Journal of Alzheimer's Disease - Volume 23, issue 2

Authors: Aznar, Susana | Knudsen, Gitte M.

Article Type: Review Article

Abstract: The existence of a high co-morbidity between Alzheimer's disease (AD) and depression has been known for a long time. More interesting though are recent studies indicating that depression and number of depressive episodes earlier in life is associated with increased risk of AD development. This suggests the existence of common neuropathological mechanisms behind depression and AD. Here we propose that the brain changes associated with depressive episodes that compromise the brain's ability to cope with stress may constitute risk factors for development of AD. Furthermore, in individuals with a genetic linkage to depression, there may be an increased vulnerability towards …the initiation of a detrimental neurodegenerative cascade. The following review will deal with the various observations reported within the different neurobiological systems known to be involved and affected in depression, like serotonergic and cholinergic system, hypothalamic-pituitary-adrenal axis and brain derived neurotrophic factor, and discussed in relation to AD. Show more

Keywords: 5-HT 1A, 5-HT 2A, BDNF, depression, HPA-axis, monoaminergic hypothesis, serotonin, stress

DOI: 10.3233/JAD-2010-100390

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 177-193, 2011

Authors: Cuadrado-Tejedor, Mar | Vilariño, Marcos | Cabodevilla, Felipe | Del Río, Joaquín | Frechilla, Diana | Pérez-Mediavilla, Alberto

Article Type: Research Article

Abstract: The mitochondrial voltage-dependent anion channel 1 (VDAC1) is involved in the release of apoptotic proteins with possible relevance in Alzheimer's disease (AD) neuropathology. Through proteomic analysis followed by Western blotting and immunohistochemical techniques, we have found that VDAC1 is overexpressed in the hippocampus from amyloidogenic AD transgenic mice models. VDAC1 was also overexpressed in postmortem brain tissue from AD patients at an advanced stage of the disease. Interestingly, amyloid-β (Aβ) soluble oligomers were able to induce upregulation of VDAC1 in a human neuroblastoma cell line, further supporting a correlation between Aβ levels and VDAC1 expression. In hippocampal extracts from transgenic …mice, a significant increase was observed in the levels of VDAC1 phosphorylated at an epitope that is susceptible to phosphorylation by glycogen synthase kinase-3β, whose activity was also increased. The levels of hexokinase I (HXKI), which interacts with VDAC1 and affects its function, were decreased in mitochondrial samples from AD models. Since phospho-VDAC and reduced HXKI levels favors a VDAC1 conformational state more prone to the release proapoptotic factors, regulation of the function of this channel may be a promising therapeutic approach to combat AD. Show more

Keywords: Alzheimer's disease, amyloid-β, hexokinase I, phospho-VDAC1, voltage-dependent anion channel 1 (VDAC1)

DOI: 10.3233/JAD-2010-100966

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 195-206, 2011

Authors: Dursun, Erdinç | Gezen-Ak, Duygu | Yilmazer, Selma

Article Type: Research Article

Abstract: Amyloid-β (Aβ) is the core component of amyloid plaques of Alzheimer's disease (AD). The effects of Aβ include damage to neuronal plasma membrane, disruption of Ca2+ homeostasis, and alterations of neurotrophic factor levels. The aim of this study was to determine the effects of Aβ treatment on vitamin D receptor (VDR), L-type voltage sensitive calcium channels A1C (LVSCC A1C), NGF, and observing the effects of vitamin D treatment on Aβ induced alterations in primary cortical neurons. As to the latter, we aimed to test the suggested neuroprotective role of vitamin D as a neglected neurosteroid. The expressions of VDR …and LVSCC A1C were studied with qRT-PCR and Western blotting. NGF and cytotoxicity levels were determined by ELISA. Apoptotic cell death was investigated with caspase-3 protein expression by Western blotting. Our results showed that the Aβ triggers neurodegeneration not only by inducing LVSCC A1C expression and NGF levels and but also by dramatically suppressing VDR expression. Administration of vitamin D to this model protected neurons by preventing cytotoxicity and apoptosis, and also by downregulating LVSCC A1C and upregulating VDR. Additionally, vitamin D brought NGF expression to a state of equilibrium and did not show its apoptosis inducing effects. Consequently, prevention of Aβ toxicity which was one of the major component of AD type pathology by vitamin D treatment and understanding how Aβ effects vitamin D related pathways, might open up new frontiers in clarifying molecular mechanisms of neurodegeneration and provide basis for novel perspectives in both preventing and treating AD. Show more

