Journal of Alzheimer's Disease - Volume 37, issue 4

Authors: Larner, A.J.

Article Type: Review Article

Abstract: Presenilin 1 (PSEN1) gene mutations deterministic for Alzheimer's disease (AD) are associated with marked heterogeneity in clinical phenotype, with behavioral and psychiatric features, parkinsonism, myoclonus, epileptic seizures, spastic paraparesis, frontal behavioral changes suggestive of the phenotype of frontotemporal dementia, aphasia, and cerebellar ataxia being described as well as cognitive decline. This article reviews publications on the clinical neurological phenotype of PSEN1 mutations published between October 2008 and April 2013 and integrates this information with previous reviews to produce tabular summaries of phenotype and genotype. With the possible exception of “variant AD” (familial AD with spastic paraparesis), no clinical genotype-phenotype correlations …are obvious. The mechanisms underpinning the clinical heterogeneity associated with PSEN1 mutations remain unclear. The “presenilin hypothesis” posits a loss of essential presenilin protein functions as a consequence of gene mutation, which might be one factor influencing disease phenotype. Show more

Keywords: Alzheimer's disease, mutation, presenilin 1

DOI: 10.3233/JAD-130746

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 653-659, 2013

Authors: Robinson, Renã A.S. | Cao, Zhiyun | Williams, Christopher

Article Type: Short Communication

Abstract: Oxidative stress plays a role in Alzheimer's disease (AD) with elevated levels being present in tissues such as brain, plasma, and cerebrospinal fluid. The role of oxidative stress in the immune system of AD is less established. Therefore, we measured protein markers of oxidative stress—protein carbonyls (PCO) and 3-nitrotyrosine (3NT)—in CD90+ T-cells of a double-transgenic AD mouse model. Higher levels of PCO and 3NT were detected in amyloid-β protein precursor/presenilin-1 (AβPP/PS-1) mice and increased with disease progression. These studies provide evidence that oxidative stress in the immune system may be useful for understanding disease pathogenesis.

Keywords: AβPP/PS-1, Alzheimer's disease, CD90+ T-cells, mice, oxidative stress

DOI: 10.3233/JAD-130665

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 661-666, 2013

Authors: Taverna, Mara | Straub, Tobias | Hampel, Harald | Rujescu, Dan | Lichtenthaler, Stefan F.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the most common neurodegenerative disorder. Frequently used diagnostic biomarkers are amyloid-β42 (Aβ42 ), tau, and phospho-tau, which are measured in cerebrospinal fluid (CSF), and allow a reasonable, but not full, separation of AD patients and controls. Besides Aβ42 , additional proteolytic cleavage products of the amyloid-β protein precursor (AβPP) have been investigated as potential biomarkers. This includes the α-secretase cleaved soluble AβPP ectodomain (sAβPPα). However, some studies found a reduction of sAβPPα, whereas other studies reported an increase of sAβPPα in the CSF of AD patients. The divergent findings may result from the detection of …sAβPPα with antibodies, such as 6E10, which do not exclusively detect sAβPPα, but also the alternative β-secretase cleavage product sAβPPβ'. Here, we used the sAβPPα-specific antibody 14D6 and developed an ELISA-like sandwich immunoassay. The assay specifically detected sAβPPα in cell culture supernatants, in human CSF and even in serum, which is more readily accessible than CSF. The assay was used to analyze sAβPPα levels in CSF and serum of AD patients and controls. The assay detected a mild, but significant increase in sAβPPα in the CSF of AD patients compared to non-demented controls, while a mild reduction was observed in serum. The 14D6 assay in CSF allowed a better separation of AD patients from controls compared to the 6E10 antibody. Taken together, the new assay is widely applicable for specific sAβPPα measurement in culture media, CSF, and serum. Show more

Keywords: α-Secretase, Alzheimer's disease, amyloid-β protein precursor, biomarker, sandwich immunoassay

DOI: 10.3233/JAD-130509

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 667-678, 2013

Authors: Manczak, Maria | Sheiko, Tatiana | Craigen, William J. | Reddy, P. Hemachandra

