Journal of Alzheimer's Disease - Volume 28, issue 4

Authors: Bruggink, Kim A. | Müller, Mareike | Kuiperij, H. Bea | Verbeek, Marcel M.

Article Type: Review Article

Abstract: Amyloid-β protein (Aβ) accumulation is one of the major hallmarks of Alzheimer's disease and plays a crucial role in its pathogenesis. Aβ aggregates into fibrils, but rather than these end-products of the aggregation process, intermediate species, referred to as oligomers, have been identified as the most neurotoxic Aβ aggregates. To characterize the different Aβ species and to study the aggregation process, a wide range of techniques has been applied over the past years. These techniques aim to visualize the different Aβ species and study their structure, to separate them, and to quantify the aggregated Aβ forms by immunology-based methods. In …this review, we provide an overview and discussion of the most important techniques used for these aims. Often a combination of techniques will be appropriate to obtain the most optimal information. Show more

Keywords: ADDL, Alzheimer's disease, amyloid-β, fibrils, immunoassay, microscopy, oligomers, separation techniques, spectroscopy, spectrum analysis, structural analysis

DOI: 10.3233/JAD-2011-111421

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 735-758, 2012

Authors: Caso, Francesca | Villa, Chiara | Fenoglio, Chiara | Santangelo, Roberto | Agosta, Federica | Coppi, Elisabetta | Falautano, Monica | Comi, Giancarlo | Filippi, Massimo | Scarpini, Elio | Magnani, Giuseppe | Galimberti, Daniela

Article Type: Short Communication

Abstract: The progranulin gene (GRN) g.10325_10331delCTGCTGT (relative to nt1 in NG_007886.1), alias Cys157LysfsX97, has been so far reported only once in a patient with frontotemporal dementia. Here, we describe a 63-year old patient carrying the same mutation, presenting with a 3-year history of language disorder, and diagnosed clinically with nonfluent variant of primary progressive aphasia according to current criteria. This patient's description expands the spectrum of clinical presentations of frontotemporal lobar degeneration caused by the GRN Cys157LysfsX97 mutation.

Keywords: Alzheimer's disease, Dementia, frontotemporal lobar degeneration, GRN mutation, nonfluent variant of primary progressive aphasia, progranulin

DOI: 10.3233/JAD-2011-111544

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 759-763, 2012

Authors: Tiwari, Vivek | Patel, Anant B.

Article Type: Short Communication

Abstract: Preclinical diagnosis of Alzheimer's disease is a major challenge. The present study evaluates glutamatergic and GABAergic neurotransmitter energetics at the age of 6 months in AβPPswe-PS1dE9 mouse model of Alzheimer's disease by using 1 H-[13 C]-NMR spectroscopy together with infusion of [1,6-13 C2 ]glucose. NMR analysis suggested no significant derangement in neurochemical profile in AβPPswe-PS1dE9 mice. However, decrease in labeling of glutamate-C4, GABA-C2 and glutamine-C4 at early infusion-time together with no change in labeling at steady state from [1,6-13 C2 ]glucose indicates an impaired glutamatergic and GABAergic glucose oxidation and neurotransmitter cycle in AβPPswe-PS1dE9 mice. These findings may have implication …in preclinical diagnosis of Alzheimer's disease. Show more

Keywords: Alzheimer's disease, GABA, glutamate, neuron-glia trafficking, neurotransmitter cycle, nuclear magnetic resonance spectroscopy

DOI: 10.3233/JAD-2011-111502

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 765-769, 2012

Authors: Young-Collier, Kisha J. | McArdle, Michael | Bennett, James P.

Article Type: Research Article

Abstract: Impaired brain energy production, reflected by reduced cortical glucose metabolism seen on 2-FDG PET scans, has emerged as a robust biomarker of mild cognitive impairment (MCI). Progression from MCI to Alzheimer's disease (AD) shows further decline of cortical 2-FDG uptake, implying worsening bioenergetics. We characterized respiration, respiratory protein levels, and gene expressions for mitochondrial DNA (mtDNA), mitochondrial biogenesis, and antioxidative signaling in preparations from postmortem AD and control frontal cortex. Mitochondrial respiration was maintained in frozen brain mitochondria and reduced by approximately two-thirds in AD due to loss of mitochondrial mass. Levels of most respiratory proteins were preserved, but expressions …of gene families for mtDNA, mitobiogenesis, and mitochondrial/cytosolic antioxidant enzymes were reduced in AD cortex. None of these changes in AD were related to elevated levels of amyoid-β1-42 peptide. For unclear reasons, mitochondrial biogenesis is suppressed in AD frontal cortex, leading to reduced mitochondrial mass and impaired mitochondrial respiratory capacity. Downregulation of antioxidant proteins further threatens neuronal function. Altering progression of AD appears to require both correction of impaired mitobiogenesis and restoration of antioxidant protection. Show more

