Journal of Alzheimer's Disease - Volume 37, issue 2

Authors: Kazmerova, Zuzana | Zilka, Norbert | Cente, Martin | Neradil, Peter | Zilkova, Monika | Novak, Michal

Article Type: Review Article

Abstract: Human neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease represent unmet medical need. There is no effective cure available on the market. Several novel therapeutic approaches targeting fundamental features of these disorders have been proposed during the last two decades. Cell therapy represents one of the most promising therapeutic avenues targeting different pathological traits of these disorders. However, there are some caveats that should be taken into the consideration including ethical issues and limited utilization for routine clinical practice. It is unlikely that cell therapy constitutes the ‘magic bullet’ therapeutic approach that would meet all therapeutic needs. However, in …the future it can potentially bolster the effect of disease modifying drugs by improving the brain environment and regulation of inflammatory and neurotrophic pathways. Show more

Keywords: Alzheimer disease, cell replacement therapy, Parkinson disease, regenerative therapy, stem cells

DOI: 10.3233/JAD-130572

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 251-272, 2013

Authors: Mroczko, Barbara | Groblewska, Magdalena | Barcikowska, Maria

Article Type: Review Article

Abstract: Matrix metalloproteinases (MMPs) and their natural tissue inhibitors (TIMPs) are involved in cell signaling processes and the release of extracellular matrix (ECM) and non-ECM molecules. Nonregulated MMP activity and an imbalance between metalloproteinases and their inhibitors might contribute to various disorders, including neurodegenerative diseases such as Alzheimer's disease (AD), which is the most common cause of dementia. There is a complex relationship between MMPs and TIMPs with AD. It has been shown that MMPs and TIMPs are localized in neuritic senile plaques and neurofibrillary tangles in the postmortem brains of patients with AD. Some MMPs have also been shown to …induce tau aggregation and the formation of neurofibrillary tangles in vitro. Moreover, MMPs contribute to AD pathogenesis via the disruption of the blood-brain barrier and promotion of neurodegeneration. However, MMPs can degrade both soluble and fibrillar forms of amyloid-β (Aβ). It has also been shown that Aβ enhances the expression of MMPs in neuroglial cultures and induces the release of TIMP-1 by brain cells. Inhibition of Aβ-induced MMP activity resulted in an improvement of performance tests in mice. Moreover, simultaneous examination of MMP-9, MMP-2, and TIMP-1 in the CSF contributed to the ability to differentiate between AD and other types of dementia. Thus, the aim of this literature study was to describe the role of MMPs and TIMPs in neurodegeneration, as well as their potential usefulness as CSF or plasma biomarkers in the diagnosis of AD as well as other neurodegenerative disorders and vascular dementia. Show more

Keywords: Alzheimer's disease, amyloid-β, dementia, matrix metalloproteinases, neurodegeneration, tau protein, tissue inhibitors of matrix metalloproteinases

DOI: 10.3233/JAD-130647

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 273-283, 2013

Authors: Bernardi, Livia | Gallo, Maura | Anfossi, Maria | Conidi, Maria Elena | Colao, Rosanna | Puccio, Gianfranco | Curcio, Sabrina A.M. | Frangipane, Francesca | Clodomiro, Alessandra | Mirabelli, Maria | Vasso, Franca | Smirne, Nicoletta | Di Lorenzo, Raffaele | Maletta, Raffaele | Bruni, Amalia C.

Article Type: Short Communication

Abstract: We investigated the association between TOMM40 rs10524523, age of onset, and memory performance in patients with the PSEN1 M146L mutation in a large familial Alzheimer's disease Calabrian kindred, with a wide variability of onset not attributable to APOE. APOE33/TOMM40VL/VL patients showed a tendency for an earlier age at onset compared to those with APOE33/TOMM40VL/S and APOE33/TOMM40S/S. Moreover, TOMM40VL/VL patients had better memory performance, when compared to TOMM40S/S but not to TOMM40VL/S patients, so there is not a dose-dependent effect. Our results suggest that, in the presence of the PSEN1 mutation, the slight difference in age of onset together with memory …performance could be influenced by TOMM40 genotypes. Show more

Keywords: Familial Alzheimer's disease, large kindreds, onset variability, performance on memory, PSEN1 M146L mutation, TOMM40 rs10524523 genotype

