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