Keywords: Alzheimer's disease, mitobiogenesis, mitochondria, oxidative stress, respiration

DOI: 10.3233/JAD-2011-111487

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 771-781, 2012

Authors: Mandler, Markus | Rockenstein, Edward | Ubhi, Kiren | Hansen, Lawrence | Adame, Anthony | Michael, Sarah | Galasko, Douglas | Santic, Radmila | Mattner, Frank | Masliah, Eliezer

Article Type: Research Article

Abstract: The neurodegenerative pathology in patients with Alzheimer's disease (AD) has been associated with the progressive accumulation of aggregated and post-translationally modified amyloid-β (Aβ) species. Among them, recent studies indicate that the pyroglutamate modification of Aβ (pE(3)Aβ) catalyzed by glutaminyl cyclase might play an important role in the pathogenesis of AD. Although the effects of the pyroglutamate modification on Aβ aggregation and toxicity have been investigated, less is known about the distribution of pE(3)Aβ across the spectrum of AD and in the brains of amyloid-β protein precursor (AβPP) transgenic (tg) animals. For this purpose, we generated a novel monoclonal antibody (denominated …D129) that specifically recognizes pE(3)Aβ and characterized the patterns of distribution in the postmortem brain samples from AD patients divided by disease stage (Braak stage) and in AβPP tg mice. We found that in early stages of AD and young AβPP tg mice pE(3)Aβ was found in discrete linear and granular aggregates in the neuropil that co-localized with the pre-synaptic protein synaptophysin and was in close opposition to dendrites labeled with MAP2. In later stages of AD and in older AβPP tg mice, pE(3)Aβ was abundant in diffuse and mature plaques. In conclusion, this study suggests that peri-synaptic accumulation of pE(3)Aβ might contribute to early cognitive dysfunction in AD. Show more

Keywords: ELISA, monoclonal antibody, mThy1-hAβPP tg, synapse, Tg2576

DOI: 10.3233/JAD-2011-111208

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 783-794, 2012

Authors: Sun, Miao | Zhou, Ting | Zhou, Liang | Chen, Qiang | Yu, Yan | Yang, Huan | Zhong, Kaiyin | Zhang, Ximeng | Xu, Feng | Cai, Shaoqing | Yu, Albert | Zhang, Hui | Xiao, Ruizhong | Xiao, Dongsheng | Chui, Dehua

Article Type: Research Article

Abstract: Formononetin, an active constituent of the Chinese herb Astragali Radix, has been reported to have beneficial effects for Alzheimer's disease (AD). Yet the mechanism of this effect remains to be elucidated. The present study shows that formononetin increases soluble-AβPPα (sAβPPα) secretion and thus protects human-AβPP Swedish mutation cell (N2a-AβPP cell) from hypoxia-induced apoptosis. Using hypoxic N2a-AβPP cell as an in vitro model of AD-like pathology, we confirmed that regular treatment with formononetin could have neuroprotective effects, followed respectively by reduced caspase 3 activity and increased cell viability. Strikingly, our data revealed that the caspase 3-blocking effect of formononetin was largely …mediated by stimulation of α-secretase cleavage of AβPP, and increasing the secretion of its soluble form, sAβPPα. Moreover, the protective effect of formononetin was totally inhibited by TAPI-2, an α-secretase complex inhibitor, suggesting the role of the sAβPPα pathway in the neuroprotective response to formononetin. We also found that the stimulative effect of formononetin on α-secretase activity was mainly conducted by upregulating ADAM10 expression at the transcriptional level. Altogether, our study provides novel insights into how formononetin mediates stimulation of the ADAM10-sAβPPα pathway and exerts a neuronal protective effect. Show more

Keywords: ADAM10, amyloid-β protein precursor (AβPP), formononetin, soluble-AβPPα

