Journal of Alzheimer's Disease - Volume 62, issue 3

Authors: McGeer, Patrick L. | Guo, Jian Ping | Lee, Moonhee | Kennedy, Krista | McGeer, Edith G.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is characterized by deposits of amyloid-β protein (Aβ) in brain which become foci of inflammation. Neurons are destroyed by this inflammatory process, leading to the cognitive deficits which define AD clinical onset. Epidemiological studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) can ameliorate this destructive process if they are started well before clinical signs develop. Biomarker studies indicate that the disease process starts at least a decade before cognitive deficits appear. This pre-clinical onset explains the NSAID effect. It also opens a window of opportunity for preventive treatment that can be met with a simple diagnostic test. Salivary …levels of Aβ42 may fulfill that need. They can be measured by a simple ELISA test we have developed using commercially available reagents. By this ELISA test, normal controls, who are not at risk for AD, have levels of Aβ42 close to 20 pg/ml. AD cases, as well as high level controls, secrete levels in the range of 40–85 pg/ml. Widespread application of this test to detect high level controls, followed by NSAID consumption, could substantially reduce the prevalence of AD. Show more

Keywords: Aβ42, epidemiology, neuroinflammation, pre-clinical Alzheimer’s disease, saliva

DOI: 10.3233/JAD-170706

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1219-1222, 2018

Authors: Folch, Jaume | Busquets, Oriol | Ettcheto, Miren | Sánchez-López, Elena | Castro-Torres, Ruben Dario | Verdaguer, Ester | Garcia, Maria Luisa | Olloquequi, Jordi | Casadesús, Gemma | Beas-Zarate, Carlos | Pelegri, Carme | Vilaplana, Jordi | Auladell, Carme | Camins, Antoni

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the …excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered. Show more

Keywords: Alzheimer’s disease, amyloid β-protein, extrasynaptic N-Methyl-D-aspartate receptor, memantine, tau protein

DOI: 10.3233/JAD-170672

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1223-1240, 2018

Authors: Tamagno, Elena | Guglielmotto, Michela | Monteleone, Debora | Manassero, Giusi | Vasciaveo, Valeria | Tabaton, Massimo

Article Type: Review Article

Abstract: Amyloid-β (Aβ) has been proposed as a biomarker and a drug target for the therapy of Alzheimer’s disease (AD). The neurotoxic entity and relevance of each conformational form of Aβ to AD pathology is still under debate; Aβ oligomers are considered the major killer form of the peptide whereas monomers have been proposed to be involved in physiological process. Here we reviewed some different effects mediated by monomers and oligomers on mechanisms involved in AD pathogenesis such as autophagy and tau aggregation. Data reported in this review demonstrate that Aβ monomers could have a major role in sustaining the pathogenesis …of AD and that AD therapy should be focused not only in the removal of oligomers but also of monomers. Show more

Keywords: Alzheimer’s disease, Aβ monomers, Aβ oligomers, autophagy, tau protein

DOI: 10.3233/JAD-170581

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1241-1245, 2018

Authors: Di Fede, Giuseppe | Giaccone, Giorgio | Salmona, Mario | Tagliavini, Fabrizio

Article Type: Review Article

Abstract: Translational neuroscience integrates the knowledge derived by basic neuroscience with the development of new diagnostic and therapeutic tools that may be applied to clinical practice in neurological diseases. This information can be used to improve clinical trial designs and outcomes that will accelerate drug development, and to discover novel biomarkers which can be efficiently employed to early recognize neurological disorders and provide information regarding the effects of drugs on the underlying disease biology. Alzheimer’s disease (AD) and prion disease are two classes of neurodegenerative disorders characterized by incomplete knowledge of the molecular mechanisms underlying their occurrence and the lack of …valid biomarkers and effective treatments. For these reasons, the design of therapies that prevent or delay the onset, slow the progression, or improve the symptoms associated to these disorders is urgently needed. During the last few decades, translational research provided a framework for advancing development of new diagnostic devices and promising disease-modifying therapies for patients with prion encephalopathies and AD. In this review, we provide present evidence of how supportive can be the translational approach to the study of dementias and show some results of our preclinical studies which have been translated to the clinical application following the ‘bed-to-bench-and-back’ research model. Show more

