9, Number 3, August 2006
Keith D. Coon, Andrew M. Siegel, Stephanie J. Yee, Travis L. Dunckley, Claudius Mueller, Rashed M. Nagra, Wallace W. Tourtellotte, Eric M. Reiman, Andreas Papassotiropoulos, Floyd F. Petersen, Dietrich A. Stephan, Wolff M. Kirsch
Preliminary demonstration of an allelic association of the IREB2 gene with Alzheimer’s disease
Abstract: The role of iron metabolism in Alzheimer’s disease (AD) is well documented. Regulation of the proteins that maintain cellular iron metabolism is mediated by two cytoplasmic RNA-binding proteins, the Iron Regulatory Proteins (IRP1 and IRP2), that function through post-transcriptional interactions with RNA stem loop structures called iron-responsive elements. As the primary mediator of iron homeostasis in neuronal cells, IRP2 is a strong candidate for polymorphisms that could impact AD pathogenesis. Thus, we performed a pilot study to assess polymorphisms in the gene encoding IRP2 (IREB2) on clinically well-characterized, post-mortem samples (50 AD and 50 controls). DNA sequence analysis of the IREB2 gene region revealed 14 polymorphisms. Two (rs2656070 and rs13180) showed statistically significant skewing of allelic and genotypic distributions between AD patients and controls. In silico analyses revealed that rs2656070 lies within a probable promoter and disrupts the binding sites of at least two known transcription factors. Though silent and likely not functionally relevant, rs13180 is in complete LD with rs2656070 (D’ > 0.999), creating an IREB2-haplotype that is significantly associated with AD. Confirmation of this association in a larger cohort of cases and controls would further support the role of iron regulation in the pathogenesis of this catastrophic and increasingly common neurodegenerative disorder.
Debby W. Tsuang, Robert G.Riekse, Kristina M. Purganan, Andrew C. David, Thomas J. Montine, Gerard D. Schellenberg, Ellen J. Steinbart, Eric C. Petrie, Thomas D. Bird, James B. Leverenz
Lewy body pathology in late-onset familial Alzheimer's disease: A clinicopathological case series
Abstract: Background: Lewy body pathology (LBP) is a common finding in Alzheimer's disease (AD), but the pathophysiology for this coexistent pathology remains unclear. Methods: We ascertained late-onset dementia (mean age > 60 years old) families with at least 3 autopsies. We then conducted systematic alpha-synuclein (SNCA) immunostaining to determine the frequency and distribution of LBP in families with late-onset AD. Results: All 32 subjects met NIA-Reagan neuropathological criteria for “high likelihood” of having AD. Hematoxylin and eosin staining detected LBP in the substantia nigra (SN) in 8 (25%) individuals. SNCA immunostaining detected LBP in 21 individuals (66%). While all subjects with SN LBP had co-existent amygdala LBP, many (9/21, 43%) of the cases with amygdala LBP did not have coexistent SN LBP (McNemar's chi-square test, p = 0.008). Each family had at least two cases with LBP, but no family had LBP in all autopsied cases. Conclusions: Presence of significant AD pathology in one family member was highly predictive of similar pathology in other family members. However, despite the use of more sensitive SNCA immunohistochemistry, the presence of LBP was variable within all 7 families. Consistent with previous studies in sporadic and familial AD, the amygdala appeared to be the most vulnerable region for LBP in AD. Additional clinical, neuropathologic, and genetic studies are necessary to determine the clinical and pathological significance of LBP in AD.
Leigh A. Holcomb, Muralikrishnan Dhanasekaran, Angie R. Hitt, Keith A. Young, Mark Riggs, Bala V. Manyam
Bacopa monniera extract reduces amyloid levels in PSAPP mice
Abstract: PSAPP mice expressing the “Swedish” amyloid ß protein precursor and M146L presenilin-1 mutations are a well-characterized model for spontaneous amyloid plaque formation. Bacopa monniera has a long history of use in India as an anti-aging and memory-enhancing ethnobotanical therapy. To evaluate the effect of Bacopa monniera extract (BME) on amyloid (Aß pathology in PSAPP mice, two doses of BME (40 or 160 mg/kg/day) were administered starting at 2 months of age for either 2 or 8 months. Our present data suggests that BME lowers Aß1-40 and 1-42 levels in cortex by as much as 60%, and reverses Y-maze performance and open field hyperlocomotion behavioral changes present in PSAPP mice. The areas encompassed by Congo Red-positive fibrillar amyloid deposits, however, were not altered by BME treatment. The data suggest that BME has potential application in Alzheimer’s disease therapeutics.