DOI: 10.3233/JAD-2011-110506

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 795-808, 2012

Authors: Borghys, Herman | Tuefferd, Marianne | Van Broeck, Bianca | Clessens, Ellen | Dillen, Lieve | Cools, Willy | Vinken, Petra | Straetemans, Roel | De Ridder, Filip | Gijsen, Harrie | Mercken, Marc

Article Type: Research Article

Abstract: Gamma-secretase, a membrane bound protease which cleaves the transmembrane protein amyloid-β protein precursor (AβPP), is a therapeutic target for Alzheimer's disease. Gamma-secretase inhibitors (GSIs) and modulators (GSMs) are being investigated as potential disease-modifying agents. Preclinical in vivo models to monitor the activity on gamma-secretase are described in different species such as mouse, rat, and guinea pigs. All these models have their value in testing compounds with amyloid lowering properties, however, compound characteristics and pharmacokinetic properties, as well as other species characteristics such as limited sampling volumes of cerebrospinal fluid (CSF), recommended the use of a larger, non-rodent animal species. For …this purpose, a screening model in dogs was developed for testing GSIs and GSMs. We showed that GSIs and GSMs had a dose- and time-dependent effect on Aβ37 , Aβ38 , Aβ40 , and Aβ42 in CSF. Changes in liver function were evidenced by a transient increase in bilirubin with the GSMs and incidental increases in alanine aminotransferase for GSMs as well as GSIs. Microarray analysis of liver biopsies enabled to elucidate potential mechanisms behind the liver function changes. The relevance of the liver findings should be further evaluated in chronic pre-clinical safety studies and in humans. Based on our data, we can conclude that the dog is a very appropriate species to assess efficacy and safety of compounds which have an effect on AβPP processing such as GSMs, GSIs, and BACE-inhibitors. Show more

Keywords: Alzheimer's disease, amyloid-β, dog, γ-secretase, gene expression, liver

DOI: 10.3233/JAD-2011-111475

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 809-822, 2012

Authors: Barbeau, Emmanuel J. | Didic, Mira | Joubert, Sven | Guedj, Eric | Koric, Lejla | Felician, Olivier | Ranjeva, Jean-Philippe | Cozzone, Patrick | Ceccaldi, Mathieu

Article Type: Research Article

Abstract: An increasing number of studies indicate that semantic memory is impaired in mild cognitive impairment (MCI). However, the extent and the neural basis of this impairment remain unknown. The aim of the present study was: 1) to evaluate whether all or only a subset of semantic domains are impaired in MCI patients; and 2) to assess the neural substrate of the semantic impairment in MCI patients using voxel-based analysis of MR grey matter density and SPECT perfusion. 29 predominantly amnestic MCI patients and 29 matched control subjects participated in this study. All subjects underwent a full neuropsychological assessment, along with …a battery of five tests evaluating different domains of semantic memory. A semantic memory composite Z-score was established on the basis of this battery and was correlated with MRI grey matter density and SPECT perfusion measures. MCI patients were found to have significantly impaired performance across all semantic tasks, in addition to their anterograde memory deficit. Moreover, no temporal gradient was found for famous faces or famous public events and knowledge for the most remote decades was also impaired. Neuroimaging analyses revealed correlations between semantic knowledge and perirhinal/entorhinal areas as well as the anterior hippocampus. Therefore, the deficits in the realm of semantic memory in patients with MCI is more widespread than previously thought and related to dysfunction of brain areas beyond the limbic-diencephalic system involved in episodic memory. The severity of the semantic impairment may indicate a decline of semantic memory that began many years before the patients first consulted. Show more

Keywords: Long-term memory, mild cognitive impairment, neuroimaging, semantic memory

DOI: 10.3233/JAD-2011-110989

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 823-837, 2012

Authors: Ho, Yuen-Shan | Yang, Xifei | Lau, Jeffery Chi-Fai | Hung, Clara Hui-Ling | Wuwongse, Suthicha | Zhang, Qishan | Wang, Jianzhi | Baum, Larry | So, Kwok-Fai | Chang, Raymond Chuen-Chung