Article Type: Research Article

Abstract: The objective of this study was to elucidate the effect of VDAC1 on Alzheimer's disease (AD)-related genes, mitochondrial activity, and synaptic viability. Recent knockout studies of VDAC1 revealed that homozygote VDAC1 knockout (VDAC1−/− ) mice exhibited disrupted learning and synaptic plasticity, and in contrast, VDAC1+/− mice appeared normal in terms of lifespan, fertility, and viability relative to wild-type mice. However, the effects of reduced VDAC1 on mitochondrial/synaptic genes and mitochondrial function in AD-affected neurons are not well understood. In the present study, we characterized mitochondrial/synaptic and AD-related genes and mitochondrial function in VDAC1+/− mice and VDAC1+/+ mice. …We found reduced mRNA levels in the AD-related genes, including AβPP, Tau, PS1, PS2, and BACE1; increased levels of the mitochondrial fusion genes Mfn1, Mfn2; reduced levels of the fission genes Drp1 and Fis1; and reduced levels of the mitochondrial permeability transition pore genes VDAC1, ANT, and CypD in VDAC1+/− mice relative to VDAC1+/+ mice. Hexokinase 1 and 2 were significantly upregulated in the VDAC+/− mice. The synaptic genes synaptophysin, synapsin 1 and 2, synaptobrevin 1 and 2, neurogranin, and PSD95 were also upregulated in the VDAC1+/− mice. Free radical production and lipid peroxidation levels were reduced in the VDAC1+/− mice, and cytochrome oxidase activity and ATP levels were elevated, indicating enhanced mitochondrial function in the VDAC1+/− mice. These findings suggest that reduced VDAC1 expression, such as that we found in the VDAC1+/− mice, may be beneficial to synaptic activity, may improve function, and may protect against toxicities of AD-related genes. Show more

Keywords: Amyloid-β, knockout mouse model, mitochondrial function, oxidative stress, real-time reverse transcriptase PCR, voltage-dependent anion channel 1

DOI: 10.3233/JAD-130761

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 679-690, 2013

Authors: Noguchi-Shinohara, Moeko | Yuki, Sohshi | Dohmoto, Chiaki | Ikeda, Yoshihisa | Samuraki, Miharu | Iwasa, Kazuo | Yokogawa, Masami | Asai, Kimiko | Komai, Kiyonobu | Nakamura, Hiroyuki | Yamada, Masahito

Article Type: Research Article

Abstract: Significant differences exist in demographic characteristics between responders and non-responders in population-based studies on mental health and cognitive status, but much less is known regarding differences in the prevalence of dementia and cognitive dysfunction between them. Here we compared the prevalence of dementia and mild cognitive impairment between early responders of a mass brain function examination and delayed responders (non-responders of the mass brain function examination) in a survey of elderly Japanese citizens (≥65 years) to evaluate non-responder bias. All residents in an area of Nakajima, Japan, were considered as potential candidates (n = 783). Participants of a mass brain …function examination were considered as “early responders.” The cognitive functions of delayed responders were assessed by home visits. To assess the correlation between sociodemographic characteristics and cognitive functions, the early and delayed responders completed the same questionnaires and neuropsychological tests. Delayed responders (n = 320) were significantly older and less educated than the early responders (n = 307). The delayed responders also exhibited a higher frequency of dementia and mild cognitive impairment than the early responders, even when the groups were restricted to the age group 65–89 years. Our results suggest that population-based studies likely underestimate the prevalence of dementia and mild cognitive impairment, especially if the participation rate is low. Show more

Keywords: Bias, dementia, mild cognitive impairment, prevalence, prospective studies

