Journal of Alzheimer's Disease - Volume 37, issue 1

Authors: Sabbagh, Marwan N. | Perry, George | Hunsaker III, John C. | Schreurs, Bernard

Article Type: Obituary

DOI: 10.3233/JAD-131312

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 1-1, 2013

Authors: Di Francesco, Andrea | Arosio, Beatrice | Gussago, Cristina | Dainese, Enrico | Mari, Daniela | D'Addario, Claudio | Maccarrone, Mauro

Article Type: Short Communication

Abstract: Lipoxygenases play a major role in the neuropathology of Alzheimer's disease (AD), even though the underlying mechanisms are as yet poorly understood. Here, we studied the epigenetic regulation of 5-lipoxygenase (5-LOX) in peripheral blood mononuclear cells of subjects with late-onset AD and age-matched controls. We found a significant increase in 5-LOX gene expression in AD subjects compared to healthy controls, paralleled by increased 5-LOX protein and leukotriene B4 , the 5-LOX product. In addition, a consistent reduction in DNA methylation at 5-LOX gene promoter was documented in AD versus healthy subjects. Taken together, our findings further support a role for …5-LOX in vulnerability to neurodegeneration. Show more

Keywords: Alzheimer's disease, biomarker, DNA methylation, fatty acid amide hydrolase, 5-lipoxygenase, peripheral blood mononuclear cells

DOI: 10.3233/JAD-130506

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 3-8, 2013

Authors: Hou, Liming | Lee, Hyoung-gon | Han, Fang | Tedesco, Johnathan M. | Perry, George | Smith, Mark A. | Zagorski, Michael G.

Article Type: Research Article

Abstract: Oxidative stress and amyloid-β (Aβ) formation are important processes that occur in Alzheimer's disease (AD). Amyloid formation is associated with the aggregation and precipitation of the Aβ peptide, while oxidative stress results from an imbalance in pro-oxidant/antioxidant homeostasis that produces harmful reactive oxygen species. The methionine-35 (Met35) residue of the Aβ peptide plays an important role in AD oxidative stress events and the associated neurotoxicity. We and other research groups previously demonstrated that in vitro oxidation of the Met35 side-chain to the sulfoxide (Met35red → Met35ox ) impedes assembly and aggregation of monomeric Aβ peptide into protofibrils, the latter …being the immediate precursors of amyloid plaques. Here, we report that Met35 oxidation state affects the stability of preexisting amyloid fibrils and plaques, where the Met35red → Met35ox process leads to changes in the morphology of filaments, protofibrils, mature fibrils, and loss of Congo red birefringence in senile plaques isolated from the brains of AD patients. The most notable differences were in fibril flexibility, as evidenced by changes from straight fibrils to irregularly shaped, rope-like fibrils. These findings suggest that the Met35 oxidation state and amyloid plaque formation may be intimately linked. Show more

Keywords: Alzheimer's disease, amyloid-β, atomic force microscopy, fibrillization, oxidative stress

DOI: 10.3233/JAD-122389

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 9-18, 2013

Authors: Cui, Lili | Zhang, Yuan | Cao, Hao | Wang, Yan | Teng, Teng | Ma, Guoda | Li, You | Li, Keshen | Zhang, Yingjiu

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is neurodegenerative disease that occurs among the aging population and is associated with impaired cognitive function. Amyloid-β (Aβ) oligomers initiate the pathological cascade and represent a neuropathic hallmark of AD. Therefore, an approach that inhibits Aβ aggregation is an attractive therapeutic strategy for the treatment of AD. Ferulic acid (FA) is a phenolic compound that can inhibit Aβ42 fibril-induced cytotoxicity both in vitro and in vivo. However, few studies have demonstrated that FA interacts with Aβ42 oligomers. Here, we investigated whether FA inhibits Aβ42 oligomer-induced cytotoxicity and the effect of FA on Aβ aggregation. …Our results showed that FA reduced Aβ42 -induced neurotoxicity in SH-SY5Y cells. Moreover, using CD spectroscopy, we found that FA inhibited the formation of the β-sheets that are required for the Aβ42 monomer-to-oligomer transition but accelerated the Aβ42 oligomer-to-fibril transition. These phenomena were confirmed by transmission electron microscopy and thioflavin T fluorescence assay. The docking analysis between FA and Aβ42 monomer showed that FA may inhibit the aggregation of Aβ42 oligomers by blocking the hydrogen bond with the forming β-sheets. Taken together, we have identified a novel phenomenon in which FA inhibits the formation of Aβ42 oligomers while accelerating the transition of Aβ42 oligomers to fibrils, and we have shown that FA protects against Aβ42 -induced toxicity in vitro by preventing Aβ42 from forming oligomers. Show more

Keywords: Alzheimer's disease, amyloid-β, ferulic acid, oligomer

DOI: 10.3233/JAD-130164

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 19-28, 2013

Authors: Magnusson, Kristina | Sehlin, Dag | Syvänen, Stina | Svedberg, Marie M. | Philipson, Ola | Söderberg, Linda | Tegerstedt, Karin | Holmquist, Mats | Gellerfors, Pär | Tolmachev, Vladimir | Antoni, Gunnar | Lannfelt, Lars | Hall, Håkan | Nilsson, Lars N.G.