Article Type: Research Article

Abstract: Accumulation of unfolded proteins can disturb the functions of the endoplasmic reticulum (ER), leading to ER-stress or unfolded protein response (UPR). Recent data have shown that activation of UPR can be found in postmortem brains of Alzheimer's disease (AD) patients; and biological markers for activation of UPR are abundant in neurons with diffuse phosphorylated tau. Although these observations suggest a linkage between ER-stress and tau pathology, little is known of their relationship. In this study, we found that high levels of phosphorylated PKR-like ER-resident kinase (p-PERK) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) as markers for activation of UPR …in the hippocampus of aged P301L mutant tau transgenic mice. The immunoreactivity of p-PERK was found to co-localize with that of phosphorylated tau. We then hypothesized that phosphorylation of tau could induce ER-stress and vice versa in promoting AD-like pathogenesis. By using the protein phosphatase 2A inhibitor okadaic acid (OA) as an inducer for phosphorylation of tau, we found that primary cultures of rat cortical neurons treated with OA triggered UPR as indicated by increased levels of p-PERK and p-eIF2α, splicing of mRNA for xbp-1 and elevated levels of mRNA for GADD153. On the other hand, thapsigargin as an ER-stress inducer stimulated phosphorylation of tau at Thr231, Ser262 and Ser396. Thapsigargin also induced activation of caspase-3 and cleavage of tau. These findings suggested that ER-stress and hyperphosphorylation of tau could be induced by each other to form a vicious cycle to propagate AD-like neurodegeneration. Show more

Keywords: Alzheimer's disease, ER stress, okadaic acid, tau phosphorylation, thapsigargin

DOI: 10.3233/JAD-2011-111037

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 839-854, 2012

Authors: Bartley, Matthew G. | Marquardt, Kristin | Kirchhof, Danielle | Wilkins, Heather M. | Patterson, David | Linseman, Daniel A.

Article Type: Research Article

Abstract: Aberrant processing of amyloid-β protein precursor (AβPP) into amyloid-β (Aβ) fragments underlies the formation of senile plaques in Alzheimer's disease (AD). Moreover, Aβ fragments, particularly Aβ42 , exert direct toxic effects within neurons including the induction of mitochondrial oxidative stress (MOS). Interestingly, individuals with Down syndrome (DS) frequently develop early onset AD as a major co-morbid phenotype. One hypothesis for AD associated with DS involves the overexpression of wild type (WT) AβPP protein, due to its location on chromosome 21. However, the mechanism by which the overexpression of WT AβPP might trigger MOS and induce cell death is presently unclear. …Here we show that transient overexpression of DsRed2-tagged AβPP (WT) in CHO cells induces caspase-3 activation and nuclear fragmentation indicative of apoptosis. AβPP localizes to the mitochondrial fraction of transfected CHO cells and induces glutathione-sensitive opening of the mitochondrial permeability transition pore (mPTP) and cytochrome c release. MOS and intrinsic apoptosis induced by AβPP are significantly inhibited by co-expression of Bcl-2 or treatment with either glutathione or a pan-caspase inhibitor. The mPTP inhibitor, cyclosporin A, also significantly attenuates AβPP-induced apoptosis. AβPP-induced apoptosis is unaffected by a β-secretase inhibitor and is independent of detectable Aβ42 ; however, a γ-secretase inhibitor significantly protects against AβPP overexpression, suggesting a possible role of the AβPP intracellular domain in cell death. These data indicate that overexpression of WT AβPP is sufficient to induce MOS and intrinsic apoptosis, suggesting a novel pro-oxidant role for AβPP at mitochondria which may be relevant in AD and DS disease pathologies. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, apoptosis, Down syndrome, glutathione, oxidative stress

DOI: 10.3233/JAD-2011-111172

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 855-868, 2012

Authors: Beach, Thomas G. | Sue, Lucia I. | Walker, Douglas G. | Sabbagh, Marwan N. | Serrano, Geidy | Dugger, Brittany N. | Mariner, Monica | Yantos, Kim | Henry-Watson, Jonette | Chiarolanza, Glenn | Hidalgo, Jose A. | Souders, Leslie

