogenic-cleavage of AβPP, in addition to resveratrol as a potent therapeutic drug in CHO-APPswe cell lines. High levels of cholesterol were found to enhance the maturation of AβPP and altered the expression and subcellular localization of ADAM10, BACE1, and PS1 thereby promoting Aβ generation, whereas high isoprenoids increased both maturation as well as amyloidogenic-cleavage of AβPP, which was evident through β-CTF production. Interestingly, the therapeutic efficacy of resveratrol maintained cholesterol homeostasis and reduced the amyloidogenic burden through its ability to enhance SIRT1 expression and thereby regulating differential expression of AD determinants. Show more

Keywords: Alzheimer’s disease determinants, amyloid-β protein precursor, cholesterol, geranyl geranyl pyrophosphate, farnesyl pyrophosphate, resveratrol, SIRT1

DOI: 10.3233/JAD-161034

Citation: Journal of Alzheimer's Disease, vol. 60, no. s1, pp. S3-S23, 2017

Authors: Gill, Iqbal | Kaur, Sukhchain | Kaur, Navrattan | Dhiman, Monisha | Mantha, Anil K.

Article Type: Research Article

Abstract: Oxidative stress is an upsurge in reactive oxygen/nitrogen species (ROS/RNS), which aggravates damage to cellular components viz. lipids, proteins, and nucleic acids resulting in impaired cellular functions and neurological pathologies including Alzheimer’s disease (AD). In the present study, we have examined amyloid-β (Aβ)-induced oxidative stress responses, a major cause for AD, in the undifferentiated and differentiated human neuroblastoma SH-SY5Y cells. Aβ1-42 -induced oxidative damage was evaluated on lipids by lipid peroxidation; proteins by protein carbonyls; antioxidant status by SOD and GSH enzyme activities; and DNA and RNA damage levels by evaluating the number of AP sites and 8-OHG base damages …produced. In addition, the neuro-protective role of the phytochemical ginkgolide B (GB) in countering Aβ1-42 -induced oxidative stress was assessed. We report that the differentiated cells are highly vulnerable to Aβ1-42 -induced oxidative stress events as exerted by the deposition of Aβ in AD. Results of the current study suggest that the pre-treatment of GB, followed by Aβ1-42 treatment for 24 h, displayed neuro-protective potential, which countered Aβ1-42 -induced oxidative stress responses in both undifferentiated and differentiated SH-SY5Y neuronal cells by: 1) hampering production of ROS and RNS; 2) reducing lipid peroxidation; 3) decreasing protein carbonyl content; 4) restoring antioxidant activities of SOD and GSH enzymes; and 5) maintaining genome integrity by reducing the oxidative DNA and RNA base damages. In conclusion, Aβ1-42 induces oxidative damage to the cellular biomolecules, which are associated with AD pathology, and are protected by the pre-treatment of GB against Aβ-toxicity. Taken together, this study advocates for phytochemical-based therapeutic interventions against AD. Show more

Keywords: Aβ1-42, amyloid-beta, antioxidants, DNA/RNA base damage, ginkgolide B, neuronal differentiation, oxidative stress

DOI: 10.3233/JAD-161086

Citation: Journal of Alzheimer's Disease, vol. 60, no. s1, pp. S25-S40, 2017

Authors: Yin, Zhuoran | Valkenburg, Femke | Hornix, Betty E. | Mantingh-Otter, Ietje | Zhou, Xingdong | Mari, Muriel | Reggiori, Fulvio | Van Dam, Debby | Eggen, Bart J.L. | De Deyn, Peter P. | Boddeke, Erik

