Journal of Alzheimer's Disease - Volume 25, issue 1

Authors: Perry, George

Article Type: Editorial

DOI: 10.3233/JAD-2011-1439

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 1-1, 2011

Authors: Haapasalo, Annakaisa | Kovacs, Dora M.

Article Type: Review Article

Abstract: The Alzheimer's disease (AD)-associated amyloid-β protein precursor (AβPP) is cleaved by α-, β-, and presenilin (PS)/γ-secretases through sequential regulated proteolysis. These proteolytic events control the generation of the pathogenic amyloid-β (Aβ) peptide, which excessively accumulates in the brains of individuals afflicted by AD. A growing number of additional proteins cleaved by PS/γ-secretase continue to be discovered. Similarly to AβPP, most of these proteins are type-I transmembrane proteins involved in vital signaling functions regulating cell fate, adhesion, migration, neurite outgrowth, or synaptogenesis. All the identified proteins share common structural features, which are typical for their proteolysis. The consequences of the PS/γ-secretase-mediated …cleavage on the function of many of these proteins are largely unknown. Here, we review the current literature on the proteolytic processing mediated by the versatile PS/γ-secretase complex. We begin by discussing the steps of AβPP processing and PS/γ-secretase complex composition and localization, which give clues to how and where the processing of other PS/γ-secretase substrates may take place. Then we summarize the typical features of PS/γ-secretase-mediated protein processing. Finally, we recapitulate the current knowledge on the possible physiological function of PS/γ-secretase-mediated cleavage of specific substrate proteins. Show more

Keywords: Alzheimer's disease, amyloid-β protein precursor, γ-secretase, presenilin, regulated intramembrane processing

DOI: 10.3233/JAD-2011-101065

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 3-28, 2011

Authors: Kuljiš, Rodrigo O. | Šalković-Petrišić, Melita

Article Type: Review Article

Abstract: Dementia is an increasingly prevalent condition that intersects worldwide with the epidemic of type 2 diabetes mellitus (DM2). It would seem logical to expect that the occurrence of DM2 increases the likelihood of developing dementia, due to its deleterious effect on the cerebral vasculature and the associated hormonal and metabolic changes. Many reports indicate that it also increases the risk of developing Alzheimer's disease (AD). However, other studies suggest that diabetes might have a relatively strong protective effect against AD, whereas genetically engineered animal models of the condition deteriorate more severely when there is a concomitant insulin resistant brain state …(IRBS). Furthermore, IRBS alone is associated with anatomical, behavioral, and molecular changes that justify the proposal that AD may be due to an IRBS. This is explored in the context of accumulating evidence that the IRBS need not be related to peripheral insulin resistance, and that administration of insulin directly to the brain improves selected cognitive parameters targeted in AD. This view is consistent with the Damage Signals hypothesis of AD pathogenesis, which can help unifying the pleiotropic effects of agents toxic to insulin-producing/secreting (e.g., pancreatic β) cells, as well as IRBS caused by different mechanisms in AD. Such approach may help tackling the Innovation Gap, which results from a host of factors slowing down progress towards innovative palliation and prevention of AD, as well as dementia due to complications of diabetes distinct from AD, and both conditions combined with their commonly associated metabolic and hormonal alterations. Show more

Keywords: Alzheimer's disease, dementia, diabetes, insulin resistance, streptozotocin

DOI: 10.3233/JAD-2011-101392

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 29-41, 2011

Authors: House, Emily | Jones, Krista | Exley, Christopher

Article Type: Short Communication

Abstract: Recent evidence showed that amyloid-β, Aβ42 , formed spherulites in vitro and, possibly, in vivo in Alzheimer's disease brain tissue. We now confirm the presence of spherulites in human brains and that they are composed of β sheets of amyloid. The spherulites were identical in appearance to spherulites of Aβ42 formed in vitro which suggested that they may too be composed of Aβ. The physiological significance of this finding may be in its support of previous speculation that spherulites in human brain tissue are the 3-dimensional manifestations of what are otherwise identified as senile or neuritic plaques.

Keywords: Alzheimer's disease, amyloid-β, Congo red, human brain, senile plaque, spherulites, thioflavin T

DOI: 10.3233/JAD-2011-110071

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 43-46, 2011

Authors: Ramírez-Lorca, Reposo | Boada, Mercé | Antúnez, Carmen | López-Arrieta, Jesús | Moreno-Rey, Concha | Hernández, Isabel | Marín, Juan | Gayán, Javier | González-Pérez, Antonio | Alegret, Montserrat | Tárraga, Lluis | Real, Luis M. | Ruiz, Agustín

Article Type: Short Communication

Abstract: The MTHFD1L gene SNP variant rs11754661 was found to increase the risk of Alzheimer's disease in a recent Whole Genome Association Study [1]. We have carried out an independent study of this genetic variant in 2467 individuals from Spain. We found no evidence of association between the MTHFD1L marker and susceptibility to Alzheimer's disease in our sample.

