Current Alzheimer Research (v.10, #6)
Editorial (Hot Topic: Neurodegeneration: The First IBRO-Middle East Neuroscience Conference) by Abdu Adem, Omar El Agnaf, Marwan N. Sabbagh (557-558).
The Role of -Synuclein in Neurodegenerative Diseases: From Molecular Pathways in Disease to Therapeutic Approaches by Karima M. Al-Mansoori, Mohamed Y. Hasan, Abdulmonem Al-Hayani, Omar M.A. El-Agnaf (559-568).
Parkinson disease (PD) is the second most prevalent neurodegenerative disorder after Alzheimer?s disease(AD). The formation of the cytoplasmic inclusions named ?Lewy bodies? in the brain, considered to be a marker for neuronaldegeneration in PD and dementia with Lewy bodies. However, Lewy bodies (LBs) are also observed in approximately60 percent of both sporadic and familial cases with AD. LBs consist of fibrils mainly formed by post-translationalmodified α -synuclein (α -syn) protein. The modifications can be truncation, phosphorylation, nitration and mono-, di-, ortri-ubiquitination. Development of disease seems to be linked to events that increase the concentration of α-syn or causeits chemical modification, either of which can accelerate α -syn aggregation. Examples of such events include increasedcopy number of genes, decreased rate of degradation via the proteasome or other proteases, or modified forms of α-syn.As the aggregation of α -syn in the brain has been strongly implicated as a critical step in the development of several neurodegenerativediseases, the current search for disease-modifying drugs is focused on modification of the process of α -syndeposition in the brain. Recently researchers have screened and designed various molecules that are selectively focused oninhibiting or preventing α -syn aggregation and toxicity. Another strategy that has emerged is to target α -syn expression asa potential therapy for neurodegenerative diseases associated with LBs.
Neuropathological Correlates of Cerebral Multimorbidity by Johannes Attems, Kurt Jellinger (569-577).
Age associated neurodegenerative diseases are characterized by intra- and extracellular aggregation and depositionof misfolded proteins. The neuropathological classification of neurodegenerative diseases is based on the semiquantitativeassessment of these misfolded proteins, that constitute the neuropathological hallmark lesion for the respectivedisease: e.g. Alzheimer's disease (AD), amyloid-β (Aβ) hyperphosphorylated tau (tau); Lewy body diseases, α-synuclein (α-syn); frontotemporal lobar degeneration, tau, TDP-43, ubiquitin or FUS. In addition, cerebovascular lesionsare assessed for the diagnosis of vascular dementia. However, in brains of elderly patients suffering from neurodegenerativediseases multiple pathologies are usually present and even in clinically characterized prospective cohorts additionalpathologies are frequently found at post mortem examination. On the other hand, various amounts of AD pathology arefrequently seen in brains of non-demented elderly and the threshold to cause clinical overt dementia is ill defined as additionalco-morbidities (e.g., cerebrovascular lesions) might lower the threshold for clinical dementia in some cases. It becomesincreasingly clear that the clinical picture of dementia in most aged patients results from a multimorbid condition inthe CNS rather than from one single disease and data from animal studies suggest that Aβ, tau, and α-syn interact in vivoto promote the aggregation and accumulation of each other. We suggest that clinico-pathologocal correlative studies usinga more quantitative approach in the assessment of neuropathological lesions are warranted to elucidate cerebral multimorbidityand to identify suitable targets for targeted therapeutic strategies against age associated neurodegeneration.
Transcranial Magnetic Stimulation of Degenerating Brain: A Comparison of Normal Aging, Alzheimer?s, Parkinson?s and Huntington's Disease by M. R. Ljubisavljevic, F. Y. Ismail, S. Filipovic (578-596).
