Journal of Alzheimer's Disease - Volume 31, issue 4

Authors: Xia, Weiming | Wong, Stephen T. | Hanlon, Eugene | Morin, Peter

Article Type: Review Article

Abstract: The outcomes of the clinical trials of the γ-secretase inhibitor Semagacestat (LY-450139) and the γ-secretase modulator (GSM) Tarenflurbil were disappointing, but may not represent the end of the γ-secretase era. γ-Secretase modulators, by definition, only block the γ-secretase cleavage of amyloid-β protein precursor (AβPP) to generate the longer, 42-residue amyloid-β (Aβ42 ) without changing the production of total Aβ. The first generation GSMs were shown to block Aβ42 generation while increasing Aβ38 . The non-steroidal anti-inflammatory drug, Tarenflurbil, binds to AβPP and shifts the cleavage site from Aβ42 to Aβ38 . In addition, Tarenflurbil does not affect the …γ-secretase cleavage of Notch. Even before the failed clinical trials of Tarenflurbil, second generation GSMs had emerged, and some of these GSMs interact with presenilin, which carries the active site of the γ-secretase. While second generation GSMs are pharmacologically superior to first generation GSMs, in vivo Aβ profiles (decreased levels of Aβ38 , Aβ40 , and Aβ42 ) in animals treated with potent GSMs are strikingly different from those in cultured cells. Thus, the unique pharmacologic properties of new GSMs and their mechanisms of action need to be elucidated in order to avoid the fate of Tarenflurbil. It is critical to understand how GSMs shift the “end” in vivo, i.e., shifting the γ-secretase cleavage at the C-terminal end of Aβ. In view of the myriad effects of candidate GSMs on Aβ production in cells and animals, drug development would benefit from better definition of the target-GSM interaction and physiological function of shorter Aβ peptides. Show more

Keywords: Alzheimer's disease, amyloid, inhibitor, modulator, Notch, presenilin, secretase

DOI: 10.3233/JAD-2012-120751

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 685-696, 2012

Authors: Pérez-Martínez, Francisco C. | Carrión, Blanca | Ceña, Valentín

Article Type: Review Article

Abstract: Nanoparticles represent an alternative to viral vectors for genetic material transfer to the nervous system. However, to increase transfection efficiency in the central nervous system and to decrease toxicity, the design of nanoparticles needs to be improved to enhance blood-brain barrier crossing and endosomal escape. This paper reviews the strategies used to solve these difficulties and covers the use of various nanoparticles including natural inorganic particles, natural polymers, cationic lipids, polyethylenimine derivatives, dendrimers, and carbon-based nanoparticles. The effectiveness, both in vivo and in vitro, of each method to deliver genetic material to neural tissue is discussed.

Keywords: Blood-brain barrier, dendrimers, gene transfer, nanoparticles, neurons, siRNA

DOI: 10.3233/JAD-2012-120661

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 697-710, 2012

Authors: Figueiro, Mariana G. | Hamner, Robert | Higgins, Patricia | Hornick, Thomas | Rea, Mark S.

Article Type: Short Communication

Abstract: The absence of daily robust light-dark exposure patterns may contribute to sleep disturbances in persons with Alzheimer's disease and related dementias (ADRD). Personal light-dark and activity-rest patterns were measured for healthy older adults and for persons with ADRD. Persons with ADRD experienced lower light levels, exhibited lower activity levels, and had greater levels of circadian disruption than healthy older adults during winter. Seasonal differences were observed for persons with ADRD; lower levels of light exposure and greater levels of circadian disruption were seen during the winter than during the summer, although activity levels did not differ for the two seasons.