DOI: 10.3233/JAD-130119

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 285-289, 2013

Authors: Sun, Lei | Tan, Meng-Shan | Hu, Nan | Yu, Jin-Tai | Tan, Lan

Article Type: Short Communication

Abstract: BIN1, as an important genetic susceptibility locus in late-onset Alzheimer's disease (AD), is overexpressed in AD brains. Our study investigated BIN1 diagnostic value by quantifying its transcription level and plasma expression from 112 AD and 200 control subjects. We observed significant increase in BIN1 mRNA and protein levels in AD patients. Receiver operating characteristic curve analysis shown the sensitivity and specificity were 73% and 75% for plasma BIN1 in identifying AD. Although this is a pilot study requiring corroboration on a larger cohort of patients, our results highlight the possible use of plasma BIN1 as a biomarker for AD diagnosis.

Keywords: Alzheimer's disease, BIN1, biomarker, ELISA, plasma, qRT-PCR

DOI: 10.3233/JAD-130392

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 291-295, 2013

Authors: Yang, Hongqian | Wittnam, Jessica L. | Zubarev, Roman A. | Bayer, Thomas A.

Article Type: Research Article

Abstract: AβpE3-42 (N-terminal truncated amyloid-β peptide starting with pyroglutamate at the third position) is abundant in Alzheimer's disease (AD) brain and has high aggregation propensity and cellular toxicity. Transgenic TBA42 mice expressing AβpE3-42 exhibit a neurological phenotype evident at the age of 12 months. As AD has a long presymptomatic period, early detection of imminent neurodegeneration is highly desirable. In the present work we used four-month-old presymptomatic TBA42 mice and performed a whole-brain proteome analysis in order to elucidate early AD-related pathological changes and the molecular networks involved. At least three proteins were found to be moderately (by 17% …to 28%) but statistically significantly upregulated, including: nectin-like molecule 1 involved in cell-cell adhesion; Homer proteins involved in scaffolding, organizing proteins at synapse and regulating intracellular calcium within neurons; and inositol-trisphosphate 3-kinase A, which is important for InsP3 induced calcium signaling in the brain. Analysis of key nodes (regulatory molecules found on pathway intersections) identified Rho-kinase (ROCK), a serine/threonine kinase and one of the major downstream effectors of the small GTPase Rho, as well as three key nodes of the mTOR/p70S6K signaling pathway previously implicated in multiple fundamental biological processes including synaptic plasticity, and upregulated in AD. These data confirm that AD-typical molecular pathways can be detected by whole-brain shotgun proteomics in young presymptomatic mice long before the onset of behavioral changes. Show more

Keywords: Amyloid-β peptide, LC/MS, mass spectrometry, shotgun proteomics

DOI: 10.3233/JAD-130476

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 297-308, 2013

Authors: Huber, Bertrand R. | Meabon, James S. | Martin, Tobin J. | Mourad, Pierre D. | Bennett, Raymond | Kraemer, Brian C. | Cernak, Ibolja | Petrie, Eric C. | Emery, Michael J. | Swenson, Erik R. | Mayer, Cynthia | Mehic, Edin | Peskind, Elaine R. | Cook, David G.

Article Type: Research Article

Abstract: Mild traumatic brain injury (mTBI) is considered the ‘signature injury’ of combat veterans that have served during the wars in Iraq and Afghanistan. This prevalence of mTBI is due in part to the common exposure to high explosive blasts in combat zones. In addition to the threats of blunt impact trauma caused by flying objects and the head itself being propelled against objects, the primary blast overpressure (BOP) generated by high explosives is capable of injuring the brain. Compared to other means of causing TBI, the pathophysiology of mild-to-moderate BOP is less well understood. To study the consequences of BOP …exposure in mice, we employed a well-established approach using a compressed gas-driven shock tube that recapitulates battlefield-relevant open-field BOP. We found that 24 hours post-blast a single mild BOP provoked elevation of multiple phospho- and cleaved-tau species in neurons, as well as elevating manganese superoxide-dismutase (MnSOD or SOD2) levels, a cellular response to oxidative stress. In hippocampus, aberrant tau species persisted for at least 30 days post-exposure, while SOD2 levels returned to sham control levels. These findings suggest that elevated phospho- and cleaved-tau species may be among the initiating pathologic processes induced by mild blast exposure. These findings may have important implications for efforts to prevent blast-induced insults to the brain from progressing into long-term neurodegenerative disease processes. Show more

Keywords: Blast-induced neurotrauma, brain trauma, cerebellum, mitochondrial oxidative stress, neurodegeneration, tauopathy