Although the brain?s ability to change constantly in response to external and internal inputs is now well recognizedthe mechanisms behind it in normal aging and neurodegeneration are less well understood. To gain a better understanding,transcranial magnetic stimulation (TMS) has been used extensively to characterize non-invasively the corticalneurophysiology of the aging and degenerating brain. Furthermore, there has been a surge of studies examining whetherrepetitive TMS (rTMS) can be used to improve functional deficits in various conditions including normal aging, Alzheimer?sand Parkinson?s disease. The results of these studies in normal aging and neurodegeneration have emerged reasonablycoherent in delineating the main pathology in spite of considerable technical limitations, omnipresent methodologicalvariability, and extraordinary patient heterogeneity. Nevertheless, comparing and integrating what is known aboutTMS measurements of cortical excitability and plasticity in disorders that predominantly affect cortical brain structureswith disorders that predominantly affect subcortical brain structures may provide better understanding of normal and abnormalbrain aging fostering new. The present review provides a TMS perspective of changes in cortical neurophysiologyand neurochemistry in normal aging and neurodegeneration by integrating what is revealed in individual TMS measurementsof cortical excitability and plasticity in physiological aging, Alzheimer?s, Parkinson?s, and Huntington?s, disease.The paper also reflects on current developments in utilizing TMS as a physiologic biomarker to discriminate physiologicaging from neurodegeneration and its potential as a method of therapeutic intervention.
Cell Clocks and Neuronal Networks: Neuron Ticking and Synchronization in Aging and Aging-Related Neurodegenerative Disease by Marta Bonaconsa, Valeria Colavito, Fabien Pifferi, Fabienne Aujard, Esther Schenker, Sophie Dix, Gigliola Grassi-Zucconi, Marina Bentivoglio, Giuseppe Bertini (597-608).
Body function rhythmicity has a key function for the regulation of internal timing and adaptation to the environment.A wealth of recent data has implicated endogenous biological rhythm generation and regulation in susceptibilityto disease, longevity, cognitive performance. Concerning brain diseases, it has been established that many molecularpathways implicated in neurodegeneration are under circadian regulation. At the molecular level, this regulation relies onclock genes forming interconnected, self-sustained transcriptional/translational feedback loops. Cells of the master circadianpacemaker, the hypothalamic suprachiasmatic nucleus, are endowed with this molecular clockwork. Brain cells inmany other regions, including those which play a key role in learning and memory, as well as peripheral cells show a circadianoscillatory behavior regulated by the same molecular clockwork. We here address the question as to whether intracellularclockwork signaling and/or the intercellular dialogue between ?brain clocks? are disrupted in aging-dependentneurodegenerative diseases, such as Parkinson?s disease and Alzheimer?s disease. The potential implications of clockgenes in cognitive functions in normal conditions, clinical disturbances of circadian rhythms, and especially the sleepwakecycle, in aging-dependent neurodegenerative diseases and data in animal models are reviewed. The currently limitedknowledge in this field is discussed in the context of the more extensive body of data available on cell clocks and molecularclockwork during normal aging. Hypotheses on implications of the synchronization between brain oscillators in informationprocessing in neural networks lay ground for future studies on brain health and disease.
Alzheimer Disease and Diabetes Mellitus: Do They have Anything in Common? by Ernest Adeghate, Tibor Donath, Abdu Adem (609-617).
The prevalence of diabetes mellitus (DM) continues to increase because of sedentary life style and inappropriatediet. DM is one of the most common metabolic diseases, affecting more than 240 million people worldwide. It is projectedthat the number of people with DM will continue to increase in the next decade. Alzheimer disease (AD) is themost common cause of dementia, and affects over 24 million people globally, mostly senior citizens. The worldwideprevalence of AD is estimated to double in the next 20 years.How are these two chronic and debilitating diseases similar? Do they have common denominators? AD is similar to DMin many ways, in that both are associated with defective insulin release and/or signalling, impaired glucose uptake, amyloidosis,increased oxidative stress, stimulation of the apoptotic pathway, angiopathy, abnormal lipid peroxidation, ageing(in type 2 DM), brain atrophy, increased formation of advanced glycation end products and tau phosphorylation, impairedlipid metabolism and mitochondrial pathology. The pathogenesis of both AD and DM has genetic as well as environmentalcomponents. Both can also cause impaired cognition and dementia. All of these common denominators indicatethat AD and DM share a lot of factors in terms of pathophysiology, histopathology and clinical outcome. These similaritiescan be used in the search for and design of effective pharmacotherapy for AD, since potent therapeutic agents such asinsulin, incretins, oral hypoglycaemic agents and antioxidants used in the management of DM may play a key role in thetreatment of patients with AD.
On the Interaction of β-Amyloid Peptides and α7-Nicotinic Acetylcholine Receptors in Alzheimer?s Disease by Murat Oz, Dietrich E. Lorke, Keun-Hang S. Yang, Georg Petroianu (618-630).