DOI: 10.3233/JAD-130398

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 691-698, 2013

Authors: Wu, Nan | Rao, Xiaoping | Gao, Yunling | Wang, Jie | Xu, Fuqiang

Article Type: Research Article

Abstract: Olfactory dysfunction is closely related to Alzheimer's disease (AD). Yet the mechanism behind this dysfunction remains largely unknown. To clarify the relationship between olfactory and memory deficits, we assessed behavioral and olfactory system pathology in AβPP/PS1 transgenic mice using the olfactory threshold test, the Morris water maze, Western blotting, immunohistochemistry (IHC), and thioflavine-s staining. Western blotting revealed the following spatial-temporal deposition of amyloid-β (Aβ): appeared in the olfactory epithelium at 1-2 months old (mo); expanded to the olfactory bulb at 3-4 mo; expanded to the anterior olfactory nucleus, piriform cortex, entorhinal cortex, and hippocampus at 6-7 mo; and increased with …age (9-10 mo) in the more central cortices. IHC staining showed similar results, but the appearance time points for the spotty signals in these brain regions were earlier due to the higher spatial resolution compared with Western blotting. The spread of Aβ deposits from the olfactory epithelium to the olfactory bulb, the anterior olfactory nucleus, and piriform cotex (faint) at 3-4 mo correlated with the olfactory detection deficit found at the corresponding age; and the high level of depositions in the more central regions at 9-10 mo correlated with spatial memory deficit at the same age. We also found that a decline in the levels of olfactory marker protein, a marker of functioning olfactory sensory neuron, coincided with soluble Aβ aggregates from a very early age in the olfactory epithelium, indicating early olfactory sensory neuron degeneration in the AβPP/PS1 mouse as in AD patients. The current data suggest that the early deposition of soluble Aβ aggregates in the olfactory system and the early deficit in olfactory dysfunction have the potential to serve as molecular markers for the early diagnosis of AD. Show more

Keywords: Aβ deposition pattern, AβPP/PS1 transgenic mice, Alzheimer's disease, olfactory system

DOI: 10.3233/JAD-122443

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 699-712, 2013

Authors: Zheng, Lin | Calvo-Garrido, Javier | Hallbeck, Martin | Hultenby, Kjell | Marcusson, Jan | Cedazo-Minguez, Angel | Terman, Alexei

Article Type: Research Article

Abstract: Amyloid-β peptide (Aβ), the main component of Alzheimer's disease (AD) senile plaques, has been found to accumulate within the lysosomal compartment of AD neurons. We have previously shown that in differentiated SH-SY5Y neuroblastoma cells cultured under normal conditions, the majority of Aβ is localized extralysosomally, while oxidative stress significantly increases intralysosomal Aβ content through activation of macroautophagy. It is, however, not clear which cellular compartments contain extralysosomal Aβ in intact SH-SY5Y cells, and how oxidative stress influences the distribution of extralysosomal Aβ. Using confocal laser scanning microscopy and immunoelectron microscopy, we showed that in differentiated neuroblastoma cells cultured under normal …conditions Aβ (Aβ40 , Aβ42 , and Aβ oligomers) is colocalized with both membrane-bound organelles (endoplasmic reticulum, Golgi complexes, multivesicular bodies/late endosomes, lysosomes, exocytotic vesicles and mitochondria) and non-membrane-bound cytosolic structures. Neuroblastoma cells stably transfected with AβPP Swedish KM670/671NL double mutation showed enlarged amount of Aβ colocalized with membrane compartments. Suppression of exocytosis by 5 nM tetanus toxin resulted in a significant increase of the amount of cytosolic Aβ as well as Aβ colocalized with exocytotic vesicles, endoplasmic reticulum, Golgi complexes, and lysosomes. Hyperoxia increased Aβ localization in the endoplasmic reticulum, Golgi apparatus, mitochondria, and lysosomes, but not in the secretory vesicles. These results indicate that in SH-SY5Y neuroblastoma cells intracellular Aβ is not preferentially localized to any particular organelle and, to a large extent, is secreted from the cells. Challenging cells to hyperoxia, exocytosis inhibition, or Aβ overproduction increased intracellular Aβ levels but did not dramatically changed its localization pattern. Show more

Keywords: Alzheimer's disease, amyloid β-protein, endosomes, exocytosis, lysosomes

DOI: 10.3233/JAD-122455

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 713-733, 2013

Authors: Zolezzi, Juan M. | Carvajal, Francisco J. | Ríos, Juvenal A. | Ordenes, Daniela | Silva-Alvarez, C. | Godoy, Juan A. | Inestrosa, Nibaldo C.

Article Type: Research Article

Abstract: St. John's wort has been the subject of studies focused on its therapeutic properties against several diseases, including Alzheimer's disease (AD). Amyloid β-peptide (Aβ), a critical peptide in AD, has been linked to the mitochondrial dysfunction often observed in this disease. Despite many efforts to prevent Aβ levels from increasing in AD, less has been done regarding the mitochondrial component. Therefore, we studied the effects of tetrahydrohyperforin (THH) on mitochondrial dysfunction of hippocampal neurons, challenged with Aβ oligomers (Aβo) and Aβo-AChE complexes. We show that THH prevents mitochondrial calcium overload and induces the modulation of fusion-fission events, arresting mitochondrial dysfunction. …Moreover, our results suggest that the modulation of mitochondrial dynamics probably occurs through a peroxisome proliferator-activated receptor γ co-activator 1α-mediated mechanism, inducing mitochondrial fusion-fission protein expression. Our results offer further explanation for the effects observed for THH and the beneficial effects of this ethno-botanical drug in AD. Show more

