Journal of Alzheimer's Disease - Volume 38, issue 4

Article Type: Letter

DOI: 10.3233/JAD-132372

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 699-703, 2014

Authors: Yan, Xiao-Xin | Ma, Chao | Gai, Wei-Ping | Cai, Huaibin | Luo, Xue-Gang

Article Type: Review Article

Abstract: β-Secretase-1 (BACE1) is the rate-limiting enzyme for the genesis of amyloid-β (Aβ) peptides, the main constituents of the amyloid plaques in the brains of Alzheimer's disease (AD) patients. BACE1 is being evaluated as an anti-Aβ target for AD therapy. Recent studies indicate that BACE1 elevation is associated with axonal and presynaptic pathology during plaque development. Evidence also points to a biological role for BACE1 in axonal outgrowth and synapse formation during development. Axonal, including presynaptic, pathology exists in AD as well as many other neurological disorders such as Parkinson's disease, epilepsy, stroke, and trauma. In this review, we discuss pharmaceutical …BACE1 inhibition as a therapeutic option for axonal pathogenesis, in addition to amyloid pathology. We first introduce the amyloidogenic processing of amyloid-β protein precursor and describe the normal expression pattern of the amyloidogenic proteins in the brain, with an emphasis on BACE1. We then address BACE1 elevation relative to amyloid plaque development, followed by updating recent understanding of a neurotrophic role of BACE1 in axon and synapse development. We further elaborate the occurrence of axonal pathology in some other neurological conditions. Finally, we propose pharmacological inhibition of excessive BACE1 activity as an option to mitigate early axonal pathology occurring in AD and other neurological disorders. Show more

Keywords: Aging, Alzheimer's disease, anti-amyloid therapy, dementia, dystrophic neurites, neurodegenerative disorders, neuroplasticity, senile plaques, synaptic dysfunction

DOI: 10.3233/JAD-131400

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 705-718, 2014

Authors: Wirz, Kerstin T.S. | Keitel, Stella | Swaab, Dick F. | Verhaagen, Joost | Bossers, Koen

Article Type: Review Article

Abstract: Alzheimer disease (AD) is the most common form of dementia and characterized by deposition of amyloid-β (Aβ) plaques, neurofibrillary tangles consisting of hyperphosphorylated tau, atrophy, and progressive neurodegeneration. While the familial, early onset form of AD is known to be caused by specific mutations in genes encoding presenilin 1, presenilin 2, or amyloid-β protein precursor, the underlying mechanisms leading to the development of sporadic AD are still not known. The major risk factors are, however, aging and APOE ε4. Here we review the latest evidence for the involvement of malfunctioning insulin signaling, dysfunction of mitochondria-associated membranes, cerebrovascular changes, increased oxidative …stress and free radical formation, DNA damage, disturbed energy metabolism, and synaptic dysfunction in early stages of AD. We focus on whether the changes in these processes precede or succeed the earliest symptoms in AD patients, i.e., minimal cognitive impairment. Since changes in Aβ processing are probably a key event in AD we also highlight the relationship of the above mentioned processes with the formation, secretion, aggregation, and toxicity of Aβ. Based on our literature findings we propose a model in which insulin dysfunction, pathological cerebrovascular changes, dysfunction of mitochondria-associated membranes, and/or synaptic changes are likely to interact with each other, thereby initiating and facilitating the development of AD pathology by accelerating the production and deposition of Aβ. Increased oxidative stress and free radical formation, DNA damage, disturbed energy metabolism, and synaptic loss follow these events, but still occur very early in AD. Show more

Keywords: Alzheimer disease, amyloid beta-protein, cerebrovascular disorders, DNA damage, energy metabolism, insulin, mitochondrial membranes, oxidative stress, physiopathology, synaptic transmission

DOI: 10.3233/JAD-130920

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 719-740, 2014

Authors: Mancuso, Roberta | Baglio, Francesca | Cabinio, Monia | Calabrese, Elena | Hernis, Ambra | Nemni, Raffaello | Clerici, Mario