Deterioration of the cortical cholinergic system is a leading neurochemical feature of Alzheimer?s Disease(AD). This review summarizes evidence that the homomeric α7- nicotinic acetylcholine receptor (nAChR) plays a crucialrole in the pathogenesis of this disease, which is characterized by amyloid-β (Aβ) accumulations and neurofibrillary tanglesoriginating from of hyperphosphorylated tau protein. Aβ binds to α7-nAChRs with a high affinity, either activatingor inhibiting this receptor in a concentration-dependent manner. There is strong evidence that α7-nAChRs are neuroprotective,reducing Aβ-induced toxicity; but co-localization of α7- nAChRs, Aβ and amyloid plaques also points to neurodegenerativeactions. Aβ induces tau phosphorylation via α7-nAChR activation. Aβ influences hippocampus-dependentmemory and long-term potentiation in a dose-dependent way: there is evidence that enhancement by picomolar Aβ concentrationsis mediated by α7-nAChRs, whereas inhibition by nanomolar concentrations is independent of nAChRs andprobably mediated by small Aβ42 oligomers. α7-nAChRs located on vascular smooth muscle cells and astrocytes are alsoinvolved in the pathogenesis of AD. Although these data strongly point to an important role of α7-nAChRs in the developmentof AD, dose-dependence of the effects, rapid desensitization of the receptor and dependence of the effects on Aβaggregation (monomers, oligomers, fibrils) make it difficult to develop simple therapeutic strategies acting upon this receptor.
Dynamics of Nicotinic Acetylcholine Receptors and Receptor-Associated Proteins at the Vertebrate Neuromuscular Junction by Marcelo Pires-Oliveira, Derek Moen, Mohammed Akaaboune (631-641).
The mature neuromuscular junction (NMJ) is the best characterized cholinergic synapse. The maintenance of ahigh number and density of nicotinic acetylcholine receptors (nAChRs) at the postsynaptic membrane adjacent to thenerve terminal are crucial for NMJ function. This density is maintained by several factors, ranging from synaptic activityto postsynaptic scaffold proteins. Decreases in postsynaptic nAChR density are related to myasthenic syndromes in theperipheral NMJ, but are also associated in central synapses with neurodegenerative diseases such as Alzheimer?s. In thisreview, we focus particularly on our increasing knowledge about the molecular dynamics of nAChR at the peripheral cholinergicNMJ and their regulation by the postsynaptic proteins of the dystrophin glycoprotein complex (DGC).
Vascular Risk Factors and Neurodegeneration in Ageing Related Dementias: Alzheimer?s Disease and Vascular Dementia by Rufus O. Akinyemi, Elizabeta B. Mukaetova-Ladinska, Johannes Attems, Masafumi Ihara, Raj N. Kalaria (642-653).
Age is the strongest risk factor for brain degeneration whether it results from vascular or neurodegenerativemechanisms or both. To evaluate the current views on the impact of vascular disease on the most common causes of dementia,most relevant articles to the selected subject headings were reviewed until November 2011 from the popularlyused databases including Pubmed, Cochrane Database and Biological Abstracts. Within the past decade, there has beenfour-fold increased interest in the vascular basis of neurodegeneration and dementia. Vascular ageing involving arterialstiffness, endothelial changes and blood-brain barrier dysfunction affects neuronal survival by impairing several intracellularprotective mechanisms leading to chronic hypoperfusion. Modifiable risk factors such as hypertension, diabetes,dyslipidaemia and adiposity linked to Alzheimer?s disease and vascular dementia promote the degeneration and reduce theregenerative capacity of the vascular system. These in tandem with accumulation of abnormal proteins such as amyloid β likely disrupt cerebral autoregulation, neurovascular coupling and perfusion of the deeper structures to variable degrees toproduce white matter changes and selective brain atrophy. Brain pathological changes may be further modified by geneticfactors such as the apoliopoprotein E ε4 allele. Lifestyle measures that maintain or improve vascular health including consumptionof healthy diets, moderate use of alcohol and implementing regular physical exercise in general appear effectivefor reducing dementia risk. Interventions that improve vascular function are important to sustain cognitive status even duringageing whereas preventative measures that reduce risk of vascular disease are predicted to lessen the burden of dementiain the long-term.