Keywords: Alzheimer's disease, circadian, circadian dysregulation, circadian light, phasor magnitude

DOI: 10.3233/JAD-2012-120484

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 711-715, 2012

Authors: von Arnim, Christine A.F. | Herbolsheimer, Florian | Nikolaus, Thorsten | Peter, Richard | Biesalski, Hans K. | Ludolph, Albert C. | Riepe, Matthias | Nagel, Gabriele | the ActiFE Ulm study group

Article Type: Research Article

Abstract: Oxidative stress is believed to play a central role in the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disease. Antioxidants may prevent the onset AD as high dietary intake of vitamin C and E were reported to be associated with lower risk of the disease. The objective of this study was to evaluate the serum levels of antioxidants in persons with mild dementia to test whether it is associated with lower levels of antioxidants in a cross-sectional study in the population of the “Activity and Function in the Ederly in Ulm” (ActiFE) study. Main exposure measures were vitamin C, vitamin …E, β-carotene, lycopene, and coenzyme Q10 as analyzed by HPLC. Main outcome measures were mild cognitive impairment among 74 mildly demented compared to 158 age- and gender-matched controls. We found that blood vitamin C and β-carotene concentrations were significantly lower in demented than in control persons even after adjusting for school education, intake of dietary supplements, smoking habits, body mass index, and alcohol consumption (3rd versus 1st tertile: OR: 0.29, 95% CI, 0.09–0.96 and 0.13, 95% CI, 0.03–0.55, respectively). No associations were found for vitamin E, lycopene, and coenzyme Q10. Our findings suggest an association of vitamin C and β-carotene with dementia. However this is limited to the cross-sectional character of our study and longitudinal data will give further insight into this association. Show more

Keywords: Antioxidants, beta carotene, dementia, older population, oxidative stress, vitamin C

DOI: 10.3233/JAD-2012-120634

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 717-724, 2012

Authors: Exley, Christopher | House, Emily | Polwart, Anthony | Esiri, Margaret M.

Article Type: Research Article

Abstract: The deposition in the brain of amyloid-β as beta sheet conformers associated with senile plaques and vasculature is frequently observed in Alzheimer's disease. While metals, primarily aluminum, iron, zinc, and copper, have been implicated in amyloidβ deposition in vivo, there are few data specifically relating brain metal burden with extent of amyloid pathologies in human brains. Herein brain tissue content of aluminum, iron, and copper are compared with burdens of amyloid-β, as senile plaques and as congophilic amyloid angiopathy, in 60 aged human brains. Significant observations were strong negative correlations between brain copper burden and the degree of severity of …both senile plaque and congophilic amyloid angiopathy pathologies with the relationship with the former reaching statistical significance. While we did not have access to the dementia status of the majority of the 60 brain donors, this knowledge for just 4 donors allowed us to speculate that diagnosis of dementia might be predicted by a combination of amyloid pathology and a ratio of the brain burden of copper to the brain burden of aluminum. Taking into account only those donor brains with either senile plaque scores ≥4 and/or congophilic amyloid angiopathy scores ≥12, a Cu : Al ratio of <20 would predict that at least 39 of the 60 donors would have been diagnosed as suffering from dementia. Future research should test the hypothesis that in individuals with moderate to severe amyloid pathology low brain copper is a predisposition to developing dementia. Show more

Keywords: Aluminum, Alzheimer's disease, amyloid-β, congophilic amyloid angiopathy, copper, iron, human brain tissue, senile plaque

DOI: 10.3233/JAD-2012-120766

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 725-730, 2012

Authors: Seripa, Davide | Bizzarro, Alessandra | Pilotto, Andrea | Palmieri, Orazio | Panza, Francesco | D'Onofrio, Grazia | Gravina, Carolina | Archetti, Silvana | Daniele, Antonio | Borroni, Barbara | Padovani, Alessandro | Masullo, Carlo