Article Type: Short Communication

Abstract: HSV-1 infection of the central nervous system targets the same brain regions most affected in Alzheimer's disease (AD) and could play a pathogenic role in AD. HSV-1 serum IgG titers were analyzed in patients with mild AD (n = 83) and healthy controls (HC, n = 51); results were correlated with cortical grey matter (GM) volumes as analyzed by MRI. Seroprevalence and antibody (Ab) titers were comparable between AD and HC; elevated Ab titers (>75th percentile) were nevertheless significantly more frequent in AD and were positively correlated with cortical bilateral temporal and orbitofrontal GM volumes. HSV-1-specific-Ab could possibly play a …protective role in the early stages of AD. Show more

Keywords: Alzheimer's disease, HSV-1, humoral immunity, magnetic resonance imaging

DOI: 10.3233/JAD-130977

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 741-745, 2014

Authors: Carecchio, Miryam | Galimberti, Daniela | Fenoglio, Chiara | Serpente, Maria | Scarpini, Elio | Comi, Cristoforo | Terazzi, Emanuela | Cantello, Roberto

Article Type: Short Communication

Abstract: Parkinsonism can be the presenting feature of frontotemporal dementia due to Progranulin (GRN) mutations or develop over the course of the disease, mimicking idiopathic Parkinson's disease or atypical parkinsonism. Here we report on a patient carrying a novel GRN mutation who presented with asymmetric parkinsonism and developed cognitive decline and language alterations two years later. Brain MRI showed mild asymmetric fronto-parietal atrophy. Single-photon emission computed tomography with I123 ioflupane (DAT-Scan) demonstrated reduced tracer uptake in the left putamen. Larger studies are needed to clarify whether presynaptic dopaminergic deficit is present in all GRN mutation carriers or only in those …with parkinsonism. Show more

Keywords: Atypical, DAT-Scan, frontotemporal dementia, parkinsonism, progranulin

DOI: 10.3233/JAD-131151

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 747-752, 2014

Authors: Milojevic, Julijana | Costa, Montserrat | Ortiz, Ana M. | Jorquera, Juan I. | Melacini, Giuseppe

Article Type: Research Article

Abstract: Background: A promising approach for treating Alzheimer’s disease relies on the net efflux of the amyloid-β (Aβ) peptide from the brain to peripheral plasma, as a result of plasma Aβ clearance promoted by plasma removal and therapeutic albumin replacement. Objective: To assess the binding of therapeutic albumin (Albutein® , Grifols) to monomeric and aggregated Aβ according to methods previously tested on the interactions between Aβ and research-grade albumin. Methods: Albumin integrity and the interactions with albumin stabilizers (octanoic acid and N-Ac-Trp) were assessed through one-dimensional (1D) 1 H-NMR and saturation transfer difference (STD) NMR spectra. The …interactions between monomeric Aβ1-40 and albumin were probed by 2D 1 H-15 N HSQC spectra of labeled Aβ1-40 . The formation of cross-β structured Aβ1-42 assemblies was monitored by ThT fluorescence. The interactions between self-assembled Aβ1-42 and albumin were probed by Trp fluorescence. Results: NMR spectra indicated that both therapeutic and research-grade albumin are similarly well-folded proteins. No significant changes in either HSQC peak position or intensity were observed upon addition of albumin to 15 N-labeled Aβ1-40 , which rules out binding of albumin to monomeric Aβ with dissociation constant in the µM or lower range. When aggregated Aβ1-42 was added to albumin, quenching of Trp fluorescence was observed, which indicates albumin binding to Aβ1-42 aggregates. The relative potency of therapeutic albumin as an Aβ self-association inhibitor was in the same order of magnitude as research-grade albumin. Conclusions: Albutein® inhibited Aβ self-association by selectively binding Aβ aggregates rather than monomers and by preventing further growth of the Aβ assemblies. Show more

Keywords: Alzheimer's disease, amyloid, amyloid-β peptide, NMR, oligomers, therapeutic albumin

DOI: 10.3233/JAD-131169

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 753-765, 2014

Authors: Paganetti, Paolo | Antoniello, Katia | Devraj, Kavi | Toni, Nicolas | Kieran, Dairin | Madani, Rime | Pihlgren, Maria | Adolfsson, Oskar | Froestl, Wolfgang | Schrattenholz, André | Liebner, Stefan | Havas, Daniel | Windisch, Manfred | Cirrito, John R. | Pfeifer, Andrea | Muhs, Andreas

