Journal of Alzheimer's Disease - Volume 53, issue 3

Authors: Arendash, Gary W.

Article Type: Review Article

Abstract: We have demonstrated in multiple studies that daily, long-term electromagnetic field (EMF) treatment in the ultra-high frequency range not only protects Alzheimer’s disease (AD) transgenic mice from cognitive impairment, but also reverses such impairment in aged AD mice. Moreover, these beneficial cognitive effects appear to be through direct actions on the AD process. Based on a large array of pre-clinical data, we have initiated a pilot clinical trial to determine the safety and efficacy of EMF treatment to mild-moderate AD subjects. Since it is important to establish the safety of this new neuromodulatory approach, the main purpose of this review …is to provide a comprehensive assessment of evidence supporting the safety of EMFs, particularly through transcranial electromagnetic treatment (TEMT). In addition to our own pre-clinical studies, a rich variety of both animal and cell culture studies performed by others have underscored the anticipated safety of TEMT in clinical AD trials. Moreover, numerous clinical studies have determined that short- or long-term human exposure to EMFs similar to those to be provided clinically by TEMT do not have deleterious effects on general health, cognitive function, or a variety of physiologic measures—to the contrary, beneficial effects on brain function/activity have been reported. Importantly, such EMF exposure has not been shown to increase the risk of any type of cancer in human epidemiologic studies, as well as animal and cell culture studies. In view of all the above, clinical trials of safety/efficacy with TEMT to AD subjects are clearly warranted and now in progress. Show more

Keywords: Aβ oligomers, Alzheimer’s disease, cognition, electromagnetic treatment, memory, transcranial

DOI: 10.3233/JAD-160165

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 753-771, 2016

Authors: Allué, José Antonio | Sarasa, Leticia | Izco, María | Pérez-Grijalba, Virginia | Fandos, Noelia | Pascual-Lucas, María | Ogueta, Samuel | Pesini, Pedro | Sarasa, Manuel

Article Type: Research Article

Abstract: APPswe/PS1dE9 and Tg2576 are very common transgenic mouse models of Alzheimer’s disease (AD), used in many laboratories as tools to research the mechanistic process leading to the disease. In order to augment our knowledge about the amyloid-β (Aβ) isoforms present in both transgenic mouse models, we have developed two chromatographic methods, one acidic and the other basic, for the characterization of the Aβ species produced in the brains of the two transgenic mouse models. After immunoprecipitation and micro-liquid chromatography-electrospray ionization mass spectrometry/mass spectrometry, 10 species of Aβ, surprisingly all of human origin, were detected in the brain of Tg2576 mouse, …whereas 39 species, of both murine and human origin, were detected in the brain of the APP/PS1 mouse. To the best of our knowledge, this is the first study showing the identification of such a high number of Aβ species in the brain of the APP/PS1 transgenic mouse, whereas, in contrast, a much lower number of Aβ species were identified in the Tg2576 mouse. Therefore, this study brings to light a relevant phenotypic difference between these two popular mice models of AD. Show more

Keywords: Alzheimer’s disease, amyloid peptide, immunoprecipitation, MALDI-TOF/TOF, Micro-LC-ESI-Q-TOF, transgenic mouse models

DOI: 10.3233/JAD-160280

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 773-785, 2016

Authors: Pickett, Eleanor K. | Koffie, Robert M. | Wegmann, Susanne | Henstridge, Christopher M. | Herrmann, Abigail G. | Colom-Cadena, Marti | Lleo, Alberto | Kay, Kevin R. | Vaught, Melissa | Soberman, Roy | Walsh, Dominic M. | Hyman, Bradley T. | Spires-Jones, Tara L.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by memory loss, insidious cognitive decline, profound neurodegeneration, and the extracellular accumulation of amyloid-β (Aβ) peptide in senile plaques and intracellular accumulation of tau in neurofibrillary tangles. Loss and dysfunction of synapses are believed to underlie the devastating cognitive decline in AD. A large amount of evidence suggests that oligomeric forms of Aβ associated with senile plaques are toxic to synapses, but the precise sub-synaptic localization of Aβ and which forms are synaptotoxic remain unknown. Here, we characterize the sub-synaptic localization of Aβ oligomers using three high-resolution imaging techniques, stochastic optical reconstruction microscopy, immunogold electron …microscopy, and Förster resonance energy transfer in a plaque-bearing mouse model of AD. With all three techniques, we observe oligomeric Aβ inside synaptic terminals. Further, we tested a panel of Aβ antibodies using the relatively high-throughput array tomography technique to determine which forms are present in synapses. Our results show that different oligomeric Aβ species are present in synapses and highlight the potential of array tomography for rapid testing of aggregation state specific Aβ antibodies in brain tissue. Show more