Leslie C. Baxter, D. Larry Sparks, Sterling C. Johnson, Brian Lenoski, Jean E. Lopez, Donald J. Connor, Marwan N. Sabbagh
Relationship of Cognitive Measures and Gray and White Matter In Alzheimer’s Disease
Abstract: OBJECTIVE: To examine the relationship between commonly used screening cognitive measures with gray and white matter integrity in patients with mild to moderate AD. BACKGROUND: New neuroimaging techniques, such as voxel-based morphometry (VBM), make it possible to study the relationship between structural brain integrity and cognitive functioning in AD. METHODS: Gray and white matter integrity was evaluated using VBM in fifteen patients with mild to moderate AD. ADAS-Cog and MMSE scores were also performed as part of the baseline assessment for a larger clinical trial in the AD patients. Correlations between cognitive measures and VBM were performed. RESULTS: Both the ADAS-Cog and the MMSE showed a similar relationship with gray matter degeneration, reflecting greater cognitive impairment with decreased gray matter in the left temporal lobe. However, the MMSE score was much more reflective of underlying white matter changes than ADAS-Cog scores, particularly in frontotemporal region. These findings suggest that the ADAS-Cog and MMSE reflect different aspects of the underlying brain changes observed in AD. The ADAS-Cog was more specific to gray matter integrity whereas the MMSE reflected a more global reduction in both gray and white matter. CONCLUSIONS: These results support using neuroimaging markers of neural integrity as an important consideration when evaluating treatment efficacy. Furthermore, whole-brain analyses such as VBM help to evaluate neural systems that are not necessarily targeted by the treatment.
Edna Grünblatt, Eleni Koutsilieri, Siegfried Hoyer, Peter Riederer (Communicated by Angelika Bierhaus)
Gene expression alterations in brain areas of intracerebroventricular streptozotocin treated rat
Abstract: Streptozotocin is well known inducer of experimental diabetes mellitus when injected peripherally. However, when administered intracerebroventricular , streptozotocin showed a whole spectrum of specific biochemical and behavioural alterations with regard to cognitive functions, feeding, nociception, brain glucose metabolism, neurotransmission and oxidative stress, without producing arterial hyperglycaemia, similarly to Alzheimer's disease. In order to reveal the mechanism of action of neurodegeneration in streptozotocin rat model we investigated the expression of several genes involved in inflammation, oxidative stress, growth- and transcription-factors in the cortex, striatum and cerebellum, using real-time quantitative RT-PCR. Genes such as GDNF, BDNF and integrin-alpha-M were up-regulated, while immediate-early-gene-transcription-factor NGF-IB and metallothionein-1/2 were down-regulated in the cortex of streptozotocin-treated rats. Conversely, NGF-IB, GDNF and BDNF mRNA expression did not alter in the striatum and cerebellum. However, integrin alpha-M and metallothionein-1/2 expressions decreased significantly in the striatum and increased in the cerebellum. These gene changes may provide an insight into the cascade of physiological abnormalities following the inhibition of neuronal insulin signal transduction. Additionally, similarities to neuronal cell death in sporadic Alzheimer's disease may become apparent.
Roberto Monastero, Angelo B. Cefalù, Cecilia Camarda, Davide Noto, Lawrence K. Camarda, Rosalia Caldarella, Emilia Imbornone, Maurizio R. Averna, Rosolino Camarda (Communicated by Patrizia Mecocci)
Association of Estrogen Receptor a Gene with Alzheimer's Disease: a Case-Control Study
Abstract: Recent experimental data have offered the biological background to study the estrogen receptor (ER) alpha gene as a candidate gene for AD. Genetic association studies proposed ERalpha PvuII and XbaI gene polymorphisms as susceptibility factors for AD, although subsequent studies did not replicate this finding. To verify this association in a Caucasian Italian sample, we conducted a case-control study of a dataset of 172 clinic-based probable AD cases and 172 age- and sex-matched controls. Possible interaction between ER a polymorphisms and sex, age at onset of AD or apolipoprotein E (APOE) was examined. The xx-genotype of the XbaI polymorphism was associated with the risk of developing AD in the total sample (OR 1.9, 95% CI [1.2-3.1]) . The risk increased in women (OR 2.3, 95% CI [1.3-4.2]) , and in subjects with late-onset AD (OR 2.1, 95% CI [1.2-3.5]) . PvuII polymorphism did not contribute to the risk of AD. There was no evidence for a statistical interaction between the APOE and either the PvuII and XbaI polymorphisms. This result shows that ERalpha XbaI polymorphism is an additional risk factor for women with late-onset AD.