DOI: 10.3233/JAD-130182

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 309-323, 2013

Authors: Shiota, Satomi | Takekawa, Hidenori | Matsumoto, Shin-ei | Takeda, Kazuya | Nurwidya, Fariz | Yoshioka, Yasuko | Takahashi, Fumiyuki | Hattori, Nobutaka | Tabira, Takeshi | Mochizuki, Hideki | Takahashi, Kazuhisa

Article Type: Research Article

Abstract: Previous studies have shown a high prevalence of obstructive sleep apnea (OSA) among patients with Alzheimer's disease (AD). However, it is poorly assessed whether chronic intermittent hypoxia (CIH), which is a characteristic of OSA, affects the pathophysiology of AD. We aimed to investigate the direct effect of intermittent hypoxia (IH) in pathophysiology of AD in vivo and in vitro. In vivo, 15 male triple transgenic AD mice were exposed to either CIH or normoxia (5% O2 and 21% O2 every 10 min, 8 h/day for 4 weeks). Amyloid-β (Aβ) profile, cognitive brain function, and brain pathology were evaluated. …In vitro, human neuroblastoma SH-SY5Y cells stably expressing wild-type amyloid-β protein precursor were exposed to either IH (8 cycles of 1% O2 for 10 min followed by 21% O2 for 20 min) or normoxia. The Aβ profile in the conditioned medium was analyzed. CIH significantly increased levels of Aβ42 but not Aβ40 in the brains of mice without the increase in hypoxia-inducible factor 1, alpha subunit (HIF-1α) expression. Furthermore, CIH significantly increased intracellular Aβ in the brain cortex. There were no significant changes in cognitive function. IH significantly increased levels of Aβ42 in the medium of SH-SY5Y cells without the increase in the HIF-1α expression. CIH directly and selectively increased levels of Aβ42 in the AD model. Our results suggest that OSA would aggravate AD. Early detection and intervention of OSA in AD may help to alleviate the progression of the disease. Show more

Keywords: Alzheimer's disease, amyloid-β peptide, hypoxia, obstructive sleep apnea

DOI: 10.3233/JAD-130419

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 325-333, 2013

Authors: Pires, Carolina | Coelho, Miguel | Valadas, Anabela | Barroso, Cândida | Pimentel, José | Martins, Madalena | Duyckaerts, Charles | de Mendonça, Alexandre | Verdelho, Ana | Miltenberger-Miltenyi, Gabriel

Article Type: Research Article

Abstract: The clinical phenotype of frontotemporal dementia patients carrying progranulin (GRN) mutations is known to be heterogeneous. We present a patient with corticobasal syndrome and a family with progressive aphasia and behavioral features who were found to have the same p.Gln257Profs*27 mutation. These cases depict the variability of GRN mutation carriers regarding clinical presentation and age of onset. In addition to giving a detailed report of a GRN mutation, we highlight the importance of searching for the presence of GRN mutations in selected sporadic cases and suggest a broadening of GRN genetic screening to better understand the clinical spectrum of these …mutations. Show more

Keywords: Frontotemporal dementia, frontotemporal lobar degeneration, GRN protein, primary progressive nonfluent aphasia

DOI: 10.3233/JAD-130146

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 335-342, 2013

Authors: Descamps, Olivier | Spilman, Patricia | Zhang, Qiang | Libeu, Clare P. | Poksay, Karen | Gorostiza, Olivia | Campagna, Jesus | Jagodzinska, Barbara | Bredesen, Dale E. | John, Varghese

Article Type: Research Article

Abstract: A systematic approach was used to identify AβPP-selective BACE inhibitors (ASBI) and to evaluate their in vivo ability to modulate AβPP processing selectively. We identified a bioflavonoid nutritional supplement as a molecular lead that acts as an ASBI in cell models, and show that increasing brain levels of this bioflavonoid through a pro-drug approach leads to reduction of Aβ42 in an Alzheimer's disease mouse model. ASBIs represent a novel class of candidate therapeutic agents for Alzheimer's disease.