Article Type: Research Article

Abstract: The formation and accumulation of toxic amyloid-β peptides (Aβ) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating Aβ homeostasis. Examples are the inhibition of production, misfolding, and accumulation of Aβ or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain Aβ burden in AβPPPS1, hAβPPSL , and AβPP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced Aβ …peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecally-injected Aβ in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected Aβ in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial Aβ peptide in pre-plaque mhAβPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of Aβ peptide. Finally, ACI-91 was found to consistently affect, in vitro and in vivo, the expression of endothelial cell genes involved in Aβ transport across the Blood Brain Barrier (BBB). Thus increased Aβ clearance through the BBB may contribute to reduced Aβ burden and associated phenotypes. Inhibition of muscarinic AChR restricted to the periphery may present a therapeutic advantage as it avoids adverse central cholinergic effects. Show more

Keywords: Aβ brain efflux, Aβ clearance, Aβ homeostasis, AβPP transgenic mice, amyloid-β peptides, drug treatment, muscarinic receptors, plaque deposition

DOI: 10.3233/JAD-131091

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 767-786, 2014

Authors: Gheorghiu, Mihaela | Enciu, Ana-Maria | Popescu, Bogdan O. | Gheorghiu, Eugen

Article Type: Research Article

Abstract: Recently, the blood-brain barrier (BBB) has been pointed to as an active player in neurodegenerative disorders, albeit the actual succession of pathogenic events remains to be elucidated. Amyloid-β (Aβ) is an important pathogenic player in Alzheimer's disease, and it is cleared from the brain partly by transportation across the BBB. In this work we asked the question whether Aβ-induced alteration of tight junction (TJ) protein expression is a result of the complex in situ microenvironment of the BBB or if it can be replicated in an externalized environment, such as an in vitro epithelial barrier, where barrier property changes can …be investigated without confounding factors. Therefore, we treated barrier forming MDCKI and II epithelial cells with Aβ42 and investigated TJ occludin and claudin-2 protein levels and cellular distribution through western blot and immunofluorescence. To assess barrier function, we measured transepithelial resistance (TEER) and studied cell polarity through atomic force microscopy (AFM). We found that Aβ42 cell treatment increased occludin expression and decreased claudin-2 expression. With TEER, an increase in paracellular resistance was noted, which started at 10 hours and peaked at 20 hours of Aβ42 treatment. AFM analysis demonstrated an associated morphological alteration of the cell monolayer. In conclusion, we demonstrated that Aβ42 is able to modify TJ protein expression and to functionally alter barrier properties in vitro and that this effect is not conditioned by other pathogenic Alzheimer's disease events taking place in the complex brain microenvironment. Show more

Keywords: Alzheimer's disease, amyloid-β, blood-brain barrier, claudin-2, endothelial cells, occluding, permeability

DOI: 10.3233/JAD-122374

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 787-798, 2014

Authors: Benussi, Luisa | Rossi, Giacomina | Glionna, Michela | Tonoli, Elisa | Piccoli, Elena | Fostinelli, Silvia | Paterlini, Anna | Flocco, Rosa | Albani, Diego | Pantieri, Roberta | Cereda, Cristina | Forloni, Gianluigi | Tagliavini, Fabrizio | Binetti, Giuliano | Ghidoni, Roberta

Article Type: Research Article

Abstract: Expansion of a hexanucleotide repeat in the C9ORF72 gene has been identified as the most common pathogenic mutation in families with autosomal dominant frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis. Herein we investigated frequency and penetrance of the C9ORF72 hexanucleotide repeat pathological expansion in a large cohort of familial and sporadic FTLD and related disorders (FTLD and related disorders, n = 388; Controls, n = 201). Moreover, we weighed the impact of C9ORF72 genotype on clinical phenotype taking into account the hexanucleotide repeat units number as a possible disease modifier. In our cohort, the C9ORF72 pathological expansion: i) showed …a prevalence of 7.5%; ii) showed a full penetrance by the age of 80; iii) was rarely found in sporadic patients; iv) was solely associated with FTLD; v) was mainly associated with bvFTD clinical subtype; and vi) was associated with earlier age of onset in the youngest generation compared with the previous generation within a pedigree. Interestingly, intermediate C9ORF72 expansion had a risk effect in familial/sporadic FTLD. Eventually, the C9ORF72 repeat units number influenced the disease phenotype in terms of age of onset and associated clinical subtype. Genome-wide studies in well characterized clinical cohorts will be essential in order to decipher pathways of disease expression in C9ORF72-associated neurodegeneration. Show more

Keywords: C9ORF72 repeat units number, endophenotype, frontotemporal dementia, genetic testing, mutation penetrance, mutation prevalence, pedigree

DOI: 10.3233/JAD-131028

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 799-808, 2014

Authors: Squitti, Rosanna | Simonelli, Ilaria | Ventriglia, Mariacarla | Siotto, Mariacristina | Pasqualetti, Patrizio | Rembach, Alan | Doecke, James | Bush, Ashley I.