Ismael Santa-María, Mar Pérez, Félix Hernández, Jesús Avila, Francisco J. Moreno
Characteristics of the binding of thioflavin S to tau paired helical filaments
Abstract: Binding of histological benzothiazole dye thioflavin S (ThS) to protein aggregates has been related with the presence of amyloid ß sheet structure in those protein aggregates. Paired helical filaments (PHF) from Alzheimer's disease (AD) patients, (whose main component is the microtubule associated protein, tau) bind to thioflavins. By using a novel immunofluorescence method, the binding of ThS to isolated tau filaments was tested. Also, the characteristics of this binding of ThS to PHF or to the in vitro assembled tau filaments, have been analyzed. Our results suggests that ThS binds to PHF with a higher affinity than to the straight filaments (SF), also found in AD.
Amy Chan, Valerie Graves and Thomas B. Shea
Apple juice concentrate maintains acetylcholine levels
following dietary compromise
Abstract: Oxidative stress contributes to age-related cognitive decline. In some instances, consumption of fruits and vegetables rich in antioxidant can provide superior protection than supplementation with purified antioxidants. Our prior studies have shown that supplementation with apple juice concentrate (AJC) alleviates oxidative damage and cognitive decline in adult (9-12months) mice lacking ApoE (as a model of increased oxidative stress) and in normal aged (2-2.5years) mice when challenged with a vitamin-deficient, oxidative stress-promoting diet. Here, we demonstrate that AJC, administered in drinking water, maintains acetylcholine levels that otherwise decline when adult and aged mice are maintained on the above deficient diet. Normal mice aged either 9-10 months or 2-2.5 years and ApoE-/- mice aged 9-10months were maintained for 1 month on a complete diet or a diet lacking folate and vitamin E and containing iron as a pro-oxidant, and additional groups received 0.5% AJC ad libitum in drinking water. Spectrophotometric assay of acetylcholine levels revealed a significant decline in homogenates of combined frontal cortex and hippocampus for all mice maintained on the deficient diet, and a prevention of this decline in mice maintained on the deficient diet when supplemented with AJC. These findings provide a likely mechanism by which consumption of antioxidant-rich foods such as apples can prevent the decline in cognitive performance that accompanies dietary and genetic deficiencies and aging.
Fadi Abdi, Joseph F.Quinn, Joseph Jankovic, Martin McIntosh, James B. Leverenz, Elaine Peskind, Randy Nixon, John Nutt, Katherine Chung, Cyrus Zabetian, Ali Samii, Melanie Lin, Stephen Hattan, Catherine Pan, Yan Wang, Jinghua Jin, David Zhu, G. Jane Li, Yan Liu, Dana Waichunas, Thomas J. Montine, Jing Zhang
Detection of Biomarkers with a Multiplex Quantitative Proteomic Platform in Cerebrospinal Fluid of Patients with Neurodegenerative Disorders
Abstract: Biomarkers are needed to assist in the diagnosis and medical management of various neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and dementia with Lewy body (DLB). We have employed a multiplex quantitative proteomics method, iTRAQ (isobaric Tagging for Relative and Absolute protein Quantification), in conjunction with multidimensional chromatography, followed by tandem mass spectrometry (MS/MS), to simultaneously measure relative changes in the proteome of cerebrospinal fluid (CSF) obtained from patients with AD, PD, and DLB compared to healthy controls. The diagnosis of AD and DLB was confirmed by autopsy, whereas the diagnosis of PD was based on clinical criteria. The proteomic findings showed quantitative changes in AD, PD, and DLB as compared to controls; among more than 1,500 identified CSF proteins, 136, 72, and 101 of the proteins displayed quantitative changes unique to AD, PD, and DLB, respectively. Eight unique proteins were confirmed by Western blot analysis, and the sensitivity at 95% specificity was calculated for each marker alone and in combination. Several panels of unique makers were capable of distinguishing AD, PD and DLB patients from each other as well as from controls with high sensitivity at 95% specificity. Although these preliminary findings must be validated in a larger and different population of patients, they suggest that a roster of proteins may be generated and developed into specific biomarkers that could eventually assist in clinical diagnosis and monitoring disease progression of AD, PD and DLB.
Transcript: Alzheimer Research Forum Live Discussion
Is Alzheimer's a Type 3 Diabetes?