Keywords: Alzheimer's disease, amyloid-β protein, calcium channels, nerve growth factor vitamin D, vitamin D 3 receptor

DOI: 10.3233/JAD-2010-101377

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 207-219, 2011

Authors: Teipel, Stefan J. | Kaza, Evangelia | Hadlich, Stefan | Bauer, Alexandra | Brüning, Thomas | Plath, Anne-Sophie | Krohn, Markus | Scheffler, Katja | Walker, Lary C. | Lotze, Martin | Pahnke, Jens

Article Type: Research Article

Abstract: In vivo imaging of amyloid-β (Aβ) load as a biomarker of Alzheimer's disease (AD) would be of considerable clinical relevance for the early diagnosis and monitoring of treatment effects. Here, we investigated automated quantification of in vivo T2 relaxation time as a surrogate measure of plaque load in the brains of ten AβPP/PS1 transgenic mice (age 20 weeks) using in vivo MRI acquisitions on a 7T Bruker ClinScan magnet. AβPP/PS1 mice present with rapid-onset cerebral β-amyloidosis, and were compared with eight age-matched, wild-type control mice (C57Bl/6J) that do not develop Aβ-deposition in brain. Data were analyzed with a novel automated …voxel-based analysis that allowed mapping the entire brain for significant signal changes. In AβPP/PS1 mice, we found a significant decrease in T2 relaxation times in the deeper neocortical layers, caudate-putamen, thalamus, hippocampus, and cerebellum compared to wildtype controls. These changes were in line with the histological distribution of cerebral Aβ plaques and activated microglia. Grey matter density did not differ between wild-type mice and AβPP/PS1 mice, consistent with a lack of neuronal loss in histological investigations. High-field MRI with automated mapping of T2 time changes may be a useful tool for the detection of plaque load in living transgenic animals, which may become relevant for the evaluation of amyloid lowering intervention effects in future studies. Show more

Keywords: Alzheimer's disease, amyloid-β, high-field MRI, iron deposition, transgenic mouse models, T2 relaxation time

DOI: 10.3233/JAD-2010-101035

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 221-237, 2011

Authors: Squitti, Rosanna | Ghidoni, Roberta | Scrascia, Federica | Benussi, Luisa | Panetta, Valentina | Pasqualetti, Patrizio | Moffa, Filomena | Bernardini, Silvia | Ventriglia, Mariacarla | Binetti, Giuliano | Rossini, Paolo Maria

Article Type: Research Article

Abstract: In patients affected by Alzheimer's disease (AD), serum copper not bound to ceruloplasmin (‘free’ copper) appears elevated, slightly but significantly enough to distinguish AD patients from healthy elderly subjects. In this paper we tested the hypothesis that this is also the case for individuals affected by mild cognitive impairment (MCI). A sample of 83 MCI subjects were compared with 100 elderly control subjects in terms of levels of serum copper, free copper, ceruloplasmin, apolipoprotein E4 genotype (APOE4), iron, transferrin, and total antioxidant capacity (TRAP). The groups were also compared in terms of demographic and cardiovascular risk factors. The comparison with …an additional group of 105 mild to moderate AD patients was also evaluated. The possible effects of copper dysfunction on cognitive decline were evaluated by multinomial logistic regression analysis. A linear regression model was applied to define the role of metals and antioxidant dysfunction in explaining Mini-Mental Status Examination (MMSE) variations. APOE4 and free copper differentiated the MCI group from the healthy control group. The probability of aquiring MCI increased by about 24% for each free copper unit (μmol/L) increment. APOE4 and free copper differentiated the MCI group also from the AD group. APOE4 and free copper appeared associated to MMSE worsening, as did age and gender. These results suggest that free copper can help in discriminating MCI subjects from healthy controls, but not on an individual basis. Show more

Keywords: Alzheimer's disease, apolipoprotein E, copper, mild cognitive impairment

DOI: 10.3233/JAD-2010-101098

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 239-248, 2011

Authors: Wilson, Robert S. | Barral, Sandra | Lee, Joseph H. | Leurgans, Sue E. | Foroud, Tatiana M. | Sweet, Robert A. | Graff-Radford, Neill | Bird, Thomas D. | Mayeux, Richard | Bennett, David A. | for the National Institute on Aging Late-Onset Alzheimer's Disease Genetics Study