Keywords: Calcium, DRP1, FIS1, mitochondrial fusion-fission, neurodegeneration, PGC-1α

DOI: 10.3233/JAD-130173

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 735-746, 2013

Authors: Krako, Nina | Magnifico, Maria Chiara | Arese, Marzia | Meli, Giovanni | Forte, Elena | Lecci, Agnese | Manca, Annalisa | Giuffrè, Alessandro | Mastronicola, Daniela | Sarti, Paolo | Cattaneo, Antonino

Article Type: Research Article

Abstract: The 7WD4 and 7PA2 cell lines, widely used as cellular models for Alzheimer's disease (AD), have been used to investigate the effects of amyloid-β protein precursor overexpression and amyloid-β (Aβ) oligomer accumulation on mitochondrial function. Under standard culture conditions, both cell lines, compared to Chinese hamster ovary (CHO) control cells, displayed an ~5% decrease of O2 respiration as sustained by endogenous substrates. Functional impairment of the respiratory chain was found distributed among the protein complexes, though more evident at the level of complex I and complex IV. Measurements of ATP showed that its synthesis by oxidative phosphorylation is decreased …in 7WD4 and 7PA2 cells by ~25%, this loss being partly compensated by glycolysis (Warburg effect). Compensation proved to be more efficient in 7WD4 than in 7PA2 cells, the latter cell line displaying the highest reactive oxygen species production. The strongest deficit was observed in mitochondrial membrane potential that is almost 40% and 60% lower in 7WD4 and 7PA2 cells, respectively, in comparison to CHO controls. All functional parameters point to a severe bioenergetic impairment of the AD cells, with the extent of mitochondrial dysfunction being correlated to the accumulation of Aβ peptides and oligomers. Show more

Keywords: Alzheimer's disease, amyloid-β oligomers, bioenergetics, mitochondrial dysfunction

DOI: 10.3233/JAD-130728

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 747-758, 2013

Authors: Yener, Görsev G. | Kurt, Pınar | Emek-Savaş, Derya Durusu | Güntekin, Bahar | Başar, Erol

Article Type: Research Article

Abstract: Mild cognitive impairment (MCI) is considered as a prodromal stage for Alzheimer's disease (AD) in the majority of cases. Event-related oscillations might be used for detection of cognitive deficits. Our group's earlier results showed diminished delta visual and auditory target oscillatory responses in AD, and we investigated whether this prevails for MCI. Eighteen MCI subjects and 18 age-matched healthy elderly controls were investigated. The maximum peak-to-peak amplitudes of oscillatory responses for each subject's averaged oscillatory target responses in delta, theta, and alpha frequency bands upon application of visual oddball paradigm were measured. Repeated measures of ANOVA was used to analyze …four locations (frontal, central, parietal, occipital), at three coronal (left, midline, right) sites. Independent t tests were applied for post-hoc analyses. The oddball target delta response (0.5–3.0 Hz) was 26–32% lower in MCI than healthy controls over fronto-central-parietal regions [F(1.34) = 4.562, p = 0.04]. Without a group effect, theta oscillatory responses (4–7 Hz) showed significant differences in coronal electrodes indicating highest values over mid-electrode sites, and a anteriorposterior x coronal effect, being maximum at mid-central. Alpha frequency band analyses indicated no statistical differences. Peak-to-peak amplitudes of visual target delta oscillatory responses were lower in fronto-central-parietal regions in MCI than in healthy controls. This supports our earlier findings in AD, showing hypoactive delta fronto-central-parietal regions during cognitive tasks. These results indicate that event-related oscillations may detect early changes of brain dynamics in MCI, and deserves to be investigated as a candidate biomarker in further studies using multimodal techniques. Show more

Keywords: Biomarker, early diagnosis of Alzheimer's disease, electroencephalographic rhythms, event-related potentials, mild cognitive impairment, oscillations

DOI: 10.3233/JAD-130569

Citation: Journal of Alzheimer's Disease, vol. 37, no. 4, pp. 759-767, 2013