Article Type: Research Article

Abstract: The aim of this study was to investigate the apolipoprotein E (APOE) chromosomal region in frontotemporal lobar degeneration (FTLD), and in particular in primary progressive aphasia (PPA) and the behavioral variant frontotemporal dementia (bvFTD). To this aim, we selected three single-nucleotide polymorphisms (SNPs) rs2075650 and rs157590 (TOMM40), and rs1064725 (APOC1), representative of the linkage disequilibrium (LD) blocks at the 19q13-q13.2 chromosomal region. The SNPs rs429358 and rs7412 forming the APOE polymorphism were also included in the study. The analysis was made in 282 patients with a clinical diagnosis of sporadic FTLD, namely 207 bvFTD and 75 PPA, and 296 cognitively …healthy control subjects. LD (r2 = 0.35) between TOMM40 (rs2075650) and APOC1 (rs1064725) was observed in PPA, but not in controls and in bvFTD. Inside this region of 26.9 kb, LD (r2 ≥ 0.50) between TOMM40 (rs2075650) and APOE (rs429358) was observed in bvFTD and in controls, but not in PPA. Inside this region of 16.3 kb, LD (r2 = 0.14) between TOMM40 (rs157590) and APOE (rs429358) was observed in PPA, but not in bvFTD and in controls. Although the genetics of PPA and bvFTD needs further investigation, our results suggested the presence of a different genetic background underlying PPA and bvFTD at the 19q13-q13.2 chromosomal region. Show more

Keywords: APOC1, APOE E, behavioral variant of frontotemporal dementia, frontotemporal lobar degeneration, primary progressive aphasia, TOMM40

DOI: 10.3233/JAD-2012-120403

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 731-740, 2012

Authors: Deramecourt, Vincent | Lebert, Florence | Maurage, Claude-Alain | Fernandez-Gomez, Francisco-Jose | Dujardin, Simon | Colin, Morvane | Sergeant, Nicolas | Buée-Scherrer, Valérie | Clot, Fabienne | Ber, Isabelle Le | Brice, Alexis | Pasquier, Florence | Buée, Luc

Article Type: Research Article

Abstract: MAPT mutations cause autosomal dominant frontotemporal lobar degeneration. These diseases are characterized by considerable heterogeneity in their clinical, neuropathological, and biochemical presentations. We describe the full characterization of a family with autosomal dominant frontotemporal lobar degeneration caused by a novel MAPT mutation. Clinical, imaging, neuropathological, and biochemical data are presented. The proband was a woman who died at 85 years old, 25 years after the onset of a slowly progressive and isolated anarthria and opercular syndrome. The pathological examination of her brain showed marked atrophy of primary motor and premotor cortices, associated with predominant neuronal tau-positive lesions mimicking Pick bodies. …At the biochemical level, the six tau isoforms aggregate to display a pathological triplet at 60, 64, and 69 kDa. Two of her sons presented at 48 and 50 years old with a right temporal variant of frontotemporal degeneration characterized by severe prosopagnosia, semantic impairment, and behavioral modifications. In these three patients, the molecular analysis of MAPT showed the c.1945C>T mutation on exon 11 resulting in the P332S substitution in tau sequence. This mutation changes the PGGG motif of the third repeat domain of the protein and therefore reduces the ability of tau to bind microtubule. From a clinical point of view, this mutation is associated with considerable intrafamilial phenotypic variation. Show more

Keywords: Frontotemporal lobar degeneration, FTDP-17, MAPT, Pick body, progressive anarthria, semantic dementia, tau protein

DOI: 10.3233/JAD-2012-120160

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 741-749, 2012

Authors: Arlt, Sönke | Schwedhelm, Edzard | Kölsch, Heike | Jahn, Holger | Linnebank, Michael | Smulders, Yvo | Jessen, Frank | Böger, Rainer H. | Popp, Julius

Article Type: Research Article

Abstract: Dimethylarginine and homocysteine metabolism are closely linked and alterations of both were observed in plasma and cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD). CSF parameters of homocysteine metabolism have recently been found to be associated with the CSF level of the AD biomarker phosphorylated tau (ptau) in AD patients. To investigate possible relationships between homocysteine and dimethylarginine metabolism and the AD CSF biomarkers ptau181 and amyloid-β 1-42 (Aβ42 ), we assessed parameters of homocysteine metabolism (CSF homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), 5-methyltetrahydrofolate (5-MTHF)) and dimethylarginine metabolism (plasma and CSF asymmetric dimethylarginine (ADMA), symmetric dimethylarginine, L-arginine) as well as …CSF Aβ42 and ptau181 in 98 controls and 51 AD patients. Multivariate linear regression analyses were performed to assess associations between the considered parameters. SAH concentrations show significant associations to CSF ADMA levels, and CSF ADMA and L-arginine to ptau181, but not to Aβ42 concentrations in AD patients. When including concentrations of homocysteine, 5-MTHF, SAM, and SAH into the analysis, CSF ADMA concentrations independently predicted ptau181 levels in AD patients but homocysteine-related metabolites were associated with ptau181 only when ADMA was removed from the analysis model. These results suggest that CSF ADMA may interact with CNS homocysteine metabolism and may contribute to neurodegeneration and accumulation of phosphorylated tau in AD. Functional and interventional studies are needed to further proof this hypothesis. Show more