Keywords: Alzheimer's disease, AβPP, ASBI, galangin, pro-drug, rutin

DOI: 10.3233/JAD-130578

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 343-355, 2013

Authors: Handels, Ron L.H. | Xu, Weili | Rizzuto, Debora | Caracciolo, Barbara | Wang, Rui | Winblad, Bengt | Verhey, Frans R.J. | Severens, Johan L. | Fratiglioni, Laura | Joore, Manuela A. | Wimo, Anders

Article Type: Research Article

Abstract: Background: Empirical models of the natural history of Alzheimer’s disease (AD) may help to evaluate new interventions for AD. Objective: We aimed to estimate AD-free survival time in people with mild cognitive impairment (MCI) and decline of cognitive and physical function in AD cases. Methods: Within the Kungsholmen project, 153 incident MCI and 323 incident AD cases (international criteria) were identified during 9 years of follow-up in a cognitively healthy cohort of elderly people aged ⩾75 at baseline (n = 1,082). Global cognitive function was assessed with the Mini-Mental State Examination (MMSE), and daily life function …was evaluated with the Katz index of activities of daily living (ADL) at each follow-up examination. Data were analyzed using parametric survival analysis and mixed effect models. Results: Median AD-free survival time of 153 participants with incident MCI was 3.5 years. Among 323 incident AD cases, the cognitive decline was 1.84 MMSE points per year, which was significantly associated with age. Physical functioning declined by 0.38 ADL points per year and was significantly associated with age, education, and MMSE, but not with gender. Conclusion: Elderly people with MCI may develop AD in approximately 3.5 years. Both cognitive and physical function may decline gradually after AD onset. The empirical models can be used to evaluate long-term disease progression of new interventions for AD. Show more

Keywords: Alzheimer's disease, dementia, disease progression, economic model, mild cognitive impairment

DOI: 10.3233/JAD-130296

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 357-365, 2013

Authors: Jantaratnotai, Nattinee | Ling, Alden | Cheng, Jenny | Schwab, Claudia | McGeer, Patrick L. | McLarnon, James G.

Article Type: Research Article

Abstract: Immunohistochemical staining has been used to determine expression patterns of the angiogenic transcription factor, Ets-1, in the brains of Alzheimer's disease (AD) individuals. Brain tissue from non-demented controls showed little expression of Ets-1 whereas in AD brain tissue, Ets-1 was ubiquitously expressed in cortex and hippocampus. Double immunostaining with von Willerbrand factor demonstrated prominent Ets-1 intravascular immunoreactivity (ir) in AD cortical microvessels. In addition, Ets-1 also exhibited extravascular expression characterized by a diffuse pattern of Ets-1 ir in AD brain. Double staining also showed Ets-1 colocalization in microvasculature with the potent angiogenic agent, vascular endothelial growth factor (VEGF). Cell-associated tumor …necrosis factor-α (TNF-α), a pro-inflammatory cytokine with pro-angiogenic activity, was primarily associated with diffuse extravascular Ets-1 ir. Clusters of HLA-DR positive microglia, resident immune cells of brain which release TNF-α, were also localized with diffuse Ets-1. Intravascular Ets-1 ir was maximally co-localized with soluble amyloid-β peptide (Aβ), Aβ1-40 , in microvasculature whereas diffuse extravascular Ets-1 ir appeared in proximity to Aβ plaques in brain parenchyma. Similar overall results were obtained for patterns of Ets-1 staining in AD hippocampal tissue. This work provides novel findings on expression of the angiogenic transcription factor, Ets-1, in vascular remodeling and its association with pro-angiogenic factors, reactive microglia, and Aβ deposition in AD brain. Show more

Keywords: Alzheimer's disease, amyloid-β, angiogenesis, Ets-1, microglia, tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF)

DOI: 10.3233/JAD-122191

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 367-377, 2013

Authors: Sorensen, Katrine Christa Nordskov | Simonsen, Anja Hviid | Holmetoft, Ulla Bachmann | Hasselbalch, Steen Gregers | Heegaard, Niels H.H.