Article Type: Research Article

Abstract: Tauopathies include a variety of neurodegenerative diseases associated with the pathological aggregation of hyperphosphorylated tau, resulting in progressive cognitive decline and motor impairment. The underlying mechanism for motor deficits related to tauopathy is not yet fully understood. Here, we use a novel transgenic tau mouse line, Tau 58/4, with enhanced neuron-specific expression of P301S mutant tau to investigate the motor abnormalities in association with the peripheral nervous system. Using stationary beam, gait, and rotarod tests, motor deficits were found in Tau 58/4 mice already 3 months after birth, which deteriorated during aging. Hyperphosphorylated tau was detected in the cell bodies …and axons of motor neurons. At the age of 9 and 12 months, significant denervation of the neuromuscular junction in the extensor digitorum longus muscle was observed in Tau 58/4 mice, compared to wild-type mice. Muscle hypotrophy was observed in Tau 58/4 mice at 9 and 12 months. Using electron microscopy, we observed ultrastructural changes in the sciatic nerve of 12-month-old Tau 58/4 mice indicative of the loss of large axonal fibers and hypomyelination (assessed by g-ratio). We conclude that the accumulated hyperphosphorylated tau in the axon terminals may induce dying-back axonal degeneration, myelin abnormalities, neuromuscular junction denervation, and muscular atrophy, which may be the mechanisms responsible for the deterioration of the motor function in Tau 58/4 mice. Tau 58/4 mice represent an interesting neuromuscular degeneration model, and the pathological mechanisms might be responsible for motor signs observed in some human tauopathies. Show more

Keywords: Alzheimer’s disease, axonal degeneration, motor dysfunction, neuromuscular junction denervation, tauopathy

DOI: 10.3233/JAD-161206

Citation: Journal of Alzheimer's Disease, vol. 60, no. s1, pp. S41-S57, 2017

Authors: Lakey-Beitia, Johant | González, Yisett | Doens, Deborah | Stephens, David E. | Santamaría, Ricardo | Murillo, Enrique | Gutiérrez, Marcelino | Fernández, Patricia L. | Rao, K.S. | Larionov, Oleg V. | Durant-Archibold, Armando A.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disorder affecting the elderly population worldwide. Brain inflammation plays a key role in the progression of AD. Deposition of senile plaques in the brain stimulates an inflammatory response with the overexpression of pro-inflammatory mediators, such as the neuroinflammatory cytokine. interleukin-6. Curcumin has been revealed to be a potential agent for treating AD following different neuroprotective mechanisms, such as inhibition of aggregation and decrease in brain inflammation. We synthesized new curcumin derivatives with the aim of providing good anti-aggregation capacity but also improved anti-inflammatory activity. Nine curcumin derivatives were synthesized by etherification and …esterification of the aromatic region. From these derivatives, compound 8 exhibited an anti-inflammatory effect similar to curcumin, while compounds 3 , 4 , and 10 were more potent. Moreover, when the anti-aggregation activity is considered, compounds 3 , 4 , 5 , 6 , and 10 showed biological activity in vitro . Compound 4 exhibited a strong anti-aggregation effect higher than curcumin. Monofunctionalized curcumin derivatives showed better bioactivity than difunctionalized compounds. Moreover, the presence of bulky groups in the chemical structure of curcumin derivatives decreased bioactivity. Show more

Keywords: Aβ aggregation, anti-inflammatory activity, Alzheimer’s disease, brain inflammation, curcumin, curcumin derivatives, IL-6, synthesis

DOI: 10.3233/JAD-170071

Citation: Journal of Alzheimer's Disease, vol. 60, no. s1, pp. S59-S68, 2017

Authors: Srinivas Bharath, M.M.