Keywords: Alzheimer’s disease, amyloid-β, array tomography, synapses

DOI: 10.3233/JAD-160007

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 787-800, 2016

Authors: Dermody, Nadene | Wong, Stephanie | Ahmed, Rebekah | Piguet, Olivier | Hodges, John R. | Irish, Muireann

Article Type: Research Article

Abstract: Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer’s disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD …and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information. Show more

Keywords: Neurodegenerative diseases, orbitofrontal cortex, right hemisphere, social cognition, theory of mind

DOI: 10.3233/JAD-160175

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 801-816, 2016

Authors: Oboshi, Yumi | Kikuchi, Mitsuru | Terada, Tatsuhiro | Yoshikawa, Etsuji | Bunai, Tomoyasu | Ouchi, Yasuomi

Article Type: Research Article

Abstract: Background: Evidence shows that the cholinergic system plays an important role in regulating working memory and that working memory-related prefrontal activation decreases with age and neuronal degeneration, such as Alzheimer’s disease (AD). However, the relation between attention-related α 4β2 nicotinic cholinergic function and task-induced prefrontal activation especially time course-related activation remains to be explored. Objective: We aimed to elucidate the relationship between changes in task-induced oxy-hemoglobin concentration (cerebral blood flow, CBF) in the prefrontal cortex and the availability of α 4β2 nicotinic receptors in the brain of AD patients in light of their task performance. Methods: …Eleven mild-to-moderate AD patients and eleven normal elderly subjects underwent the near-infrared spectroscopy during easy and difficult working memory tasks for estimating prefrontal CBF changes and positron emission tomography with the α 4β2 tracer [18 F]2FA-85380 ([18 F]2FA) for measuring the α 4β2 nicotinic receptor binding. Results: Significant correlations between mean oxy-hemoglobin concentration in the channels with significant [group] main effects and prefrontal [18 F]2FA binding were observed during the early easy task period in the normal group and during the late difficult task in the AD group. In addition, those prefrontal CBF responses were significantly correlated with not correct performance but the execution time to spend. Conclusion: The α 4β2 nicotinic acetylcholine receptors in the prefrontal cortex play an important role in increasing prefrontal activation when attending to novel stimuli, irrespective of the accuracy of the outcome. A delay in the cholinergic-induced increase in prefrontal activation in AD patients might explain their delayed responses in the cognitive task. Show more

Keywords: Alzheimer’s disease, cerebral blood flow, nicotinic acetylcholine receptor, prefrontal cortex, working memory

DOI: 10.3233/JAD-151165

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 817-830, 2016

Authors: Campanari, Maria-Letizia | Navarrete, Francisco | Ginsberg, Stephen D. | Manzanares, Jorge | Sáez-Valero, Javier | García-Ayllón, María-Salud

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by a decrease in the enzymatic activity of the enzyme acetylcholinesterase (AChE). AChE is expressed as multiple splice variants, which may serve both cholinergic degradative functions and non-cholinergic functions unrelated with their capacity to hydrolyze acetylcholine. We have recently demonstrated that a prominent pool of enzymatically inactive AChE protein exists in the AD brain. In this study, we analyzed protein and transcript levels of individual AChE variants in human frontal cortex from AD patients by western blot analysis using specific anti-AChE antibodies and by quantitative real-time PCR (q RT-PCR). We found similar protein and mRNA …levels of the major cholinergic “tailed”-variant (AChE-T) and the anchoring subunit, proline-rich membrane anchor (PRiMA-1) in frontal cortex obtained from AD patients and non-demented controls. Interestingly, we found an increase in the protein and transcript levels of the non-cholinergic “readthrough” AChE (AChE-R) variants in AD patients compared to controls. Similar increases were detected by western blot using an antibody raised against the specific N-terminal domain, exclusive of alternative N-extended variants of AChE (N-AChE). In accordance with a subset of AChE-R monomers that display amphiphilic properties that are upregulated in the AD brain, we demonstrate that the increase of N-AChE species is due, at least in part, to N-AChE-R variants. In conclusion, we demonstrate selective alterations in specific AChE variants in AD cortex, with no correlation in enzymatic activity. Therefore, differential expression of AChE variants in AD may reflect changes in the pathophysiological role of AChE, independent of cholinergic impairment or its role in degrading acetylcholine. Show more

