Journal of Alzheimer's Disease - Volume 16, issue 2

Authors: Xu, Xuemin

Article Type: Review Article

Abstract: The biogenesis of the amyloid-β peptide (Aβ) is a central issue in Alzheimer's disease (AD) research. Aβ is produced by β- and γ-secretases from the amyloid-β protein precursor (AβPP). These proteases are targets for the development of therapeutic compounds to downregulate Aβ production. γ-secretase has received more attention 1) because it generates the C-terminus of Aβ, which is important in the pathogenesis of AD because the longer Aβ species are more amyloidogenic, and 2) because it cleaves AβPP within its transmembrane domain. In the understanding the mechanism of γ-secretase cleavage, three major cleavage sites have been identified, namely, γ-cleavage site …at Aβ40/42 , ζ-cleavage site at Aβ46 , and ε-cleavage site at Aβ49 . Moreover, the novel finding that some of the known γ-secretase inhibitors inhibit the formation of secreted Aβ40 and Aβ42 , but cause an intracellular accumulation of long Aβ46 , provided information extremely important for the development of strategies aimed at the design of γ-secretase inhibitors to prevent and treat AD. In addition, it has been established that the C-terminus of Aβ is generated by a series of sequential cleavages: first, ε-cleavage, followed by ζ-cleavage and finally by γ-cleavage, commencing from the membrane boundary to the middle of the AβPP membrane domain. Show more

Keywords: Alzheimer's disease, amyloid, amyloid-β protein precursor, presenilin, secretase

DOI: 10.3233/JAD-2009-0957

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 211-224, 2009

Authors: Small, David H. | Gasperini, Robert | Vincent, Adele J. | Hung, Amos C. | Foa, Lisa

Article Type: Review Article

Abstract: Although many of the biochemical mechanisms which regulate production or clearance of the amyloid-β protein (Aβ) of Alzheimer's disease (AD) are now well understood, the mechanism of Aβ neurotoxicity remains unclear. A number of studies have shown that Aβ can disrupt neuronal Ca2+ homeostasis by inducing influx of extracellular Ca2+ into the neuronal cytoplasm. Ca2+ is known to play an important role in neuronal excitability, synaptic plasticity and neurotoxicity. Therefore, Aβ-induced Ca2+ dysregulation may contribute to many of the cognitive and neuropathologic features of AD. In vitro studies show that Aβ can increase ion permeability in …lipid membranes. This increased permeability is reportedly associated with the formation of artificial ion pores formed from Aβ oligomers. However, a number of other studies show that Aβ can activate endogenous ion channels on the cell surface. There is also increasing evidence that presenilin mutations alter intracellular Ca2+ stores. It is likely that elucidation of the mechanism by which Aβ and presenilin cause Ca2+ dysregulation in neurons will help to identify new drug targets for the treatment of AD. Show more

Keywords: Alzheimer's disease, amyloid, calcium, neurotoxicity, synaptic plasticity

DOI: 10.3233/JAD-2009-0951

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 225-233, 2009

Authors: Andrieu, Sandrine | Coley, Nicola | Aisen, Paul | Carrillo, Maria C. | DeKosky, Steven | Durga, Jane | Fillit, Howard | Frisoni, Giovanni B. | Froelich, Lutz | Gauthier, Serge | Jones, Roy | Jönsson, Linus | Khachaturian, Zaven | Morris, John C. | Orgogozo, Jean-Marc | Ousset, Pierre-Jean | Robert, Philippe | Salmon, Eric | Sampaio, Cristina | Verhey, Frans | Wilcock, Gordon | Vellas, Bruno

Article Type: Review Article

Abstract: The prevention of neurodegenerative dementias, such as Alzheimer's disease, is a public health priority. Due to the large numbers of affected patients, even interventions bringing about a relatively small delay in disease onset could have large public health effects. Randomized controlled trials (RCTs) are required to demonstrate the effectiveness of preventive interventions, but such trials raise specific methodological questions because they are new in the field of neurodegenerative diseases, and require large numbers of elderly subjects and lengthy follow-up periods. We performed a literature search to identify primary prevention RCTs for neurodegenerative dementia. The methodology of the trials was summarized …and discussed during two expert meetings. Overall, 39 trials were identified that assessed dementia incidence or cognitive decline as a primary or secondary study outcome. Age was the most common selection criteria for target populations. Follow-up periods ranged from one month to nine years and were longest in studies measuring dementia incidence as an outcome. Results of RCTs have so far been generally negative and conflicting with those of observational studies, perhaps due to methodological issues. Future trials must therefore carefully consider the target population, outcomes and duration of follow-up to be used, and should assess the problem of attrition. Show more

Keywords: Alzheimer's disease, clinical trials, clinical trials methodology, cognitive aging, cognitive decline, dementia, prevention trials, study design

DOI: 10.3233/JAD-2009-0971

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 235-270, 2009

Authors: Veo, Bethany L. | Krushel, Les A.