Article Type: Research Article

Abstract: A relation between amyloid-β peptide (Aβ) accumulation and neprilysin (NEP), an Aβ degrading enzyme, has been proposed but studies of NEP and the levels of the pathological hallmarks of Alzheimer's disease (AD), Aβ and tau, in cerebrospinal fluid (CSF) are scarce. In this study, we measured the level and enzyme activity of NEP in serum and CSF, using a sandwich enzyme-linked immunosorbent assay and a fluorescence resonance energy transfer assay, respectively, in patients with AD, frontotemporal dementia (FTD), Creutzfeldt-Jakob disease (CJD), and depression. Results were correlated with the levels of CSF AD biomarkers Aβ42 , hyperphosphorylated tau (p-tau), and total …tau (t-tau). In serum, we found no differences in NEP-like activity or concentration between the groups and there were no correlations between NEP and AD biomarkers. In CSF, no influence of age or gender on NEP levels or enzyme activity was seen. However, NEP concentration was lower and the specific activity was higher in FTD compared to AD. Aβ42 levels in CSF did not correlate with NEP concentration or activity in the AD, CJD, or depression groups, but NEP-like activity and Aβ42 levels correlated significantly in the FTD group. In AD and depression, the NEP-like activity in CSF correlated with levels of p-tau, and, in the AD group, it also was correlated with t-tau levels. Our results suggest that the relation between the specific activity of NEP and t-tau and p-tau is a characteristic trait of AD. The correlation between NEP concentration and Aβ42 in FTD is unexpected and warrants further investigation. Show more

Keywords: Alzheimer's disease, amyloid-β42, cerebrospinal fluid, depression, frontotemporal dementia, hyperphosphorylated tau, neprilysin, serum, total tau

DOI: 10.3233/JAD-122410

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 379-387, 2013

Authors: Morgen, Katrin | Frölich, Lutz | Tost, Heike | Plichta, Michael M. | Kölsch, Heike | Rakebrandt, Fabian | Rienhoff, Otto | Jessen, Frank | Peters, Oliver | Jahn, Holger | Luckhaus, Christian | Hüll, Michael | Gertz, Hermann-Josef | Schröder, Johannes | Hampel, Harald | Teipel, Stefan J. | Pantel, Johannes | Heuser, Isabella | Wiltfang, Jens | Rüther, Eckart | Kornhuber, Johannes | Maier, Wolfgang | Meyer-Lindenberg, Andreas

Article Type: Research Article

Abstract: Background: The E4 isoform of the APOE genotype is the most significant genetic risk factor for sporadic Alzheimer’s disease (AD) and has recently been found to modulate disease expression in patients with AD. Objective: To investigate APOE-dependent cognitive and structural phenotypes in subjects with mild cognitive impairment who converted to AD within the following three years. Methods: Subjects converting to AD (n = 63) were compared to a control group with stable mild cognitive impairment (n = 131). Clinical, neuropsychological, and MRI data were obtained by the German Dementia Competence Network. Subgroups of converting and stable …APOE E4 carriers and non-carriers were investigated longitudinally with MRI to examine structural correlates of conversion. Voxel-based morphometry was applied to investigate gray matter distribution. Results: At baseline, executive performance correlated with global and bilateral prefrontal gray matter volume and predicted conversion only among non-carriers. Converting carriers and non-carriers presented distinct patterns of brain atrophy on longitudinal analysis, in line with a dissociation between more pronounced occipital atrophy in carriers and more frontoparietal volume loss in non-carriers at follow-up. Conclusions: The current findings suggest that in APOE E4 non-carriers with AD, executive dysfunction is closely linked to frontal gray matter atrophy and predictive of progression to dementia. The results are consistent with APOE genotype-dependent profiles of structural damage and cognitive decline in patients with imminent conversion to AD. Show more

Keywords: APOE, Alzheimer's disease, magnetic resonance imaging, mild cognitive impairment, phenotypes, voxel-based morphometry

DOI: 10.3233/JAD-130326

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 389-401, 2013

Authors: Zhao, Liqin | Mao, Zisu | Chen, Shuhua | Schneider, Lon S. | Brinton, Roberta D.

Article Type: Research Article

Abstract: Our recent developments have yielded a novel phytoestrogenic formulation, referred to as the phyto-β-SERM formulation, which exhibits an 83-fold binding selectivity for the estrogen receptor subtype β (ERβ) over ERα. Earlier studies indicate that the phyto-β-SERM formulation is neuroprotective and promotes estrogenic mechanisms in the brain while devoid of feminizing activity in the periphery. Further investigation in a mouse model of human menopause indicates that chronic exposure to the phyto-β-SERM formulation at a clinically relevant dosage prevents/alleviates menopause-related climacteric symptoms. This study assessed the efficacy, in an early intervention paradigm, of the phyto-β-SERM formulation in the regulation of early stages …of physical and neurological changes associated with Alzheimer's disease (AD) in a female triple transgenic mouse model of AD. Results demonstrated that, when initiated prior to the appearance of AD pathology, a 9-month dietary supplementation with the phyto-β-SERM formulation promoted physical health, prolonged survival, improved spatial recognition memory, and attenuated amyloid-β deposition and plaque formation in the brains of treated AD mice. In comparison, dietary supplementation of a commercial soy extract preparation showed no effect on cognitive measures, although it appeared to have a positive impact on amyloid pathology. In overall agreement with the behavioral and histological outcomes, results from a gene expression profiling analysis offered insights on the underlying molecular mechanisms associated with the two dietary treatments. In particular, the data suggests that there may be a crosstalk between ERβ and glycogen synthase kinase 3 signaling pathways that could play a role in conferring ERβ-mediated neuroprotection against AD. Taken together, these results support the therapeutic potential of the phyto-β-SERM formulation for prevention and/or early intervention of AD, and warrants further investigations in human studies. Show more