Article Type: Research Article

Abstract: Amyloid imaging may revolutionize Alzheimer's disease (AD) research and clinical practice but is critically limited by an inadequate correlation between cerebral cortex amyloid plaques and dementia. Also, amyloid imaging does not indicate the extent of neurofibrillary tangle (NFT) spread throughout the brain. Currently, the presence of dementia as well as a minimal brain load of both plaques and NFTs is required for the diagnosis of AD. Autopsy studies suggest that striatal amyloid plaques may be mainly restricted to subjects in higher Braak NFT stages that meet clinicopathological diagnostic criteria for AD. Striatal plaques, which are readily identified by amyloid imaging, …might therefore be used to predict the presence of a higher Braak NFT stage and clinicopathological AD in living subjects. This study determined the sensitivity and specificity of striatal plaques for predicting a higher Braak NFT stage and clinicopathological AD in a postmortem series of 211 elderly subjects. Subjects included 87 clinicopathologically classified as non-demented elderly controls and 124 with AD. A higher striatal plaque density score (moderate or frequent) had 95.8% sensitivity, 75.7% specificity for Braak NFT stage V or VI and 85.6% sensitivity, 86.2% specificity for the presence of dementia and clinicopathological AD (National Institute on Aging – Reagan Institute “intermediate” or “high”). Amyloid imaging of the striatum may be useful as a predictor, in living subjects, of Braak NFT stage and the presence or absence of dementia and clinicopathological AD. Validation of this hypothesis will require autopsy studies of subjects that had amyloid imaging during life. Show more

Keywords: Alzheimer's disease, amyloid imaging, amyloid plaques, asymptomatic, autopsy, diagnosis, preclinical, striatum, therapy

DOI: 10.3233/JAD-2011-111340

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 869-876, 2012

Authors: Saint-Aubert, Laure | Planton, Mélanie | Hannequin, Didier | Albucher, Jean-François | Delisle, Marie-Bernadette | Payoux, Pierre | Hitzel, Anne | Viallard, Gérard | Péran, Patrice | Campion, Dominique | Laquerrière, Annie | Barbeau, Emmanuel J. | Puel, Michéle | Raposo, Nicolas | Chollet, François | Pariente, Jérémie

Article Type: Research Article

Abstract: We report the case of a 62-year-old asymptomatic carrier of AβPP gene duplication. He was investigated by MRI and the amyloid ligand 18 F-AV45, and compared to Alzheimer's disease patients (n = 11) and healthy controls (n = 11). The neuropsychological examination was normal. Cortical thickness and AV45 retention were comparable to Alzheimer's disease patients. AβPP duplication was diagnosed because cerebral amyloid angiopathy and Alzheimer's disease pathology were found on the neuropathological examination of his youngest brother, who died at 42 from intracerebral hemorrhage. This is the first description of a pre-symptomatic AβPP duplication carrier over 60, despite widespread cerebral …amyloid angiopathy, “Alzheimer's like” atrophy, and amyloid deposition. Show more

Keywords: AβPP duplication, Alzheimer's disease, amyloid, AV45 PET, cerebral amyloid angiopathy, genetics, MRI

DOI: 10.3233/JAD-2011-111598

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 877-883, 2012

Authors: Lemos, Raquel | Figueiredo, Patrícia | Santana, Isabel | Simões, Mário R. | Castelo-Branco, Miguel

Article Type: Research Article

Abstract: The nature of visual impairments in Alzheimer's disease (AD) and their relation with other cognitive deficits remains highly debated. We asked whether independent visual deficits are present in AD and amnestic forms of mild cognitive impairment (MCI) in the absence of other comorbidities by performing a hierarchical analysis of low-level and high-level visual function in MCI and AD. Since parietal structures are a frequent pathophysiological target in AD and subserve 3D vision driven by motion cues, we hypothesized that the parietal visual dorsal stream function is predominantly affected in these conditions. We used a novel 3D task combining three critical …variables to challenge parietal function: 3D motion coherence of objects of unknown orientation, with constrained temporal integration of these cues. Groups of amnestic MCI (n = 20), AD (n = 19), and matched controls (n = 20) were studied. Low-level visual function was assessed using psychophysical contrast sensitivity tests probing the magnocellular, parvocellular, and koniocellular pathways. We probed visual ventral stream function using the Benton Face Recognition task. We have found hierarchical visual impairment in AD, independently of neuropsychological deficits, in particular in the novel parietal 3D task, which was selectively affected in MCI. Integration of local motion cues into 3D objects was specifically and most strongly impaired in AD and MCI, especially when 3D motion was unpredictable, with variable orientation and short-lived in space and time. In sum, specific early dorsal stream visual impairment occurs independently of ventral stream, low-level visual and neuropsychological deficits, in amnestic types of MCI and AD. Show more

Keywords: Alzheimer's disease, mild cognitive impairment, parietal lobe, vision

DOI: 10.3233/JAD-2011-110719

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 885-896, 2012

Authors: Wirths, Oliver | Dins, Annika | Bayer, Thomas A.