Article Type: Short Communication

Abstract: Neurofibrillary tangles are a pathological phenotype in Alzheimer's disease (AD) and are caused by the hyperphosphorylation of the microtubule associated protein tau. In mouse models of AD, decreasing tau protein expression limits the severity of symptoms and inhibits progression of AD. We now report that the 5' leader in the human tau mRNA contains an internal ribosomal entry site (IRES) and that IRES-dependent translation plays a role in the synthesis of tau protein. Consequently, targeting the tau IRES provides a novel target for regulating tau expression in AD and other tauopathies.

Keywords: Alzheimer's disease, internal ribosomal entry site, protein synthesis, tauopathy

DOI: 10.3233/JAD-2009-0978

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 271-275, 2009

Authors: Okereke, Olivia I. | Xia, Weiming | Irizarry, Michael C. | Sun, Xiaoyan | Qiu, Wei Q. | Fagan, Anne M. | Mehta, Pankaj D. | Hyman, Bradley T. | Selkoe, Dennis J. | Grodstein, Francine

Article Type: Research Article

Abstract: Identifying biomarkers of Alzheimer's disease (AD) risk will be critical to effective AD prevention. Levels of circulating amyloid-β (Aβ) 40 and 42 may be candidate biomarkers. However, properties of plasma Aβ assays must be established. Using five different protocols, blinded samples were used to assess: intra-assay reproducibility; impact of EDTA vs. heparin anticoagulant tubes; and effect of time-to-blood processing. In addition, percent recovery of known Aβ concentrations in spiked samples was assessed. Median intra-assay coefficients of variation for the assay protocols ranged from 6–24% for Aβ40 , and 8–14% for Aβ42 . There were no systematic differences in reproducibility by …collection method. Plasma concentrations of Aβ (particularly Aβ42 ) appeared stable in whole blood kept in ice packs and processed as long as 24 hours after collection. Recovery of expected concentrations was modest, ranging from −24% to 44% recovery of Aβ40 , and 17% to 61% of Aβ42 . In conclusion, across five protocols, plasma Aβ40 and Aβ42 levels were measured with generally low error, and measurements appeared similar in blood collected in EDTA versus heparin. While these preliminary findings suggest that measuring plasma Aβ40 and Aβ42 may be feasible in varied research settings, additional work in this area is necessary. Show more

Keywords: Alzheimer's disease, amyloid, assay reliability, biomarker, quality control

DOI: 10.3233/JAD-2009-0948

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 277-285, 2009

Authors: Ling, Zhi-Qun | Tian, Qing | Wang, Li | Fu, Zheng-Qi | Wang, Xiao-Chuan | Wang, Qun | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Most patients with Alzheimer's disease (AD) present decreased levels of melatonin, a day-night rhythm-related hormone. To investigate the role of melatonin deficiency in AD, we used constant illumination to interrupt melatonin metabolism and measured some of the AD-like alterations in rats. Concomitant with decreased serum melatonin, the rats developed spatial memory deficits, tau hyperphosphorylation at multiple sites, activation of glycogen synthase kinase-3 and protein kinase A, as well as suppression of protein phosphatase-1. Prominent oxidative damage and organelle lesions, demonstrated by increased expression of endoplasmic reticulum (ER) stress-related proteins including BiP/GRP78 and CHOP/GADD153, decreased number of rough ER and free …ribosome, thinner synapses, and increased superoxide dismutase and monoamine oxidase were also observed in the light exposed rats. Simultaneous supplement of melatonin partially arrested the behavioral and molecular impairments. It is suggested that melatonin deficiency may be an upstream effector responsible for the AD-like behavioral and molecular pathologies with ER stress-involved mechanisms. Show more

Keywords: Alzheimer's disease, endoplasmic reticulum stress, light illumination, melatonin, tau

DOI: 10.3233/JAD-2009-0949

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 287-300, 2009

Authors: Zhou, Dawang | Zambrano, Nicola | Russo, Tommaso | D'Adamio, Luciano

Article Type: Research Article

Abstract: The phosphorylation of Tyr-682 residue in the intracellular domain (AID) of amyloid-β protein precursor (AβPP) is significantly enhanced in Alzheimer's disease patients' brain. The role of this phosphotyrosine, however, remains elusive. Here we report that phosphorylation of Tyr-682 inhibits the interactions between AβPP and Fe65, which is the main regulatory mechanism controlling Fe65 nuclear signaling. Furthermore, we show that tyrosine phosphorylation of AβPP also inhibits interaction of the two other Fe65 family members, Fe65L1 and Fe65L2. Likewise, docking of Fe65, Fe65L1 and Fe65L2 to APLP1 and APLP2, the two other members of the AβPP-gene family, is abolished by analogous phosphorylation …events. Our results indicate that phosphorylation of the cytoplasmic tail of AβPP on Tyr-682 represents a second mechanism, alternative to AβPP processing by secretases, that regulates AβPP/Fe65 downstream signaling pathways. Show more