Keywords: Alzheimer's disease, early intervention, estrogen receptor β, glycogen synthase kinase 3, phyto-β-SERM formulation

DOI: 10.3233/JAD-122341

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 403-419, 2013

Authors: Qiu, Wei Qiao | Mwamburi, Mkaya | Besser, Lilah M. | Zhu, Haihao | Li, Huajie | Wallack, Max | Phillips, Leslie | Qiao, Liyan | Budson, Andrew E. | Stern, Robert | Kowall, Neil

Article Type: Research Article

Abstract: Our cross-sectional study showed that the interaction between apolipoprotein E4 (ApoE4) and angiotensin converting enzyme (ACE) inhibitors was associated with Alzheimer's disease (AD). The aim of this longitudinal study was to differentiate whether ACE inhibitors accelerate or reduce the risk of AD in the context of ApoE alleles. Using the longitudinal data from the National Alzheimer's Coordinating Center (NACC) with ApoE genotyping and documentation of ACE inhibitors use, we found that in the absence of ApoE4, subjects who had been taking central ACE inhibitor use (χ2 test: 21% versus 27%, p = 0.0002) or peripheral ACE inhibitor use (χ2 …test: 13% versus 27%, p < 0.0001) had lower incidence of AD compared with those who had not been taking an ACE inhibitor. In contrast, in the presence of ApoE4, there was no such association between ACE inhibitor use and the risk of AD. After adjusting for the confounders, central ACE inhibitor use (OR = 0.68, 95% CI = 0.55, 0.83, p = 0.0002) or peripheral ACE inhibitor use (OR = 0.33, 95% CI = 0.33, 0.68, p < 0.0001) still remained inversely associated with a risk of developing AD in ApoE4 non-carriers. In conclusion, ACE inhibitors, especially peripherally acting ones, were associated with a reduced risk of AD in the absence of ApoE4, but had no such effect in those carrying the ApoE4 allele. A double-blind clinical trial should be considered to determine the effect of ACE inhibitors on prevention of AD in the context of ApoE genotype. Show more

Keywords: Alzheimer's disease, apolipoprotein E4 allele (ApoE4), angiotensin converting enzyme (ACE) inhibitor

DOI: 10.3233/JAD-130716

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 421-428, 2013

Authors: Jin, Chunhui | Liu, Xiaowei | Zhang, Fuquan | Wu, Yue | Yuan, Jianmin | Zhu, Jianzhong | Zhang, Feng | Wang, Guoqiang | Cheng, Zaohuo

Article Type: Research Article

Abstract: The pathogenetic mechanism of Alzheimer's disease (AD) is still unknown; however, genetic variants play a critical role in the pathogenesis of AD. It has been reported that single nucleotide polymorphisms (SNPs) of the sortilin-related receptor with A-type repeats (SORL1, also called LR11 or sorLA) are associated with late-onset AD in Caucasian populations. Subsequently, other researchers have attempted to validate this finding in different ethnic populations. However, these findings have produced both negative and positive results. To derive a more precise estimation of whether SORL1 variants are associated with sporadic AD (SAD), we performed the meta-analysis presented in this manuscript. Databases …including PubMed, AlzGene, the China National Knowledge Infrastructure (CNKI), and Wan Fang were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association studies. A total of twenty-three case-control studies involving 11,837 cases and 20,022 controls were included. Among the eleven candidate SNPs highlighted in the previous study, four SNPs (SNP 4, SNP 5, SNP 8 and SNP 10) showed a significant association with SAD using a generalized odds ratio (ORG, a model-free approach) and linkage disequilibrium structure analysis. Meanwhile, no significant heterogeneity between the Caucasian and Asian populations for the associated SNPs was observed in the current meta-analysis. Moreover, we further confirmed that the SORL1 three-marker haplotype C-G-C at SNP 8-SNP 9-SNP 10 was significantly associated with SAD (OR = 1.37, 95% CI = 1.12–1.66, padj = 0.008). The current meta-analysis further supports the previous findings that the SORL1 gene may be associated with SAD risk. Show more