Article Type: Research Article

Abstract: The triple-transgenic Alzheimer's disease (AD) mouse model, 3xTg-AD, played an important role in supporting the intraneuronal amyloid-β (Aβ) hypothesis in AD. However, recent evidence claims that the 3xTg-AD mice accumulate amyloid-β protein precursor (AβPP) instead of Aβ within neurons. In the present report, we re-investigated the 3xTg-AD mouse model and confirmed recent findings of age-dependent AβPP accumulations. In addition, intraneuronal Aβ was detected mainly in the neocortex using conformation-specific as well as antibodies directed against Aβ neo-epitopes. In contrast to previous work, however, only minor levels of intraneuronal Aβ were detected in the CA1 region of the hippocampus in aged …3xTg-AD mice. Show more

Keywords: Alzheimer's disease, amyloid, amyloid-β protein precursor, immunohistochemistry, intraneuronal amyloid-β, pyroglutamate amyloid-β, transgenic mice

DOI: 10.3233/JAD-2011-111529

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 897-904, 2012

Authors: Dobos, Nikoletta | de Vries, Erik F.J. | Kema, Ido P. | Patas, Konstantinos | Prins, Marloes | Nijholt, Ingrid M. | Dierckx, Rudi A. | Korf, Jakob | den Boer, Johan A. | Luiten, Paul G.M. | Eisel, Ulrich L.M.

Article Type: Research Article

Abstract: Indoleamine 2,3-dioxygenase (IDO), an enzyme which is activated by pro-inflammatory cytokines, has been suggested as a potential link between neuroinflammatory processes in neurodegenerative diseases (like Alzheimer's disease) and depression. The present study aimed to determine whether neuroinflammation-induced increased IDO levels in the mammalian brain will lead to depressive-like behavior. Neuroinflammation was initiated in mice by a single intracerebroventricular injection of lipopolysaccharide (LPS). Cerebral inflammation was monitored 1, 2, 3 and 4 days after the injection with small-animal positron emission tomography (PET) using the inflammatory marker [11 C]-PK11195. In the presence or absence of systemically applied 1-methyl-tryptophan (1-MT), a competitive IDO-inhibitor, …we assessed the development of depressive-like behavioral symptoms in parallel with IDO expression and activity. The PK11195 PET signal reached a highly significant peak 3 days after LPS injection, while these animals displayed a significant increase of depressive-like behavior in the forced swim test compared to vehicle-injected animals. These findings were paralleled by a significant increase of IDO in the brainstem, and an increased kynurenine/tryptophan ratio in the serum. Moreover, we report here for the first time, that inhibition of IDO by 1-MT in centrally induced neuroinflammation under experimental conditions can prevent the development of depressive-like behavior. Show more

Keywords: Depression, indoleamine 2, 3-dioxygenase, lipopolysaccharide, neuroinflammation, positron emission tomography

DOI: 10.3233/JAD-2011-111097

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 905-915, 2012

Authors: Elfrink, Hyung Lim | Zwart, Rob | Cavanillas, María L. | Schindler, Adam Jay | Baas, Frank | Scheper, Wiep

Article Type: Research Article

Abstract: The unfolded protein response (UPR) is a stress response of the endoplasmic reticulum (ER), the first compartment of the secretory pathway. The UPR is activated in non-tangle bearing neurons in Alzheimer's disease (AD) brain, indicating it is an early phenomenon. We found that the level of Rab6, implicated in anterograde and retrograde trafficking in the secretory pathway, is increased in brains of AD patients. Rab6 expression, closely correlated with the extent of UPR activation, is not controlled by the UPR. This suggests that Rab6 and UPR activation are both increased in response to early pathogenic changes in AD. Here we …demonstrate that Rab6 modulates the UPR, increased levels inhibit whereas decreased levels augment UPR induction. Rab6 is not involved in the initial phase of the UPR; it only affects the UPR after prolonged ER stress. We propose that Rab6 is involved in the recovery from an ER stress insult. The increased Rab6 levels in AD brain in combination with UPR activation suggest that a failure to recover from ER stress may contribute to neurodegeneration in AD. The Rab6 mediated recovery pathway may provide a target to selectively inhibit the destructive pathways of the UPR. Show more