Article Type: Research Article

Abstract: Evidence suggests that amyloid-β (Aβ) protofibrils/oligomers are pathogenic agents in Alzheimer's disease (AD). Unfortunately, techniques enabling quantitative estimates of these species in patients or patient samples are still rather limited. Here we describe the in vitro and ex vivo characteristics of a new antibody-based radioactive ligand, [125 I]mAb158, which binds to Aβ protofibrils with high affinity. [125 I]mAb158 was specifically taken up in brain of transgenic mice expressing amyloid-β protein precursor (AβPP) as shown ex vivo. This was in contrast to [125 I]mAb-Ly128 which does not bind to Aβ. The uptake of intraperitoneally-administered [125 I]mAb158 into the brain was age- …and time-dependent, and saturable in AβPP transgenic mice with modest Aβ deposition. Brain uptake was also found in young AβPP transgenic mice that were devoid of Aβ deposits, suggesting that [125 I]mAb158 targets soluble Aβ protofibrils. The radioligand was diffusely located in the parenchyma, sometimes around senile plaques and only occasionally colocalized with cerebral amyloid angiopathy. A refined iodine-124-labeled version of mAb158 with much improved blood-brain barrier passage and a shorter plasma half-life might be useful for PET imaging of Aβ protofibrils. Show more

Keywords: Alzheimer's disease, amyloid-β protofibrils, antibody, brain uptake, positron emission tomography, transgenic mice

DOI: 10.3233/JAD-130029

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 29-40, 2013

Authors: Gordon, Brian A. | Blazey, Tyler | Benzinger, Tammie L. S. | Head, Denise

Article Type: Research Article

Abstract: The hippocampus is often treated as a uniform structure, but possesses differential projections to surrounding cortex along its longitudinal axis. This heterogeneity could create varied susceptibility to pathological influences, potentially leading to non-uniform volumetric associations with advancing age and Alzheimer's disease (AD). Previous examinations of aging and AD effects on hippocampal subdivisions have produced highly discrepant findings. To clarify these inconsistencies, we examined the hippocampal head, body, and tail in a large sample of 292 cognitively normal, 37 very mildly demented, and 18 mildly demented individuals, divided into two independent samples. As often done in the literature, we characterized qualitative …patterns across these regions, but extended these results by explicitly testing for quantitative differences. In each sample of cognitively normal individuals, the head and body demonstrated greater age effects than the tail. In each sample contrasting AD and cognitively normal individuals, all three regions showed significant volume reductions, with the greatest effect on the head. When examining increasing severity of dementia, the hippocampal head showed progressive volume loss, while the body and tail did not. The patterns of results examining both aging and AD were relatively consistent across the independent samples. These results indicate that there is an anterior-to-posterior gradient of loss within the hippocampus with both advancing age and AD. Show more

Keywords: Brain aging, dorsal hippocampus, long-axis, ventral hippocampus

DOI: 10.3233/JAD-130011

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 41-50, 2013

Authors: Gawinecka, Joanna | Nowak, Martin | Carimalo, Julie | Cardone, Franco | Asif, Abdul R. | Wemheuer, Wiebke M. | Schulz-Schaeffer, Walter J. | Pocchiari, Maurizio | Zerr, Inga

Article Type: Research Article

Abstract: Sporadic Creutzfeldt-Jakob disease (sCJD) is characterized by wide clinical and pathological variability, which is mainly influenced by the conformation of the misfolded prion protein (PrPSc ) and by methionine and valine polymorphism at codon 129 of the gene encoding PrP. This heterogeneity likely implies differences in the molecular cascades that lead to the development of certain disease phenotypes. Here, we investigated synaptic proteome patterns in two most common sCJD subtypes (MM1 and VV2) using 2D DIGE and mass spectrometry. We found that 23 distinct proteins were differentially expressed in at least one sCJD subtype when compared to age-matched controls. The …majority of these proteins displayed significant subtype-specific alterations, with only up-regulated glial fibrillary acidic protein and down-regulated spectrin alpha chain in both sCJD subtypes. Differentially expressed proteins found in this study are mainly involved in synaptic structure and activity, mitochondrial function, or calcium metabolism. Moreover, several of them have been already linked to the pathophysiological processes occurring in Alzheimer's disease. Show more

Keywords: Creutzfeldt-Jakob disease, 2D fluorescence difference gel electrophoresis (2D DIGE), proteomics, sCJD, synapse, synaptic dysfunction

DOI: 10.3233/JAD-130455

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 51-61, 2013

Authors: Kelly, Ronan J. | Minogue, Aedín M. | Lyons, Anthony | Jones, Raasay S. | Browne, Tara C. | Costello, Derek A. | Denieffe, Stephanie | O'Sullivan, Catherine | Connor, Thomas J. | Lynch, Marina A.