Keywords: Folate, GWAS, homocysteine, MTHFD1L, population genetics, susceptibility, SNP

DOI: 10.3233/JAD-2011-101983

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 47-50, 2011

Authors: Descamps, Olivier | Zhang, Qiang | John, Varghese | Bredesen, Dale E.

Article Type: Research Article

Abstract: Statins are drugs commonly used to inhibit cholesterol synthesis, with the goal of reducing vascular diseases such as myocardial infarction and stroke. Statins have also been suggested as a therapeutic option for Alzheimer's disease (AD), although their benefit in AD remains controversial. We have previously shown that the intracellular C-terminal cleavage of the amyloid-β protein precursor (AβPP) is a major contributor to the neuronal toxicity seen in AD, and that this cleavage can be induced by amyloid-β. We now report that certain brain permeable statins are also able to induce the C-terminal cleavage of AβPP and associated cell death, whereas …other statins do not. This statin effect on AβPP exceeded the effects of all other FDA-approved drugs in a library composed of these compounds, suggesting that this effect on AβPP cleavage is unique to a subset of the statins. Furthermore, the greatest effect occurred with cerivastatin, which has previously been shown to be the statin associated with the greatest risk of rhabdomyolysis. These results may have implications for the choice of which statins to evaluate in AD therapeutic trials; furthermore, the results may inform statin choice in individuals who are at high risk for the development of AD, such as those with an apolipoprotein E ε4 allele. Show more

Keywords: AlphaLisa assay, AβPPneo fragment, caspase cleavage; C-31, D664, Jcasp, statins

DOI: 10.3233/JAD-2011-101857

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 51-57, 2011

Authors: Morimoto, Kaori | Horio, Juri | Satoh, Haruhisa | Sue, Lucia | Beach, Thomas | Arita, Seizaburo | Tooyama, Ikuo | Konishi, Yoshihiro

Article Type: Research Article

Abstract: Neuroinflammation is involved in the pathology of Alzheimer's disease (AD). Our major focus was to clarify whether neuroinflammation plays an important role in AD pathogenesis, particularly prior to the manifestation of overt dementia. We analyzed cytokine expression profiles of the brain, with focus on non-demented patients with increasing AD pathology, referred to as high pathology control (HPC) patients, who provide an intermediate subset between AD and normal control subjects, referred to as low pathology control (LPC) patients. With real-time PCR techniques, we found significant differences in interleukin (IL)-1β, 10, 13, 18, and 33, tumor necrosis factor-α (TNFα) converting enzyme (TACE), …and transforming growth factor β1 (TGFβ1) mRNA expression ratios between HPC and AD patients, while no significant differences in the expression ratios of any cytokine tested here were observed between LPC and HPC patients. The cytokine mRNA expression ratios were determined as follows: first, cytokine mRNA levels were normalized to mRNA levels of a housekeeping gene, peptidyl-prolyl isomerase A (PPIA), which showed the most stable expression among ten housekeeping genes tested here; then, the normalized data of cytokine levels in the temporal cortex were divided by those in the cerebellum, which is resistant to AD pathology. Subsequently, the expression ratios of the temporal cortex to cerebellum were compared among LPC, HPC, and AD patient groups. Our results indicate that cytokines are more mobilized and implicated in the later AD stage when a significant cognitive decline occurs and develops than in the developmental course of AD pathology prior to the manifestation of overt dementia. Show more

Keywords: Alzheimer's disease, cytokines, interleukins, PCR, TNF-α

DOI: 10.3233/JAD-2011-101815

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 59-76, 2011

Authors: Han, Sun-Ho | Jung, Eun Sun | Sohn, Ji-Hoon | Hong, Hyun Joo | Hong, Hyun Seok | Kim, Jong Won | Na, Duk Lyul | Kim, Manho | Kim, Hee | Ha, Hee Jin | Kim, Young Ho | Huh, Namjung | Jung, Min Whan | Mook-Jung, Inhee