Article Type: Research Article

Abstract: The fraction of copper not bound to ceruloplasmin seems altered in Alzheimer's disease (AD). We have addressed this notion evaluating all the studies carried out from 1996 until March 2013 by means of meta-analysis. We performed our analysis on diverse indices evaluating the relationship between copper and ceruloplasmin in general circulation, namely ‘Non-Cp copper’, ‘% Non-Cp copper’, and ‘Adjusted copper’. For Non-Cp copper and % Non-Cp copper, the correct stoichiometry between copper and ceruloplasmin (6–8 atoms of copper for each ceruloplasmin molecule) in healthy controls has been adopted as criterion for the study to be included in the meta-analysis evaluating …data with the canonic Walshe's formula for Non-Cp copper. Copper to ceruloplasmin ratio (Cu:Cp), which is an internal quality control check for ceruloplasmin calibration, was used as an index of the actual stoichiometry in the specimens. Adjusted (Adj-Cp) copper, even though less reliable, was calculated, allowing the evaluation of all the studies selected. An additional meta-analysis of systemic total copper was re-calculated accounting for all the studies carried out from 1983 to March 2013. Ten studies were analyzed in the meta-analysis for Non-Cp copper and % Non-Cp copper reaching a pooled total of 599 AD subjects and 867 controls. For Adj-Cp copper, 14 studies were analyzed with a pooled total of 879 AD and 1,712 controls. 27 studies were considered for systemic total copper meta-analysis, with a pooled total of 1,393 AD and 2,159 controls. All the copper indices analyzed were significantly higher in AD subjects compared to healthy controls. Show more

Keywords: Alzheimer's disease, ceruloplasmin, copper, metal, plasma, serum

DOI: 10.3233/JAD-131247

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 809-822, 2014

Authors: de Souza Rolim, Thaís | Fabri, Gisele Maria Campos | Nitrini, Ricardo | Anghinah, Renato | Teixeira, Manoel Jacobsen | de Siqueira, José Tadeu T. | Cestari, José Augusto Ferrari | de Siqueira, Silvia Regina Dowgan T.

Article Type: Research Article

Abstract: Background: Dental infections are frequent and have recently been implicated as a possible risk factor for Alzheimer’s disease (AD). Despite a lack of studies investigating orofacial pain in this patient group, dental conditions are known to be a potential cause of pain and to affect quality of life and disease progression. Objectives: To evaluate oral status, mandibular function and orofacial pain in patients with mild AD versus healthy subjects matched for age and gender. Methods: Twenty-nine patients and 30 control subjects were evaluated. The protocol comprised a clinical questionnaire and dental exam, research diagnostic criteria for …temporomandibular disorders, the McGill Pain Questionnaire, the decayed, missing, and filled teeth index, and included a full periodontal evaluation. AD signs and symptoms as well as associated factors were evaluated by a trained neurologist. Results: A higher prevalence of orofacial pain (20.7%, p < 0.001), articular abnormalities in temporomandibular joints (p < 0.05), and periodontal infections (p = 0.002) was observed in the study group compared to the control group. Conclusion: Orofacial pain and periodontal infections were more frequent in patients with mild AD than in healthy subjects. Orofacial pain screening and dental and oral exams should be routinely performed in AD patients in order to identify pathological conditions that need treatment thus improving quality of life compromised due to dementia. Show more

Keywords: Alzheimer's disease, oral infections, orofacial pain, periodontitis, TMD