Keywords: Alzheimer's disease, endoplasmic reticulum stress, Rab6, unfolded protein response

DOI: 10.3233/JAD-2011-110971

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 917-929, 2012

Authors: Creavin, Samuel T. | Gallacher, John | Bayer, Antony | Fish, Mark | Ebrahim, Shah | Ben-Shlomo, Yoav

Article Type: Research Article

Abstract: We have examined whether metabolic syndrome is associated with intermediate risk of impaired cognition between people with and without diabetes. Men aged 45 to 59 years were identified from Caerphilly in South Wales, United Kingdom. Participation rate was 89% (41% of the original cohort) and 2,512 men were examined in phase one from July 1979 until September 1983. Follow-up examinations occurred at four intervals until 2004 when 1,225 men participated. Participants were categorized on the basis of their exposure to metabolic syndrome not diabetes (MSND) and diabetes (with or without metabolic syndrome) at each of the first three phases. Neuropsychological …outcomes and clinical diagnosis of cognitive impairment not dementia (CIND) and dementia were assessed at phase five. The prevalence of MSND increased from 1% to 5% and for diabetes from 3% to 9% between phase one and phase three. 15% of participants had CIND and 8% dementia. People with diabetes, but not those with MSND, at phases one, two, or three had poorer cognition at phase five (adjusted β coefficient AH4 −4.3 95% CI −7.9, −0.7; phase two: −2.5 95% CI −4.7, −0.3; phase three: −2.3 95% CI −4.2, −0.5). The adjusted odds ratio (phase one) for diabetes and CIND was 4.0 (95% CI 1.4, 11.5) and dementia 0.61 (95% CI 0.07, 5.37). After adjustment, higher systolic blood pressure was the only component of the metabolic syndrome associated with worse cognitive outcomes. Diabetes in mid-life, but not MSND, is associated with impaired cognition and increased odds of CIND in later life. Show more

Keywords: Cognition disorders/epidemiology, cohort studies, diabetes mellitus Type 2/complications, metabolic syndrome X/epidemiology, risk factors

DOI: 10.3233/JAD-2011-111550

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 931-939, 2012

Authors: Premi, Enrico | Pilotto, Andrea | Alberici, Antonella | Papetti, Alice | Archetti, Silvana | Seripa, Davide | Daniele, Antonio | Masullo, Carlo | Garibotto, Valentina | Paghera, Barbara | Caobelli, Federico | Padovani, Alessandro | Borroni, Barbara

Article Type: Research Article

Abstract: Primary progressive aphasia (PPA) is a heterogeneous disorder characterized by progressive language impairment. Polymorphisms within forkhead box P2 gene (FOXP2) gene have been associated with speech and language impairment. Apolipoprotein E (APOE) genotype and PRNP 129 codon status have been demonstrated to increase the risk of PPA, but with contrasting results. In the present study, we have evaluated the impact of FOXP2, APOE and PRNP genetic variations as risk factors and/or disease-modulators in PPA. 94 PPA patients and 200 age-matched healthy controls were considered and FOXP2 polymorphisms (rs1456031, rs17137124), APOE genotype, and PRNP codon 129 polymorphism analyzed. In 34 PPA …patients, SPECT imaging data were analyzed by Statistical Parametric Mapping (SPM8). Genetic distributions and allele frequencies of FOXP2 and PRNP polymorphisms did not differ between groups while APOE ε4 was more represented in PPA as compared to controls. PPA patients carrying at-risk FOXP2 polymorphisms (rs1456031 and/or rs17137124) showed greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus and the right cingulated gyrus compared to non-carriers (p < 0.005). PPA patients carrying at least one ε4 allele had greater hypoperfusion in orbitofrontal regions (superior frontal gyrus and orbital gyrus) as compared to non-carriers ε4 (p < 0.005). PRNP codon 129 homozigosity correlated with left frontotemporal hypoperfusion (p < 0.005). Genetic variations within FOXP2, APOE, and PRNP modulate PPA disease, leading to a specific regional hypoperfusion according to different molecular pathways. APOE ε4 is overrepresented in PPA, thus likely acting as genetic risk factor on disease development. Show more

Keywords: Apolipoprotein E ε4, FOXP2, primary progressive aphasia, progressive non-fluent aphasia, PRNP, semantic dementia, SPECT, statistical parametric mapping

DOI: 10.3233/JAD-2011-111541

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 941-950, 2012

Authors: Erickson, Michelle A. | Niehoff, Michael L. | Farr, Susan A. | Morley, John E. | Dillman, Lucy A. | Lynch, Kristin M. | Banks, William A.