Article Type: Research Article

Abstract: Whereas the classical histological hallmarks of Alzheimer's disease (AD) are deposition of amyloid-containing plaques and development of neurofibrillary tangles, there is also clear evidence of inflammatory changes accompanied by the presence of activated microglia and astrocytosis. However, at this time, it remains uncertain whether inflammatory changes contribute to pathogenesis of the disease or if they are secondary to deposition of amyloid-β or other pathological changes. A greater understanding of the sequence of events would clearly improve development of strategies to delay progression of the disease. There is a realistic expectation that advances in imaging technology may provide the key to …uncovering this sequence. In this study, we employed non-invasive imaging techniques to examine changes in tissue state in hippocampus and cortex of transgenic mice which overexpress amyloid-β protein precursor and presenilin 1 and show that the observed increase in T1 relaxation time was associated with astrogliosis while the decrease in T2 relaxation time was associated with microglial activation. We explored the possibility that interferon-γ might trigger glial activation and demonstrate a genotype-related infiltration of macrophages and natural killer cells, which release interferon-γ. The evidence suggests that IFNγ triggers glial activation and expression of proinflammatory cytokines, and these changes, in turn, contribute to the decrease in long-term potentiation. Show more

Keywords: Glial activation, macrophages, natural killer (NK) cells, T1 and T2 relaxation times

DOI: 10.3233/JAD-130539

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 63-75, 2013

Authors: O'Hare, Eugene | Ardis, Tara | Page, Deaglan | Scopes, David I.C. | Kim, Eun-Mee

Article Type: Research Article

Abstract: The current study examined behavioral and histological effects of amyloid-β (Aβ) protein precursor (AβPP) overexpression in transgenic (Tg) rats created using the same gene, mutation, and promoter as the Tg2576 mouse model of Alzheimer's disease (AD). Male Tg+ rats were bred with female wild-type rats to generate litters of hemizygous Tg+ and Tg− offspring. Tg+ rats and Tg− littermates were tested for memory deficits at 4, 8, and 12 months old using a water-maze procedure. There were no significant behavioral differences between Tg+ rats and Tg− littermates at 4 months old but there …were significant differences at 8 and 12 months old, and in probe trials at 8 and 12 months old, the Tg+ rats spent significantly less time and covered less distance in the platform zone. Under acquisition of a fixed-consecutive number schedule at 3 months old, Tg− littermates demonstrated a longer latency to learning the response rule than Tg+ rats; while this might seem paradoxical, it is consistent with the role of overexpression of AβPP in learning. Histological analyses revealed activated astrocytes in brains of Tg+ rats but not Tg− littermates at 6 months old, and thioflavin-S positive staining in the hippocampus and cortex of 17-month old Tg+ rats but not Tg− littermates. Quantification of Aβ load in the brain at 22 months indicated high levels of Aβ38 , Aβ40 , and Aβ42 in the Tg+ rats. These data suggest this model might provide a valuable resource for AD research. Show more

Keywords: Amyloid-β protein precursor, animal model, behavior, histology, transgenic rat

DOI: 10.3233/JAD-130212

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 77-88, 2013

Authors: Royall, Donald R. | Palmer, Raymond F. | for the Texas Alzheimer's Research and Care Consortium

Article Type: Research Article

Abstract: We have constructed a latent dementia proxy, “δ”, and validated it in several datasets, including well characterized subjects participating in the Texas Alzheimer's Research and Care Consortium (TARCC) study. It may be possible to construct δ homologs from almost any ad hoc combination of cognitive and functional status measures. δ homologs may also be relatively immune to measurement error, including cultural, linguistic, or educational biases. These properties make factor scores derived from latent variables a potentially attractive solution for dementia case-finding in rural or minority populations. Here we have explored an alternative and briefer assessment by which to construct a …δ homolog and validate the resulting latent variable (dMA) in Mexican-American (MA) TARCC subjects. dMA, composed of simple “bedside” dementia screening instruments, achieves Areas Under the Receiver Operative Curve that rival those of δ itself. Ethnicity has a small effect on dMA's performance. These results suggest that it may be possible to validly export dMA into other MA populations, or to export δ homolog factor scores from one population to another. Show more

Keywords: Aging, cognition, dementia, functional status, g

DOI: 10.3233/JAD-130353

Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 89-97, 2013