Article Type: Review Article

Abstract: Mitochondrial complex I (NADH: ubiquinone oxidoreductase; CI) is central to the electron transport chain (ETC), oxidative phosphorylation, and ATP production in eukaryotes. CI is a multi-subunit complex with a complicated yet organized structure that optimally connects electron transfer with proton translocation and forms higher-order supercomplexes with other ETC complexes. Efforts to understand the molecular genetics, expression profile of subunits, and structure-function relationship of CI have increased over the years due to the direct role of the complex in human diseases. Although mutations in the nuclear and mitochondrial genes of CI and altered expression of subunits could potentially lower CI activity …leading to mitochondrial dysfunction in many diseases, oxidative post-translational modifications (PTMs) have emerged as an important mechanism contributing to altered CI activity. These mainly include reversible and irreversible cysteine modifications, tyrosine nitration, carbonylation, and tryptophan oxidation that are generated following exposure to reactive oxygen species/reactive nitrogen species. Interestingly, oxidative PTMs could contribute either to CI damage, mitochondrial dysfunction, and ensuing cell death or a response mechanism with potential cytoprotective effects. This has also emerged as a promising field for structural biologists since analysis of PTMs could assist in understanding the structure-function relationship of the complex and correlate electron transfer mechanism with energy production. However, analysis of PTMs of CI and their contribution to CI function are incomplete in many physiological and pathological conditions. This review aims to highlight the role of oxidative PTMs in modulating CI activity with implications toward pathobiology of CNS diseases and novel therapeutics. Show more

Keywords: Carbonylation, cysteine, nitration, nitrosation, oxidative stress, protein oxidation, thiols

DOI: 10.3233/JAD-170117

Citation: Journal of Alzheimer's Disease, vol. 60, no. s1, pp. S69-S86, 2017

Authors: Stradecki-Cohan, Holly M. | Cohan, Charles H. | Raval, Ami P. | Dave, Kunjan R. | Reginensi, Diego | Gittens, Rolando A. | Youbi, Mehdi | Perez-Pinzon, Miguel A.

Article Type: Review Article

Abstract: Cerebral ischemia affects millions of people worldwide and survivors suffer from long-term functional and cognitive deficits. While stroke and cardiac arrest are typically considered when discussing ischemic brain injuries, there is much evidence that smaller ischemic insults underlie neurodegenerative diseases, including Alzheimer’s disease. The “regenerative” capacity of the brain relies on several aspects of plasticity that are crucial for normal functioning; less affected brain areas may take over function previously performed by irreversibly damaged tissue. To harness the endogenous plasticity mechanisms of the brain to provide recovery of cognitive function, we must first understand how these mechanisms are altered after …damage, such as cerebral ischemia. In this review, we discuss the long-term cognitive changes that result after cerebral ischemia and how ischemia alters several plasticity processes. We conclude with a discussion of how current and prospective therapies may restore brain plasticity and allow for recovery of cognitive function, which may be applicable to several disorders that have a disruption of cognitive processing, including traumatic brain injury and Alzheimer’s disease. Show more

Keywords: Biocompatible materials, brain ischemia, cognition, heart arrest, neuronal plasticity, stem cells, stroke, synapse

DOI: 10.3233/JAD-170057

Citation: Journal of Alzheimer's Disease, vol. 60, no. s1, pp. S87-S105, 2017

Authors: Fielder, Edward | von Zglinicki, Thomas | Jurk, Diana

Article Type: Review Article

Abstract: Neurons are exposed to high levels of DNA damage from both physiological and pathological sources. Neurons are post-mitotic and their loss cannot be easily recovered from; to cope with DNA damage a complex pathway called the DNA damage response (DDR) has evolved. This recognizes the damage, and through kinases such as ataxia-telangiectasia mutated (ATM) recruits and activates downstream factors that mediate either apoptosis or survival. This choice between these opposing outcomes integrates many inputs primarily through a number of key cross-road proteins, including ATM, p53, and p21. Evidence of re-entry into the cell-cycle by neurons can be seen in aging …and diseases such as Alzheimer’s disease. This aberrant cell-cycle re-entry is lethal and can lead to the apoptotic death of the neuron. Many downstream factors of the DDR promote cell-cycle arrest in response to damage and appear to protect neurons from apoptotic death. However, neurons surviving with a persistently activated DDR show all the features known from cell senescence; including metabolic dysregulation, mitochondrial dysfunction, and the hyper-production of pro-oxidant, pro-inflammatory and matrix-remodeling factors. These cells, termed senescence-like neurons, can negatively influence the extracellular environment and may promote induction of the same phenotype in surrounding cells, as well as driving aging and age-related diseases. Recently developed interventions targeting the DDR and/or the senescent phenotype in a range of non-neuronal tissues are being reviewed as they might become of therapeutic interest in neurodegenerative diseases. Show more