Keywords: Alzheimer’s disease, amyloid, APP A673V, Creutzfeldt-Jakob disease, dementia, doxycycline, Gerstmann-Sträussler-Scheinker disease, prion, prion protein, recessive mutation

DOI: 10.3233/JAD-170770

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1247-1259, 2018

Authors: Forloni, Gianluigi | Balducci, Claudia

Article Type: Review Article

Abstract: The production of soluble amyloid-β oligomers (AβOs) and the activation of inflammation are two important early steps in the pathogenesis of Alzheimer’s disease (AD). The central role of oligomers as responsible for the neuronal dysfunction associated with the clinical features has been extended to the other protein misfolding disorders definable, on this basis, as oligomeropathies. In AD, recent evidence indicates that the mechanism of inflammation as a consequence of neurodegeneration must be assessed in favor of a more direct role of glial activation in the alteration of synaptic function. Our own experimental models demonstrate the efficacy of anti-inflammatory treatments in …preventing the cognitive deficits induced acutely by AβOs applied directly in the brain. Moreover, some promising clinical tools are based on immunological activation reducing the presence of cerebral Aβ deposits. However, the strategies based on the control of inflammatory factors as well as the amyloid aggregation show poor or non-therapeutic efficacy. Numerous studies have examined inflammatory factors in biological fluids as possible markers of the neuroinflammation in AD. In some cases, altered levels of cytokines or other inflammatory markers in cerebrospinal fluid correlate with the severity of the disease. Here we propose, according to the precision medicine principles, innovative therapeutic approaches to AD based on the patient’s inflammatory profile/state. The earlier intervention and a multifactor approach are two other elements considered essential to improve the chances of effective therapy in AD. Show more

Keywords: Alzheimer’s disease therapy, amyloid, anti-inflammatory drugs, glial cells, immune system, oligomeropathy, precision medicine, toll-like receptors

DOI: 10.3233/JAD-170819

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1261-1276, 2018

Authors: Avila, Jesús

Article Type: Review Article

Abstract: Tau protein, which was discovered in Prof. Kirschner’s laboratory in 1975, has been the focus of my research over the last 40 years. In this issue of the Journal of Alzheimer ’s Disease commemorating its 20th year of publication, I will provide a short review of some of the features of my relationship with tau.

Keywords: Alzheimer’s disease, microtubules, neurons, tau

DOI: 10.3233/JAD-170600

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1277-1285, 2018

Authors: Wischik, Claude M. | Schelter, Björn O. | Wischik, Damon J. | Storey, John M. D. | Harrington, Charles R.

Article Type: Review Article

Abstract: Following our discovery of a fragment from the repeat domain of tau protein as a structural constituent of the PHF-core in Alzheimer’s disease (AD), we developed an assay that captured several key features of the aggregation process. Tau-tau binding through the core tau fragment could be blocked by the same diaminophenothiazines found to dissolve proteolytically stable PHFs isolated from AD brain. We found that the PHF-core tau fragment is inherently capable of auto-catalytic self-propagation in vitro , or “prion-like processing”, that has now been demonstrated for several neurodegenerative disorders. Here we review the findings that led to the first clinical …trials to test tau aggregation inhibitor therapy in AD as a way to block this cascade. Although further trials are still needed, the results to date suggest that a treatment targeting the prion-like processing of tau protein may have a role in both prevention and treatment of AD. Show more

Keywords: Alzheimer’s disease, clinical trials, paired helical filaments, prion-like processing, protein aggregation inhibitors, tau protein