Keywords: Acetylcholinesterase, AChE splice variants, Alzheimer’s disease, human brain, readthrough AChE variants

DOI: 10.3233/JAD-160220

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 831-841, 2016

Authors: Zhou, Xiao | Huang, Jianou | Pan, Suyue | Xu, Miaojing | He, Rongni | Ji, Zhong | Hu, Yafang

Article Type: Research Article

Abstract: Background: The transgenic mice models overexpressing human p25 contribute greatly to the in vivo neurotoxic mechanism of p25 in neurodegenerative diseases. However, it is time-consuming to manipulate existing transgenic mice models. Objective: Here we aim to establish a novel mouse model of neurodegeneration by overexpressing p25 mediated by recombinant adeno-associated virus serotype 9 (rAAV9). Methods: AAV9-GFP-p25 encoding GFP-fused p25 driven by synapsin promoter, and the control, AAV9-GFP, were delivered in mice by tail-vein injection. Assessments of p25 expression, neurodegenerative pathology, and behavioral changes were performed. Results: GFP expression was detected by in …vivo imaging as early as one week after virus injection. Notably, widespread expression of p25 was obviously found in cortex, hippocampus, and cerebellum in AAV9-GFP-p25 mice. Moreover, decreased hippocampus volumes in AAV9-GFP-p25 mice were detected by 7T MRI examination about one month after injection. Further, these AAV9-GFP-p25 mice exhibited progressive memory impairment from three-month to six-month after virus injection. At last, hyperphosphorylated tau, neurofibrillary tangles, activated astrocytes and microglia cells were elevated in these p25 mice at about six months after virus delivery. However, amyloid-β plaques, overt neuronal loss, and apoptosis in the hippocampus and cortex were not significantly induced by AAV9-mediated p25 overexpression. Conclusion: The AAV9-mediated p25 overexpression mouse model, which is a practical model exhibiting neurodegeneration-like pathological and behavioral changes, provides an easier and time-saving method to explore the functions of p25 in vivo , as well as an alternative tool for development of drugs against neurotoxic of p25. Show more

Keywords: Adeno-associated virus 9, Alzheimer’s disease, cyclin-dependent kinase 5, disease models, magnetic resonance imaging, p25, transgenic mice

DOI: 10.3233/JAD-160191

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 843-855, 2016

Authors: Eugenín, Jaime | Vecchiola, Andrea | Murgas, Paola | Arroyo, Pablo | Cornejo, Francisca | von Bernhardi, Rommy

Article Type: Research Article

Abstract: The pathological hallmarks of Alzheimer’s disease (AD) are amyloid-β (Aβ) plaques, neurofibrillary tangles, and glia activation. The pathology also includes vascular amyloidosis and cerebrovascular disease. Vascular compromise can result in hypoperfusion, local tissue hypoxia, and acidosis. Activated microglia and astrocytes can phagocytose Aβ through membrane receptors that include scavenger receptors. Changes in glial cells induced by extracellular acidosis could play a role in the development of AD. Here, we assess whether extracellular acidosis changes glial cell properties relevant for Aβ clearance capacity. Incubation of glial cells on acidified culture medium (pH 6.9 or 6.5) for 24–48 h resulted in decreased cell …diameter, with thinner branches in astrocytes, slight reduction in cell body size in microglia, a transient decrease in astrocyte adhesion to substrates, and a persistent decrease in microglia adhesion compared with control media (pH 7.4). Astrocyte Aβ phagocytosis decreased at pH 6.9 and 6.5, whereas microglia phagocytosis only transiently decreased in acidified media. Scavenger receptors class B member I (SR-BI) increased and scavenger receptors-macrophage receptors with collagenous structures (SR-MARCO) decreased in astrocytes cultured at pH 6.5. In contrast, in microglia exposed to pH 6.5, expression of SR-BI and SR-MARCO increased and fatty acid translocase (CD-36) decreased. In conclusion, the acidic environment changed the adhesiveness and morphology of both microglia and astrocytes, but only astrocytes showed a persistent decrease in Aβ clearance activity. Expression of scavenger receptors was affected differentially in microglia and astrocytes by acidosis. These changes in scavenger receptor patterns can affect the activation of glia and their contribution to neurodegeneration. Show more

