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