DOI: 10.3233/JAD-170727

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1287-1303, 2018

Authors: Yang, Ying | Wang, Jian-Zhi

Article Type: Review Article

Abstract: Neurodegeneration is defined as the progressive loss of structure or function of the neurons. As the nature of degenerative cell loss is currently not clear, there is no specific molecular marker to measure neurodegeneration. Therefore, researchers have been using apoptotic markers to measure neurodegeneration. However, neurodegeneration is completely different from apoptosis by morphology and time course. Lacking specific molecular marker has been the major hindrance in research of neurodegenerative disorders. Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and tau accumulation forming neurofibrillary tangles is a hallmark pathology in the AD brains, suggesting that tau must play a critical …role in AD neurodegeneration. Here we review part of our published papers on tau-related studies, and share our thoughts on the nature of tau-associated neurodegeneration in AD. Show more

Keywords: Alzheimer’s disease, apoptosis, neurodegenerasis, neurodegeneration, tau

DOI: 10.3233/JAD-170788

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1305-1317, 2018

Authors: Mecocci, Patrizia | Boccardi, Virginia | Cecchetti, Roberta | Bastiani, Patrizia | Scamosci, Michela | Ruggiero, Carmelinda | Baroni, Marta

Article Type: Review Article

Abstract: The Editors of the Journal of Alzheimer ’s Disease invited Professor Patrizia Mecocci to contribute a review article focused on the importance and implications of her research on aging, brain aging, and senile dementias over the last years. This invitation was based on an assessment that she was one of the journal’s top authors and a strong supporter of the concept that oxidative stress is a major contributor to several alterations observed in age-related conditions (sarcopenia, osteoporosis) and, more significantly, in brain aging suggesting a pivotal role in the pathogenesis and progression of one of the most dramatic age-related …diseases, Alzheimer’s disease (AD). Her first pioneering research was on the discovery of high level of 8-hydroxy-2’-deoxyguanosine (OH8dG), a marker of oxidation in nucleic acids, in mitochondrial DNA isolated from cerebral cortex. This molecule increases progressively with aging and more in AD brain, supporting the hypothesis that oxidative stress, a condition of unbalance between the production of reactive oxygen species and antioxidants, gives a strong contribution to the high incidence of AD in old age subjects. OH8dG also increases in peripheral lymphocyte from AD subjects, suggesting that AD is not only a cerebral but also a systemic disease. The role of antioxidants, particularly vitamin E and zinc, were also studied in longevity and in cognitive decline and dementia. This review shows the main findings from Mecocci’s laboratory related to oxidative stress in aging, brain aging, and AD and discusses the importance and implications of some of the major achievements in this field of research. Show more

Keywords: Aging, Alzheimer’s disease, antioxidant, brain aging, dementia, mitochondria, oxidative stress, vitamin E

DOI: 10.3233/JAD-170732

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1319-1335, 2018

Authors: Di Meco, Antonio | Li, Jian-Guo | Praticò, Domenico

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) affects over 40 million patients around the world and poses a huge economic burden on society since no effective therapy is available yet. While the cause(s) for the most common sporadic form of the disease are still obscure, lifestyle and different environmental factors have emerged as modulators of AD susceptibility. Hyperhomocysteinemia (HHCY), a condition of high circulating levels of homocysteine, is an independent but modifiable risk factor for AD. Studies in AD mouse models have linked HHCY with memory impairment, amyloidosis, tau pathology, synaptic dysfunction, and neuroinflammation. However, the exact mechanism by which HHCY affects AD pathogenesis …is unclear. The 5-lipoxygenase (5LO) is a protein upregulated in postmortem AD brains and plays a functional role in AD pathogenesis. Recently, in vitro and in vivo studies showed that HHCY effects on amyloid-β and tau pathology, synapse and memory impairments are dependent on the activation of the 5LO enzymatic pathway, since its genetic absence or pharmacological inhibition prevents them. HHCY induces 5LO gene upregulation by lowering the methylation of its promoter, which results in increased translation and transcription of its mRNA. Based on these findings, we propose that epigenetic modification of 5LO represents the missing biological link between HHCY and AD pathogenesis, and for this reason it represents a viable therapeutic target to prevent AD development in individuals bearing this risk factor. Show more

Keywords: Alzheimer’s disease, amyloid-β, five-lipoxygenase, homocysteine, synapse, tau protein

DOI: 10.3233/JAD-170700

Citation: Journal of Alzheimer's Disease, vol. 62, no. 3, pp. 1337-1344, 2018