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

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