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the fastest growing neurodegenerative disease in the elderly population, and the search for therapeutic targets and diagnostic AD biomarkers is an exigent issue. Because amyloid-β (Aβ) aggregation constitutes the epicenter of AD pathology, Aβ-binding proteins that regulate Aβ aggregation, such as transthyretin (TTR), have attracted much attention. TTR binds to Aβ, prevents its aggregation, and consequently inhibits Aβ-induced cellular toxicity. Decreased TTR levels in cerebrospinal fluid (CSF) from AD patients suggest that TTR is a biomarker of AD. But, studies on TTR as a biomarker have focused on CSF; no study has evaluated peripheral levels of …TTR in AD. Here, we examined the relationship between serum TTR levels and AD. We measured TTR levels in serum samples from 90 nondemented controls and 111 AD patients and observed significantly lower serum TTR levels in AD (p < 0.001). Notably, females in the control group had lower serum TTR levels compared with male in the control (p = 0.006), while no difference in gender was noted in the AD group. There were no age-related changes in serum TTR levels. Thus, this study demonstrates a clear negative correlation between serum TTR levels and AD, suggesting that TTR is not only involved in AD pathological process but also suggested as possible peripheral biomarker for AD diagnosis in serum level. Show more

Keywords: Alzheimer's disease, amyloid-β aggregation, biomarker, serum, transthyretin

DOI: 10.3233/JAD-2011-102145

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 77-84, 2011

Authors: Mulin, Emmanuel | Zeitzer, Jamie M. | Friedman, Leah | Le Duff, Franck | Yesavage, Jerome | Robert, Philippe H. | David, Renaud

Article Type: Research Article

Abstract: Apathy is the most frequently reported neuropsychiatric symptom across all stages of Alzheimer's disease (AD). Both apathy and sleep disorders are known to have independent negative effects on the quality of life in individuals with AD. The aim of this study was to assess the relationship between apathy and sleep/wake patterns in individuals with AD using ambulatory actigraphy. One hundred and three non-institutionalized individuals with AD wore a wrist actigraph continuously over seven consecutive 24-h periods. Apathy was assessed using the Neuropsychiatric Inventory. Daytime mean motor activity (dMMA) was calculated from daytime wrist actigraphy data. Actigraphic parameters of sleep included …total sleep time (TST), wake after sleep onset (WASO), time in bed (TIB), WASO normalized by TIB, sleep latency, and nighttime mean motor activity (nMMA). Among the 103 individuals with AD (aged 76.9 ± 7.2 years; MMSE = 21.4 ± 4.3), those with apathy had significantly lower dMMA, higher WASO (both raw and normalized), and spent more time in bed during the night than those without apathy. Sleep latency, nMMA and TST did not differ significantly between the two subgroups. To our knowledge, this study is the first to identify a relationship between apathy and sleep disturbance in those with mild or moderate AD: apathy was associated with increased TIB during the night and more WASO. These results suggest that AD patients with apathy have less consolidated nocturnal sleep than those without apathy. Show more

Keywords: Actigraphy behavioral disturbances, Alzheimer's disease, apathy, sleep disorders

DOI: 10.3233/JAD-2011-101701

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 85-91, 2011

Authors: Broer, Linda | Ikram, Mohammad Arfan | Schuur, Maaike | DeStefano, Anita L. | Bis, Joshua C. | Liu, Fan | Rivadeneira, Fernando | Uitterlinden, Andre G. | Beiser, Alexa S. | Longstreth, William T. | Hofman, Albert | Aulchenko, Yurii | Seshadri, Sudha | Fitzpatrick, Annette L. | Oostra, Ben A. | Breteler, Monique M.B. | van Duijn, Cornelia M.

Article Type: Research Article

Abstract: The heat shock protein (HSP) 70 family has been implicated in the pathology of Alzheimer's disease (AD). In this study, we examined common genetic variations in the 80 genes encoding HSP70 and its co-chaperones. We conducted a study in a series of 462 patients and 5238 unaffected participants derived from the Rotterdam Study, a population-based study including 7983 persons aged 55 years and older. We genotyped a total of 12,053 Single Nucleotide Polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. Replication was performed in two independent cohort studies, the Framingham Heart study (FHS; n = 806) and Cardiovascular Health …Study (CHS; n = 2150). When adjusting for multiple testing, we found a small but consistent, though not significant effect of rs12118313 located 32 kb from PFDN2, with an OR of 1.19 (p-value from meta-analysis = 0.003). However this SNP was in the intron of another gene, suggesting it is unlikely this SNP reflects the effect of PFDN2. In a formal pathway analysis we found nominally significant evidence for an association of BAG, DNAJA and prefoldin with AD. These findings corroborate with those of a study of 2032 AD patients and 5328 controls, in which several members of the prefoldin family showed evidence for association to AD. Our study did not reveal evidence for a genetic variant if the HSP70 family with a major effect on AD. However, our findings of the single SNP analysis and pathway analysis suggest that multiple genetic variants in prefoldin are associated with AD. Show more

Keywords: Alzheimer's disease, genetic association studies, heat-shock proteins, prefoldin

DOI: 10.3233/JAD-2011-101560

Citation: Journal of Alzheimer's Disease, vol. 25, no. 1, pp. 93-102, 2011