Keywords: Amyloid-β protein precursor, Fe65, phosphorylation, threonine, tyrosine

DOI: 10.3233/JAD-2009-0970

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 301-307, 2009

Authors: Schroeder, Anja | Fahrenholz, Falk | Schmitt, Ulrich

Article Type: Research Article

Abstract: The α-secretase cleaves in the non-amyloidogenic pathway the amyloid-β protein precursor (AβPP) within the region of the amyloid-β peptides to prevent their formation and aggregation in the brain. Members of the ADAM family (a disintegrin and metalloprotease) are the main candidates for physiologically relevant α-secretases. We recently demonstrated that overexpression of ADAM10 in mice transgenic for human AβPP (ADAM10 x APP[V717I] ) alleviated functional deficits related to Alzheimer's disease. To further demonstrate that this is due to the specific activity of α-secretase, we characterized mice overexpressing an inactive form of ADAM10 (ADAM10[E384A] ; ADAM10-dn). Three lines of mice (controls (C57Bl/6 …x FVB), APP[V717I] transgenics and ADAM10-dn x APP[V717I] double-transgenics) were investigated with respect to learning and memory in the Morris water maze. Double-transgenic mice overexpressing ADAM10-dn behaved similar to APP[V717I] overexpressing mice. This provides further evidence that ADAM10 in vivo by its enzymatic activity is able to counteract cognitive deficits. Stimulation of α-secretase activity might thus be a suitable approach to study treatment strategies of Alzheimer's disease. Show more

Keywords: ADAM10 dominant-negative, α-secretase, Alzheimer's disease, transgenic mice

DOI: 10.3233/JAD-2009-0952

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 309-314, 2009

Authors: Nuntagij, Paworn | Oddo, Salvatore | LaFerla, Frank M. | Kotchabhakdi, Naiphinich | Ottersen, Ole P. | Torp, Reidun

Article Type: Research Article

Abstract: Little is known about how amyloid-β (Aβ) is deposited in relation to the complex ultrastructure of the brain. Here we combined serial section immunoelectron microscopy with 3D reconstruction to elucidate the spatial relationship between Aβ deposits and ultrastructurally identified cellular compartments. The analysis was performed in a transgenic mouse model with mutant presenilin-1, and mutant amyloid-β protein precursor (AβPP) and tau transgenes (3xTg-AD mice) and in aged dogs that develop Aβ plaques spontaneously. Reconstructions based on serial ultrathin sections of hippocampus (mice) or neocortex (dogs) that had been immunolabeled with Aβ (Aβ1–42 ) antibodies showed that the organization of extracellular …Aβ deposits is more complex than anticipated from light microscopic analyses. In both species, deposits were tightly associated with plasma membranes of pyramidal cell bodies and major dendrites. The deposits typically consisted of thin sheets as well as slender tendrils that climbed along the large caliber dendritic stems of pyramidal neurons. No preferential association was observed between Aβ deposits and thin dendritic branches or spines, nor was there any evidence of preferential accumulation of Aβ around synaptic contacts or glial processes. Our data suggest that plaque formation is a precisely orchestrated process that involves specialized domains of dendrosomatic plasma membranes. Show more

Keywords: Aged dogs, amyloid-β, electron microscopy, 3D images, immunocytochemistry, 3xTg mice

DOI: 10.3233/JAD-2009-0962

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 315-323, 2009

Authors: Marques, Marcos A. | Kulstad, J. Jacob | Savard, Christopher E. | Green, Pattie S. | Lee, Sum P. | Craft, Suzanne | Watson, G. Stennis | Cook, David G.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) is cleared from the brain by both proteolytic digestion and transport across the blood-brain-barrier into the peripheral circulatory system. To investigate the role peripheral Aβ levels play in regulating Aβ brain clearance, we measured the clearance of [125 I]-Aβ1–40 injected into the brains of liver-ligated rats that allowed peripheral Aβ levels to be maintained at elevated levels for approximately one hour with/without a single peripheral bolus of unlabeled Aβ1–40 . We found that elevating peripheral Aβlevels significantly decreased [125 ]-Aβ1–40 brain clearance, thus supporting the hypothesis that peripheral Aβ levels regulate Aβ clearance from the central …nervous system. Show more

Keywords: Alzheimer's disease, blood-brain-barrier, hepatic clearance, liver, passive immunization, peripheral sink

DOI: 10.3233/JAD-2009-0964

Citation: Journal of Alzheimer's Disease, vol. 16, no. 2, pp. 325-329, 2009