Article Type: Research Article

Abstract: The senescence accelerated mouse-prone 8 (SAMP8) mouse model of Alzheimer's disease has a natural mutation leading to age-related increases in the amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) in the brain, memory impairment, and deficits in Aβ removal from the brain. Previous studies show that centrally administered antisense oligonucleotide directed against AβPP can decrease AβPP expression and Aβ production in the brains of aged SAMP8 mice, and improve memory. The same antisense crosses the blood-brain barrier and reverses memory deficits when injected intravenously. Here, we give 6 μg of AβPP or control antisense 3 times over 2 week intervals to …12 month old SAMP8 mice. Object recognition test was done 48 hours later, followed by removal of whole brains for immunoblot analysis of AβPP, low-density lipoprotein-related protein-1 (LRP-1), p-glycoprotein (Pgp), receptor for advanced glycation endproducts (RAGE), or ELISA of soluble Aβ40 . Our results show that AβPP antisense completely reverses a 30% age-associated increase in AβPP signal (p < 0.05 versus untreated 4 month old SAMP8). Soluble Aβ40 increased with age, but was not reversed by antisense. LRP-1 large and small subunits increased significantly with age (147.7%, p < 0.01 and 123.7%, p < 0.05 respectively), and AβPP antisense completely reversed these increases (p < 0.05). Pgp and RAGE were not significantly altered with age or antisense. Antisense also caused improvements in memory (p < 0.001). Together, these data support the therapeutic potential of AβPP antisense and show a unique association between AβPP and LRP-1 expression in the SAMP8 mouse. Show more

Keywords: Abcb1, amyloid-β peptides, amyloid-β protein precursor, antisense, blood-brain barrier, LRP1, oligonucleotides, Pgp, RAGE, SAMP8

DOI: 10.3233/JAD-2011-111517

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 951-960, 2012

Authors: Boddapati, Shanta | Levites, Yona | Suryadi, Vick | Kasturirangan, Srinath | Sierks, Michael R.

Article Type: Research Article

Abstract: Misfolding and aggregation of amyloid-β (Aβ) is an important early event in the pathogenesis of Alzheimer's disease. Aβ is produced by sequential proteolysis of the amyloid-β protein precursor (AβPP) by β- and γ-secretases. A third protease, α-secretase, cleaves AβPP in the middle of the Aβ sequence precluding formation of Aβ. The levels of Aβ generated from AβPP can therefore be controlled by tailoring activity of these proteases toward AβPP. We previously showed that β-secretase proteolysis of AβPP could be selectively inhibited using the single chain antibody fragment (scFv) iBSEC1, which blocks the cleavage site on AβPP, and α-secretase proteolysis of …AβPP could be selectively enhanced using a proteolytic scFv (Asec1A) engineered to have α-secretase-like activity. Here we show that DIA10D, a novel tandem bispecific scFv combining iBSEC1 with the ASec1A can control amyloidogenic processing of AβPP by simultaneously inhibiting β-secretase and increasing α-secretase processing of AβPP. When expressed in H4 (neuroglioma) cells overexpressing AβPP, DIA10D potently reduces levels of extracellular Aβ by around 50% while also increasing levels of neuroprotective sAβPPα. DIA10D activity has been designed to selectively target AβPP, so this modulation of AβPP processing should not affect endogenous activity of α-and β-secretases towards other substrates. Show more

Keywords: AβPP processing, bispecific tandem scFv, α-secretase, β-secretase

DOI: 10.3233/JAD-2011-111196

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 961-969, 2012

Article Type: Other

DOI: 10.3233/JAD-2011-111197

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 971-972, 2012

Article Type: Other

DOI: 10.3233/JAD-2012-28422

Citation: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 973-984, 2012