Keywords: Aging, apoptosis, cell senescence, DNA damage response, neurodegeneration

DOI: 10.3233/JAD-161221

Citation: Journal of Alzheimer's Disease, vol. 60, no. s1, pp. S107-S131, 2017

Authors: Vasquez, Velmarini | Mitra, Joy | Hegde, Pavana M. | Pandey, Arvind | Sengupta, Shiladitya | Mitra, Sankar | Rao, K.S. | Hegde, Muralidhar L.

Article Type: Research Article

Abstract: Alpha-synuclein (α-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson’s disease (PD). The neurotoxicity of α-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species in PD brain. Although α-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear α-Syn is unclear. Following up on our earlier report that α-Syn directly binds DNA in vitro , here we confirm the nuclear localization and chromatin association of α-Syn in neurons using proximity ligation and chromatin immunoprecipitation …analysis. Moderate (∼2-fold) increase in α-Syn expression in neural lineage progenitor cells (NPC) derived from induced pluripotent human stem cells (iPSCs) or differentiated SHSY-5Y cells caused DNA strand breaks in the nuclear genome, which was further enhanced synergistically by Fe salts. Furthermore, α-Syn required nuclear localization for inducing genome damage as revealed by the effect of nucleus versus cytosol-specific mutants. Enhanced DNA damage by oxidized and misfolded/oligomeric α-Syn suggests that DNA nicking activity is mediated by the chemical nuclease activity of an oxidized peptide segment in the misfolded α-Syn. Consistent with this finding, a marked increase in Fe-dependent DNA breaks was observed in NPCs from a PD patient-derived iPSC line harboring triplication of the SNCA gene. Finally, α-Syn combined with Fe significantly promoted neuronal cell death. Together, these findings provide a novel molecular insight into the direct role of α-Syn in inducing neuronal genome damage, which could possibly contribute to neurodegeneration in PD. Show more

Keywords: Alpha-synuclein, iPSC-derived neural progenitor cells, iron, neurodegeneration, Parkinson’s disease

DOI: 10.3233/JAD-170342

Citation: Journal of Alzheimer's Disease, vol. 60, no. s1, pp. S133-S150, 2017

Authors: Law, Betty Yuen Kwan | Wu, An Guo | Wang, Min Jun | Zhu, Yi Zhun

Article Type: Review Article

Abstract: With the increase in the proportion of aged population due to the rapid increase of life expectancy, the worldwide prevalence rate of multiple neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease has been increased dramatically. The demographic trend toward an older population has drawn the attention to new drug discovery and treatment on age-related diseases. Although a panel of drugs and/or therapies are currently available for treating the neurodegenerative diseases, side effects or insufficient drug efficacy have been reported. With the long history in prescription of Chinese medicine or natural compounds for modulating aged-related diseases, emerging evidence was …reported to support the pharmacological role of Chinese medicine in ameliorating the symptoms, or interfering with the pathogenesis of several neurodegenerative diseases. This review brings evidence about today’s trends and development of a list of potential neuroprotective herbal compounds from both the traditional and modern pharmacological point of view. With future projections, the potential hope and implication of using Chinese medicine as an alternative source for novel drug discovery for neurodegenerative diseases is proposed. Show more

Keywords: Aging, α-synuclein, Alzheimer’s disease, amyloid-β, autophagy, Chinese medicine, disease proteins, leonurine, neurodegenerative diseases, Parkinson’s disease

DOI: 10.3233/JAD-170374

Citation: Journal of Alzheimer's Disease, vol. 60, no. s1, pp. S151-S160, 2017