Article Type: Research Article

Abstract: The study aim was to estimate the genetic contribution to individual differences in different forms of memory in a large family-based group of older adults. As part of the Late Onset Alzheimer's Disease Family Study, 899 persons (277 with Alzheimer's disease, 622 unaffected) from 325 families completed a battery of memory tests from which previously established composite measures of episodic memory, semantic memory, and working memory were derived. Heritability in these measures was estimated using the maximum likelihood variance component method, controlling for age, gender, and education. In analyses of unaffected family members, the adjusted heritability estimates were 0.62 for …episodic memory, 0.49 for semantic memory, and 0.72 for working memory, where a heritability estimate of 1 indicates that genetic factors explain all of the phenotypic variance and a heritability of 0 indicates that genetic factors explain none. Adjustment for APOE genotype had little effect on these estimates. When analyses included affected and unaffected family members, adjusted heritability estimates were lower (0.47 for episodic memory, 0.32 for semantic memory, 0.42 for working memory). Adjusting for APOE slightly reduced the estimate for episodic memory (0.40) but had no effect on the remaining estimates. The results indicate that memory functions are under strong genetic influence in older persons with and without AD, and are only partly attributable to APOE. This suggests that genetic analyses of memory endophenotypes may help to identify genetic variants associated with AD. Show more

Keywords: Alzheimer's disease, apolipoprotein E, heritability, memory

DOI: 10.3233/JAD-2010-101515

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 249-255, 2011

Authors: Aluise, Christopher D. | Robinson, Renã A.S. | Cai, Jian | Pierce, William M. | Markesbery, William R. | Butterfield, D. Allan

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a central nervous system disorder pathologically characterized by senile plaques, neurofibrillary tangles, and synapse loss. A small percentage of individuals with normal antemortem psychometric scores, after adjustments for age and education, meet the neuropathological criteria for amnestic mild cognitive impairment (MCI) or AD; these individuals have been termed ‘preclinical’ or ‘asymptomatic’ AD (PCAD). In this study, we employed the immunochemical slot-blot method and two-dimensional gel-based redox proteomics to observe differences in protein levels and oxidative modifications between groups with equal levels of AD pathology who differ in regards to clinical symptoms of memory impairment. Results of …global oxidative stress measurements revealed significantly higher levels of protein carbonyls in the MCI inferior parietal lobule (IPL) relative to PCAD (and controls), despite equal levels of neuropathology. Proteomics analysis of the IPL revealed differences in protein levels and specific carbonylation that are consistent with preservation of memory in PCAD and apparent memory decline in MCI. Our data suggest that marked changes occur at the protein level in MCI that may cause or reflect memory loss and other AD symptoms. Show more

Keywords: Alzheimer's disease, brain, mild cognitive impairment, oxidative stress, preclinical Alzheimer's, proteomics, redox proteomics, two dimensional gel electrophoresis

DOI: 10.3233/JAD-2010-101083

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 257-269, 2011

Authors: Liu, Ying | Lee, Michael K. | James, Maria M. | Price, Donald L. | Borchelt, David R. | Troncoso, Juan C. | Oh, Esther S.

Article Type: Research Article

Abstract: The role of amyloid-β (Aβ) in the neurodegeneration of Alzheimer's disease remains controversial, to a large extent because of the lack of robust neurodegeneration in mouse models of AD. To address this question, we examined the effects of Aβ antibodies in the recently described monoaminergic (MAergic) axonal degeneration in AβPPswe/PS1dE9 mice. To determine if Aβ accumulation is directly involved in degeneration of MAergic axons, we examined the effects of passive anti-Aβ antibody (7B6) administration on Aβ pathology and MAergic degeneration in AβPPswe/PS1dE9 mice. Injections of monoclonal antibody (mAb) 7B6 into mice (6 to 9 months of age) resulted in a …modest reduction of Aβ load in the brains of AβPPswe/PS1dE9 mice. In addition, 7B6 treated AβPPswe/PS1dE9 mice had significantly higher densities of MAergic axons in both cortex and in hippocampus as compared to untreated mutant mice. For example, 7B6 treated mice showed almost 2-fold greater densities of serotonergic (5-HT) axons in the cortex compared to saline treated mice. Similar findings were observed in the catecholaminergic (TH) axons. Our results demonstrate that lowering of Aβ levels via passive Aβ immunotherapy ameliorates ongoing degenerative processes, supporting a causal link between Aβ and neurodegeneration. Show more