Keywords: Alzheimer's disease, asymmetric dimethylarginine, cerebrospinal fluid, homocysteine, S-adenosylhomocysteine, S-adenosylmethionine

DOI: 10.3233/JAD-2012-112138

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 751-758, 2012

Authors: Laakso, Tiina | Muggalla, Pranuthi | Kysenius, Kai | Laurén, Juha | Paatero, Anja | Huttunen, Henri J. | Airaksinen, Matti S.

Article Type: Research Article

Abstract: Neuronal LRRTM3 (leucine-rich repeat transmembrane 3) protein has been reported to promote amyloid-β protein precursor (AβPP) processing and LRRTM3 is a candidate gene in late-onset Alzheimer's disease. To address the role of LRRTM3 in AβPP processing and amyloid-β (Aβ) production in vivo, we analyzed amyloidogenic processing of AβPP in the brains of LRRTM3-deficient mice and transgenic AβPP/PS1 mice with or without LRRTM3. We did not find differences between the genotypes in the levels of Aβ or AβPP C-terminal fragments indicating that LRRTM3 is not an essential regulator of Aβ production in adult mice. Moreover, Aβ levels in primary cortical neurons …were similar between the genotypes, indicating that LRRTM3 is not required for Aβ generation in developing mice. Show more

Keywords: Amyloid-β protein precursor, BACE1, LRR-domain, neurexin, synaptogenic

DOI: 10.3233/JAD-2012-120193

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 759-764, 2012

Authors: Zeng, Yan | Liu, Yakun | Wu, Mianyun | Liu, Jun | Hu, Qi

Article Type: Research Article

Abstract: 7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a brain-derived neurotrophic factor (BDNF) mimetic to selectively activate the tropomyosin-related kinase B (TrkB) with high affinity. We have previously demonstrated that 7,8-DHF in vitro rescues long-term synaptic plasticity in the hippocampus of aged rats. The present study assessed the effectiveness of 7,8-DHF on age-related declines in fear memories and amygdalar synaptic plasticity. We found that Sprague Dawley male rats began to show significant deficits in the acquisition and retention of memories for contextual and cued fear conditioning, as well as the reduction of BDNF, TrkB, and phosphorylated TrkB at the age of …25 months. Therefore, rats at 24 months old received intraperitoneal administration of either 7,8-DHF (5 mg/kg, i.p.) or vehicle once daily for a consecutive 4 weeks. At the end of treatment period, cognitive performance, amygdalar synaptic plasticity, synaptogenesis, and the phosphorylation of several proteins crucial to synaptic plasticity were evaluated. The results show that chronic 7,8-DHF treatments significantly enhanced the activation of phosphorylated TrkB at the Y515 and Y816 sites, increased spine density and number in several brain regions that process fear memory including the amygdala, hippocampus, and prefrontal cortex, facilitated basolateral amygdalar synaptic plasticity, and in turn prevented performance in fear conditioning tasks from declining. Our results thus confirm a critical role for TrkB signaling activation by 7,8-DHF in preventing age-related declines in fear learning and memory and strongly suggest a potential usefulness for 7,8-DHF or a TrkB agonist in reversing age-related memory impairment. Show more

Keywords: 7,8-dihydroxyflavone, aging, learning and memory, synaptic plasticity, TrkB

DOI: 10.3233/JAD-2012-120886

Citation: Journal of Alzheimer's Disease, vol. 31, no. 4, pp. 765-778, 2012