Keywords: Allele, Alzheimer's disease, association, single nucleotide polymorphism, SORL1

DOI: 10.3233/JAD-130533

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 429-437, 2013

Authors: Daschil, Nina | Obermair, Gerald J. | Flucher, Bernhard E. | Stefanova, Nadia | Hutter-Paier, Birgit | Windisch, Manfred | Humpel, Christian | Marksteiner, Josef

Article Type: Research Article

Abstract: Increased activity of L-type Ca2+ channels has been implicated in the pathogenesis of dementia and Alzheimer's disease (AD). Previously we detected CaV 1.2 α1 -subunit-positive expression in reactive astrocytes surrounding the plaques of 12 month-old transgenic mice overexpressing hAβPP751 with the London (V717I) and Swedish (K670M/N671L) mutations. Here we examined whether increased CaV 1.2 α1 -subunit expression precedes plaque formation or is specifically associated with the increased amyloid-β (Aβ) load in the plaques. Quantitative RT-PCR expression profiling of all high voltage-gated Ca2+ channel subunits (α1 , β, and α2 δ) revealed no difference in the hippocampi of 2, …4, and 11 month-old wild type (wt) and transgenic (tg) mice. Immunohistochemistry demonstrated that expression of CaV 1.2 α1 -subunit, but not of the auxiliary β4 Ca2+ channel subunit, specifically associated with Aβ-positive plaques in brains of 11 month tg mice. No difference in CaV 1.2 α1 -subunit labeling was found in 2 and 4 month-old wt and tg mice prior to plaque formation. The CaV 1.2 α1 -subunit-positive cells in 11 month-old tg mice also labeled with GFAP, but not with the microglia marker Iba1. In contrast, GFAP-positive cells induced by injection of quinolinic acid did not reveal any CaV 1.2 α1 -subunit immunoreactivity. Together these results indicate that the expression of CaV 1.2 α1 -subunits in reactive astrocytes in the tg AD mouse model is related to the increased amyloid-β load in the plaques rather than caused by effects on gene regulation or mechanisms preceding the manifestation of AD as seen by plaque formation. Show more

Keywords: Alzheimer's disease, amyloid-β, astrocytes, L-type Ca2+ channel

DOI: 10.3233/JAD-130560

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 439-451, 2013

Authors: Bucossi, Serena | Polimanti, Renato | Ventriglia, Mariacarla | Mariani, Stefania | Siotto, Mariacristina | Ursini, Francesca | Trotta, Laura | Scrascia, Federica | Callea, Antonio | Vernieri, Fabrizio | Squitti, Rosanna

Article Type: Research Article

Abstract: Copper homeostasis abnormalities have been shown to be associated with Alzheimer's disease (AD), possibly by accelerating amyloid-β toxicity and plaque formation. The ATP7B gene plays a key role in controlling body copper balance. Our previous studies showed an association between ATP7B variants and AD risk. Among these variants, an intronic single nucleotide polymorphism, rs2147363, was associated with AD risk. In order to understand this intronic association, we screened a population of 286 AD patients and 283 healthy controls, and verified the presence of other functional coding variants in linkage disequilibrium (LD). Then we searched for a regulatory function region close …to rs2147363. An LD analysis revealed the presence of an LD between rs2147363 and a Wilson's disease-causing variant, rs7334118. However, this mutation did not explain the observed genetic association. Conversely, in silico analyses of rs2147363 functionality highlighted that this variant is located in a binding site of a transcription factor, and is, consequently, associated with regulatory function. These data suggest that the genetic variation in cis-regulatory elements located in non-coding regions can have a role in determining ATP7B functionality and account for some of the AD missing hereditability. Show more

Keywords: Alzheimer's disease, ATP7B, cis-regulatory element, copper, intronic variant

DOI: 10.3233/JAD-130431

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 453-459, 2013

Article Type: Other

DOI: 10.3233/JAD-130432

Citation: Journal of Alzheimer's Disease, vol. 37, no. 2, pp. 461-464, 2013