Increased Alzheimer?s Disease Neuropathology is Associated with Type 2 Diabetes and ApoE ε4 Carrier Status by Michael Malek-Ahmadi, Thomas Beach, Aleksandra Obradov, Lucia Sue, Christine Belden, Kathryn Davis, Douglas G. Walker, LihFen Lue, Abdu Adem, Marwan N. Sabbagh (654-659).
Background: Past studies investigating the association between Alzheimer?s disease (AD) pathology and diabetesmellitus type 2 (DM2) have provided conflicting results. While several studies indicate that subjects with comorbidAD and DM2 have less AD pathology, others have found no significant differences in AD pathology between the twogroups. Other studies have indicated that individuals with AD and DM2 have significantly greater neuropathology thanAD individuals who do not have DM2. Additional research has demonstrated that ApoE ε 4 carriers with AD and DM2have significantly greater pathology than ApoE ε 4 non-carriers.Methods: Data on clinically and pathologically diagnosed Alzheimer?s disease cases (NINDS-ADRDA clinically and NIAReagan intermediate or high pathologically) with DM2 (n= 40) and those without DM2 (n= 322) from the Banner SunHealth Research Institute Brain and Body Donation Program were obtained for this study. Plaque and tangle scores fromthe frontal, parietal, temporal, entorhinal and hippocampal regions were compared between the DM2+ and DM2 ? groups.In addition, total plaque count, total tangle count, and Braak scores were also compared between groups. Similar analyseswere conducted to determine the effect of ApoE ε 4 carrier status on the neuropathological variables while also accountingfor and DM2 status.Results: The DM2+ and DM2 ? groups showed no significant differences on plaque and tangle pathology. Logistic regressionanalyses, which accounted for the effects of ApoE ε4 carrier status and age at death, found no association betweentotal plaque [OR 1.05 (0.87, 1.27), p = 0.60] or total tangle [OR 0.97 (0.89, 1.07) p = 0.58] counts and DM2 status.ApoE ε4 carrier status was not significantly associated with DM2 status [Χ2 = 0.30 (df = 1), p = 0.58]. Within the DM2+group, significantly greater plaque and tangle pathology was found for ApoE ε4 carriers in relation to DM2+ ApoE ε4non-carriers.Conclusion: Overall, the presence of DM2 does not affect plaque and tangle burden in a sample of clinically and pathologicallyconfirmed AD cases. Among AD individuals with DM2, those who are ApoE ε 4 carriers had significantly greaterneuropathology than those who do not carry an ApoE ε4 allele. Positive DM2 status appears to exacerbate ADneuropathology in the presence of ApoE ε 4.
Possible Protecting Role of TNF-α in Kainic Acid-induced Neurotoxicity Via Down-Regulation of NFκB Signaling Pathway by Xing-Mei Zhang, Xiang-Yu Zheng, S. S. Sharkawi, Yang Ruan, Naheed Amir, Sheikh Azimullah, M. Y. Hasan, Jie Zhu, Abdu Adem (660-669).
We have shown previously, that mice lacking tumor necrosis factor-α (TNF-α) receptor 1 (TNFR1) exhibitgreater hippocampal neurodegeneration, suggesting that TNFR1 may be protective in kainic acid (KA)-induced neurotoxicity.Here, we aim to clarify the role of TNF-α in neurodegenerative disorders and to elucidate its potential signalingpathways. TNF-α knockout (KO) mice and wild-type (WT) mice were treated with KA intranasally and, seizure severitymeasures obtained, Behavioral tests, including Elevated Plus-Maze?, open-field, Y-maze were also performed. Five daysfollowing KA treatment, immunohistochemical methods were used to assess neuronal degeneration and glial activation.The production of nitric oxide (NO) and the expression of nuclear factor kappaB (NF-κB) and AKT in the hippocampuswere also measured. Compared with WT mice, TNF-α KO mice were more susceptibile to KA-induced neurotoxicity, asdemonstrated by more severe seizures, measurable behavior changes, greater neuronal degeneration in hippocampus, elevatedglial activation and NO production. Additionally, KA-treatment up-regulated the expression of NFκB in TNF-α KOmice to a greater degree than in KA-treated WT mice. We conclude that TNF-α deficiency adversely influences KAinducedneurotoxicity and that TNF-α may play a protective role in KA-induced neurotoxicity via the down-regulation ofNFκB signaling pathway.