Keywords: Amyloid-β, axon, immunotherapy, neurodegeneration, serotonergic

DOI: 10.3233/JAD-2010-101602

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 271-279, 2011

Authors: Kim, Ki Woong | Park, Joon Hyuk | Kim, Myoung-Hee | Kim, Moon Doo | Kim, Bong-Jo | Kim, Shin-Kyum | Kim, Jeong Lan | Moon, Seok Woo | Bae, Jae Nam | Woo, Jong Inn | Ryu, Seung-Ho | Yoon, Jong Chul | Lee, Nam-Jin | Lee, Dong Young | Lee, Dong Woo | Lee, Seok Bum | Lee, Jung Jae | Lee, Jun-Young | Lee, Chang-Uk | Chang, Sung Man | Jhoo, Jin Hyeong | Cho, Maeng Je

Article Type: Research Article

Abstract: We investigated the prevalence of dementia and mild cognitive impairment (MCI) and the factors associate with risk of dementia from a representative nationwide sample of Korean elders. 8,199 randomly-sampled Koreans aged 65 years or older were invited to participate in the Phase I screening assessment using Mini-Mental State Examination by door-to-door home visit, and 6,141 subjects (response rate = 74.9%) responded. Among them, 2,336 subjects were invited to participate in the Phase II diagnostic assessment for dementia and MCI, and 1,673 subjects responded (response rate = 71.6%). Diagnostic assessments were administered using the Korean version of the Consortium to Establish …a Registry for Alzheimer's Disease Assessment Packet (CERAD-K) Clinical Assessment Battery. The CERAD-K Neuropsychological Assessment Battery was used for diagnosing MCI. Age-, gender-, education-, and urbanicity-standardized prevalence of dementia was estimated to be 8.1% (95% CI = 6.9–9.2) for overall dementia and 24.1% (95% CI = 21.0–27.2) for MCI. Alzheimer's disease (AD) was the most prevalent type (5.7%) followed by vascular dementia (2.0%). Amnestic subtype (20.1%) was much more prevalent than nonamnestic subtype in MCI (4.0%). Older age, being male, lower education level, illiteracy, smoking, and histories of head trauma or depression were associated with increased dementia risk, and alcohol use and moderately intense exercise were associated with decreased dementia risk. We expect numbers of dementia patients to double every 20 years until 2050 in Korea and expect AD to account for progressively more dementia cases in the future. Show more

Keywords: Dementia, mild cognitive impairment (MCI), prevalence, risk, South Korea

DOI: 10.3233/JAD-2010-101221

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 281-291, 2011

Authors: Miller, David L. | Potempska, Anna | Wegiel, Jerzy | Mehta, Pankaj D.

Article Type: Research Article

Abstract: Antibodies that specifically bind to either amyloid-β peptide (Aβ) isoform Aβ40 or Aβ42 contribute to the study of Alzheimer's disease (AD) pathology and to the development of cerebrospinal fluid-based tests for the probable diagnosis of AD. Polyclonal rabbit anti-Aβ antibodies possess high affinity and specificity, but their generation requires a long immunization period, and the resulting antibodies exhibit variable specificities and affinities. To secure a continuing supply of antibodies with uniform properties, we generated and partially characterized rabbit monoclonal antibodies specific for either Aβ40 or Aβ42 . These antibodies possess nanomolar or sub-nanomolar dissociation constants and are …at least 3,000-fold more selective for one isoform over the other. These antibodies are suitable for immunoblotting and, in a sandwich ELISA, RabmAb42 (anti-Aβ42 ) is sensitive enough to measure plasma levels of Aβ42 . In addition, these antibodies have been applied to the immunohistology of Down syndrome and AD brain tissues, where they reveal fibrillar and diffuse amyloid deposits and are almost free of non-specific staining. The data indicate that diffuse amyloid deposits contain only minute amounts of Aβ40 . Thus these rabbit monoclonal anti-Aβ antibodies can be widely applied in AD and Down syndrome research and diagnosis. Show more

Keywords: Alzheimer's disease, amyloid-β peptides, anti-Aβ antibodies, ELISA, immunohistology, peptide-antibody dissociation constants, rabbit monoclonal antibodies

DOI: 10.3233/JAD-2010-101341

Citation: Journal of Alzheimer's Disease, vol. 23, no. 2, pp. 293-305, 2011