Keywords: Acidosis, amyloid-β peptide, glial activation, phagocytosis, scavenger receptors

DOI: 10.3233/JAD-160083

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 857-873, 2016

Authors: Bamji-Mirza, Michelle | Li, Yan | Najem, Dema | Liu, Qing Yan | Walker, Douglas | Lue, Lih-Fen | Stupak, Jacek | Chan, Kenneth | Li, Jianjun | Ghani, Mahdi | Yang, Ze | Rogaeva, Ekaterina | Zhang, Wandong

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by extracellular deposits of amyloid-β (Aβ) in the brain. ABCA7 is highly expressed in the brain and a susceptibility gene for late-onset AD (LOAD). The minor alleles at two ABCA7 single-nucleotide polymorphisms (SNPs), rs3764650 (T>G; intron13) and rs3752246 at a predicted myristoylation site (C>G; exon33; p.Gly1527Ala), are significantly associated with LOAD risk; however, the mechanism of this association is unknown. Functional consequences of both SNPs were examined in HEK293 and CHO cells stably expressing AβPPSwe . Luciferase reporter assays in HEK293 cells suggested that intron13 carrying rs3764650 major T-allele (int13-T) possessed promoter-enhancing capabilities. Co-transfection …experiments with hABCA7 and int13-T resulted in significantly increased ABCA7 protein level relative to that with int13-G. Expression of h ABCA7 carrying rs3752246 risk allele led to increases in secreted Aβ40 and Aβ42 and β-secretase activity in CHO- and HEK-AβPPSwe cells. Hydroxymyristic acid treatment of cells expressing h ABCA7 carrying the rs3752246 major G allele resulted in increased β-secretase activity and levels of Aβ, suggesting that lack of myristoylation contributes to the observed cell-phenotypes. Molecular weight determination, by gel-electrophoresis and mass spectrometry, of h ABCA7 peptides spanning position 1527 showed loss of post-translational modification in the risk-allele peptide. These results suggest that decreased expression, or impaired function, of ABCA7 may contribute to AD pathology. Show more

Keywords: ABC transporters, ABCA7 protein, Alzheimer’s disease, amyloid beta-peptides, BACE1 protein, genome-wide association study, myristoylation, SNPs

DOI: 10.3233/JAD-150965

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 875-892, 2016

Authors: Zhai, Yun | Yamashita, Toru | Nakano, Yumiko | Sun, Zhuoran | Shang, Jingwei | Feng, Tian | Morihara, Ryuta | Fukui, Yusuke | Ohta, Yasuyuki | Hishikawa, Nozomi | Abe, Koji

Article Type: Research Article

Abstract: Recently, aging societies have been showing an increasingly strong relationship between Alzheimer’s disease (AD) and chronic cerebral hypoperfusion (HP). In the present study, we created a new mouse model for AD with HP, and investigated its clinical and pathological characteristics. Alzheimer’s disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral HP. In contrast to simple APP23 mice, cerebral HP exacerbated motor and cognitive dysfunctions with white matter lesions and meningo-parenchymal amyloid-β (Aβ) burdens. Strong cerebrovascular inflammation and severe amyloid angiopathy with cerebrovascular remodeling were also observed in APP23 + HP …mouse brains. An acetylcholinesterase inhibitor galantamine improved such clinical dysfunctions, retrieved above neuropathological characteristics, and enhanced nicotinic acetylcholine receptor (nAChR)-binding activity. The present study demonstrates that chronic cerebral HP enhanced cognitive/motor dysfunctions with parenchymal/cerebrovascular Aβ accumulation and cerebrovascular remodeling. These neuropathological abnormalities were greatly ameliorated by galantamine treatment associated with nAChR-mediated neuroprotection by allosterically potentiating ligand action. Show more

Keywords: Alzheimer’s disease, APP23 mice, cerebral amyloid angiopathy, galantamine, hypoperfusion

DOI: 10.3233/JAD-160345

Citation: Journal of Alzheimer's Disease, vol. 53, no. 3, pp. 893-905, 2016