DOI: 10.3233/JAD-131283

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 823-829, 2014

Authors: Taher, Noor | McKenzie, Courtney | Garrett, Rebecca | Baker, Matthew | Fox, Nena | Isaacs, Gary D.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by neurofibrillary tangles and extracellular amyloid-β plaques (Aβ). Despite ongoing research, some ambiguity remains surrounding the role of Aβ in the pathogenesis of this neurodegenerative disease. While several studies have focused on the mutations associated with AD, our understanding of the epigenetic contributions to the disease remains less clear. To that end, we determined the changes in DNA methylation in differentiated human neurons with and without Aβ treatment. DNA was isolated from neurons treated with Aβ or vehicle, and the two samples were digested with either a methylation-sensitive (HpaII) or a methylation-insensitive (MspI) restriction endonuclease. …The fragments were amplified and co-hybridized to a commercial promoter microarray. Data analysis revealed a subset of genomic loci that shows a significant change in DNA methylation following Aβ treatment in comparison to the control group. After mapping these loci to nearby genes, we discovered high enrichment for cell-fate genes that control apoptosis and neuronal differentiation. Finally, we incorporated three of those genes in a possible model suggesting the means by which Aβ contributes to the brain shrinkage and memory loss seen in AD. Show more

Keywords: Alzheimer's disease, amyloid-β fragment 1-40, DNA methylation, neurogenesis

DOI: 10.3233/JAD-131061

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 831-844, 2014

Authors: Chakrabarti, Arunabha | Roy, Kasturi | Mukhopadhyay, Debashis

Article Type: Research Article

Abstract: Amyloid-β protein precursor intracellular domain (AICD), which exerts intracellular effects by interacting with proteins involved in a plethora of biological processes, is a key player behind the pathophysiology of Alzheimer's disease (AD). Keeping in mind that overwhelming presence of AICD would mimic AD-like conditions in neuroblastoma cell lines, we hypothesized alteration in the proteomic expression pattern in these cells in the presence of AICD compared to their normal proteome. The rationale behind the study was to distinguish between symptomatic pathophysiological effects as opposed to any artifactual consequence due to protein overload in the cell lines. Using 2D-DIGE analysis and MALDI-MS …identifications in neuro2A (mouse) and SHSY5Y (human) cell lines, we have identified several proteins belonging to different functional classes and involved in several biological pathways including protein folding, cytoskeletal dynamics, metabolism, and stress. Many of these were being upregulated or downregulated due to AICD effects and could be correlated directly with AD phenotypes. Show more

Keywords: Alzheimer's disease, AβPP intracellular domain, 2D-DIGE, MALDI-MS, transfection

DOI: 10.3233/JAD-130695

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 845-855, 2014

Authors: Naismith, Sharon L. | Hickie, Ian B. | Terpening, Zoe | Rajaratnam, Shanthakumar W. | Hodges, John R. | Bolitho, Samuel | Rogers, Naomi L. | Lewis, Simon J.G.

Article Type: Research Article

Abstract: Background: While it is evident that Alzheimer’s disease is associated with disturbed sleep and circadian rhythms, the extent to which such changes are evident in older people ‘at risk’ of developing dementia is unknown. Objective: In this study, we aimed to determine whether patients with mild cognitive impairment (MCI) demonstrated significant alterations in the timing of melatonin secretion onset and amount, as well as sleep architecture. Methods: Thirty patients with MCI and 28 age-matched controls underwent psychiatric, medical, and neuropsychological assessment, followed by overnight polysomnography and dim light melatonin onset assessment. Participants also performed an episodic …memory task while in the laboratory. Dim light melatonin onset was computed using a standardized algorithm, and area under the curve was computed for melatonin secretion. Sleep architecture measures including wake after sleep onset and latency to rapid eye movement sleep were derived. Results: Patients with MCI had advanced timing of their melatonin secretion onset relative to controls, but the levels of melatonin secreted did not differ between groups. The MCI group also had greater wake after sleep onset and increased rapid eye movement sleep latency. There were differential associations between dim light melatonin onset and cognition between the two groups, with earlier dim light melatonin onset being associated with poorer memory performance in MCI patients. Conclusion: Circadian misalignment and sleep disruption is evident in patients with MCI, and is consistent with changes observed in Alzheimer’s disease. Such findings could be a marker for disease trajectory, and may even be implicated in disease pathogenesis. Show more

Keywords: Circadian, melatonin, mild cognitive impairment, salivary, sleep

DOI: 10.3233/JAD-131217

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 857-866, 2014

Authors: Nelson, Amy R. | Kolasa, Krystyna | McMahon, Lori L.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaques, hyperphosphorylated tau neurofibrillary tangles, and cholinergic dysfunction. Cholinergic degeneration can be mimicked in rats by lesioning medial septum cholinergic neurons. Hippocampal cholinergic denervation disrupts retrograde nerve growth factor (NGF) transport, leading to its accumulation, which subsequently triggers sprouting of noradrenergic sympathetic fibers from the superior cervical ganglia into hippocampus. Previously we reported that coincident with noradrenergic sprouting is the partial reinnervation of hippocampus with cholinergic fibers and the maintenance of a M1 muscarinic acetylcholine receptor (M1 mAChR) dependent long-term depression at CA3-CA1 synapses that is lost in the absence of sprouting. …These findings suggest that sympathetic sprouting and the accompanying cholinergic reinnervation maintains M1 mAChR function. Importantly, noradrenergic sympathetic and cholinergic sprouting have been demonstrated in human postmortem AD hippocampus. Furthermore, M1 mAChRs are a recent focus as a therapeutic target for AD given their role in cognition and non-amyloidogenic processing of amyloid-β protein precursor (AβPP). Here we tested the hypotheses that noradrenergic sympathetic sprouting is triggered by NGF, that sprouting maintains non-amyloidogenic AβPP processing, and that sprouting is prevented by intrahippocampal Aβ42 infusion. We found that NGF stimulates sprouting, that sprouting maintains non-amyloidogenic AβPP processing, and that Aβ42 is not only toxic to central cholinergic fibers innervating hippocampus but it prevents and reverses noradrenergic sympathetic sprouting and the accompanying cholinergic reinnervation. These findings reiterate the clinical implications of sprouting as an innate compensatory mechanism and emphasize the importance of M1 mAChRs as an AD therapeutic target. Show more

Keywords: Alzheimer's disease, amyloid-β, amyloid-β protein precursor, cholinergic fibers, muscarinic receptor M1, nerve growth factor

DOI: 10.3233/JAD-130608

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 867-879, 2014

Authors: Roy, Kasturi | Raychaudhuri, Mithu | Chakrabarti, Oishee | Mukhopadhyay, Debashis

Article Type: Research Article

Abstract: The ascertainment of elevated levels of amyloid-β protein precursor intracellular domain (AICD) in Alzheimer's disease (AD) brains and the fact that it contributes to AD-like pathology has geared the search toward a new paradigm. While studying endogenous as well as overexpressed Grb2-AICD interaction in AD cell models, it was found that Grb2 co-localized to compartments along with AICD. We report now that these vesicles form in a clathrin and dynamin independent manner. Both types of vesicles mature into autophagosomes, merge with lysosomes, and relieve the cells of AICD overload. Inhibiting autophagosome formation results in vesicle accumulation. AICD-level is reduced in …Grb2 excess condition in Cycloheximide Chase setup. Reduced caspase activity and apoptosis point toward the fact that the cytotoxic effect of AICD is alleviated by its sequestration in autolysosomes. Hence we state that the entrapping of AICD in Grb2 vesicles and its clearance via autophagosomes is a survival contrivance on the part of the cell. This study unravels, for the first time, the roles of Grb2 in autophagy and in handling toxic protein overload in an AD-like scenario. Show more

Keywords: Amyloid-β protein precursor protein, autophagy, CD63, clathrin, dynamin, Grb2, LC3 protein

DOI: 10.3233/JAD-130929

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 881-895, 2014

Authors: Lupton, Michelle K. | Proitsi, Petroula | Lin, Kuang | Hamilton, Gillian | Daniilidou, Makrina | Tsolaki, Magda | Powell, John F.

Article Type: Research Article

Abstract: The ATP-binding cassette, sub-family A, member 1 gene (ABCA1) is a candidate risk gene for late onset Alzheimer's disease (LOAD) as a consequence of its role in cholesterol transport and metabolism, which is implicated in LOAD risk. ABCA1 has been shown in mouse models to enable the clearance of amyloid-β peptide from the brain, through its role in the lipidation of apolipoprotein (APOE). Although recent large scale genome wide association studies (GWAS) have failed to find significant associations with common genetic variants in this gene and LOAD, rare variants in ABCA1 have been shown to influence plasma high-density lipoprotein cholesterol …levels. Using next generation sequencing of pooled DNA samples, we sequenced all the coding regions of ABCA1 in 311 LOAD cases and 360 control individuals drawn from the Greek population to identify low frequency non-synonymous variation. There were a significantly higher proportion of rare non-synonymous variants in control individuals compared to AD cases, suggestive of a protective effect. These findings provide new evidence of an effect of ABCA1 variants on AD risk. In addition they highlight the importance of high throughput sequencing in the identification of rare variation undetected by GWAS, but with the potential to have a strong effect on risk of LOAD. Show more

Keywords: Alzheimer's disease, ATP-binding cassette transporters, ATP-binding cassette sub-family A (ABC1) member 1, candidate gene analyses, cholesterol, genetic association studies, high-throughput nucleotide sequencing

DOI: 10.3233/JAD-131121

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 897-906, 2014

Authors: Percy, Maire | Somerville, Martin J. | Hicks, Mark | Colelli, Teresa | Wright, Emily | Kitaygorodsky, Julia | Jiang, Amy | Ho, Valerie | Parpia, Alyssa | Wong, Michael K. | Garcia, Angeles

Article Type: Research Article

Abstract: Risk factors for dementia development are not well-defined. We evaluated several factors alone and in combination in a unique cohort of Caucasian volunteers over an approximately 6-year observation window using a nested case/control design. Factors included: apolipoprotein E (ApoE) gene variants (the E4 allele is the strongest confirmed genetic predisposing factor for Alzheimer's disease), the hemochromatosis-HFE gene mutations (H63D and C282Y), diabetes, and stroke. At study entry, subjects were ≥65 years of age (M ± SD = 73.0 ± 4.9), had an MMSE score ≥24, and no evidence of cerebrovascular disease or current depression. Genotyping was completed on 163 available …DNA samples from three different groups at the study end: those who still had normal cognitive function; those who had developed dementia; and those with Mild Cognitive Impairment (MCI). Analyses were interpreted at the 95% confidence level without Bonferroni corrections. In the subgroup with dementia, all cases of diabetes were type 2 and present at study entry, whereas all strokes occurred during the study. The results highlight apparently synergistic interactions between genetic and medical risk factors for dementia development, gender differences in risk factors, and involvement of HFE mutations. Having E4 (i.e., either of E3/4 or E4/4), C282Y, H63D, diabetes, or stroke alone did not attain significance. Significant predisposing factors with post-hoc power ≥80% were: E4 homozygosity (E4/4)males+females, odds ratio (OR) = 56.0); E4+diabetes (males+females, OR = 13.7; E4+H63D+diabetes (females, OR = 52.0); E4+stroke (males, OR = 46.5). The importance of preventing diabetes and stroke to ward off dementia and the possible role of iron dysmetabolism in dementia are discussed. Show more

Keywords: Alzheimer's disease, apolipoprotein E, C282Y, cohort study, dementia, HFE mutations, H63D, hemochromatosis, iron, mild cognitive impairment, risk factors, stroke, type 2 diabetes mellitus

DOI: 10.3233/JAD-131409

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 907-922, 2014

Authors: Ben-David, Boaz M. | Tewari, Anita | Shakuf, Vered | Van Lieshout, Pascal H.H.M.

Article Type: Research Article

Abstract: Selective attention, an essential part of daily activity, is often impaired in people with Alzheimer's disease (AD). Usually, it is measured by the color-word Stroop test. However, there is no universal agreement whether performance on the Stroop task changes significantly in AD patients; or if so, whether an increase in Stroop effects reflects a decrease in selective attention, a slowing in generalized speed of processing (SOP), or is the result of degraded color-vision. The current study investigated the impact of AD on Stroop performance and its potential sources in a meta-analysis and mathematical modeling of 18 studies, comparing 637 AD …patients with 977 healthy age-matched participants. We found a significant increase in Stroop effects for AD patients, across studies. This AD-related change was associated with a slowing in SOP. However, after correcting for a bias in the distribution of latencies, SOP could only explain a moderate portion of the total variance (25%). Moreover, we found strong evidence for an AD-related increase in the latency difference between naming the font-color and reading color-neutral stimuli (r2 = 0.98). This increase in the dimensional imbalance between color-naming and word-reading was found to explain a significant portion of the AD-related increase in Stroop effects (r2 = 0.87), hinting on a possible sensory source. In conclusion, our analysis highlights the importance of controlling for sensory degradation and SOP when testing cognitive performance and, specifically, selective attention in AD patients. We also suggest possible measures and tools to better test for selective attention in AD. Show more

Keywords: Aging, Alzheimer's disease, color vision, selective attention, sensory and cognitive interaction, speed of processing, Stroop test, visual perception

DOI: 10.3233/JAD-131244

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 923-938, 2014

Authors: Scrascia, Federica | Curcio, Giuseppe | Ursini, Francesca | Trotta, Laura | Quintiliani, Livia | Migliore, Simone | Altamura, Claudia | Pitocco, Francesca | Altavilla, Riccardo | Melgari, Jean-Marc | Quattrocchi, Carlo Cosimo | Vernieri, Fabrizio

Article Type: Research Article

Abstract: Magnetic resonance (MR) diffusion tensor imaging (DTI) can detect microstructural alterations by means of fractional anisotropy (FA) in patients with dementia, also in relation to cognitive status. The present study aimed at investigating the possible relation among white matter damage in DTI, quantitative electroencephalography (EEG) spectral power, and cognitive status in Alzheimer's disease (AD) and mild cognitive impairment (MCI) patients. Forty-seven subjects (8 moderate AD, 18 mild AD, 12 MCI, and 9 healthy controls) underwent brain MR, neuropsychological evaluation, and resting EEG recording. A progressive increase of EEG delta and theta spectral power was observed from controls to patients, mainly …in more anterior areas, with a parallel widespread decrease of beta power. Moreover, a progressive decrease of FA from controls to patients in frontal areas and in the corpus callosum (genu) was observed. Correlation analyses indicated convergence among EEG rhythms changes, DTI values, and cognitive status mainly over anterior areas. The decrease of FA values and EEG spectral power changes might represent markers of neurodegenerative dysfunction, possibly preceding macrostructural atrophy. Show more

Keywords: Alzheimer's disease, brain activity, dementia, diffusion tensor imaging, mild cognitive impairment

DOI: 10.3233/JAD-130788

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 939-950, 2014

Authors: Tzanoulinou, Stamatina | Brandi, Rossella | Arisi, Ivan | D'Onofrio, Mara | Urfer, Séverine M. | Sandi, Carmen | Constam, Daniel | Capsoni, Simona

Article Type: Research Article

Abstract: It has been suggested that systemic infection, occurring during aging and chronic neurodegenerative diseases, can evoke an immune response that aggravates the progression of neurodegeneration and cognitive decline. It has been shown that the AD11 neurodegeneration mouse model, expressing a recombinant anti-nerve growth factor (NGF) antibody, shows a milder phenotype when housed in murine pathogen-free (MPF) conditions with respect to AD11 mice reared in conventional (CV) housing. AD10 mice, a variant of the anti-NGF AD11 model, expressing only an immunoglobulin light chain for the transgenic anti-NGF antibody, in the absence of the corresponding transgenic antibody chain VH, exhibit a complex …neurodegenerative phenotype, similar to that of AD11 mice. Here we show that the AD10 transgenic mice, housed in murine pathogen-free conditions (MPF-AD10 mice), also display a milder behavioral and neurodegenerative phenotype compared to the corresponding mice kept under conventional housing conditions (CV-AD10). As a first step toward the identification of mechanisms underlying this difference, a differential gene expression profiling was performed on brains from CV-AD10 and MPF-AD10 mice, showing a decrease of the immune response and neuroinflammation gene expression in MPF-AD10 mice. Results suggest that the activation of the immune response gene expression in the CV-AD10, in a microbially unprotected environment, might contribute to a more severe and progressive neurodegenerative phenotype, compared to the MPF mice. Show more

Keywords: Memory deficits, murine pathogen-free, nerve growth factor, neuroinflammation, systemic inflammation

DOI: 10.3233/JAD-131037

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 951-964, 2014

Article Type: Other

DOI: 10.3233/JAD-131038

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 965-967, 2014

Article Type: Other

DOI: 10.3233/JAD-2013-38423

Citation: Journal of Alzheimer's Disease, vol. 38, no. 4, pp. 969-977, 2014