Current Alzheimer Research (v.13, #6)

Meet Our Editorial Board Member by Jianping Jia (609-609).

Evidence for Mitochondrial UPR Gene Activation in Familial and Sporadic Alzheimer's Disease by John S. Beck, Elliott J. Mufson, Scott E. Counts (610-614).
Mitochondrial perturbations such as oxidative stress, increased fission/fusion dysfunction, and mitophagy are consistent features of Alzheimer's disease (AD), yet the mechanisms that initiate these perturbations are unclear. One potential source for mitochondrial defects could be an imbalance in mitochondrial proteostasis. In this regard, studies indicate that a specialized mitochondrial unfolded protein response (mtUPR) is activated upon the aberrant accumulation of damaged or unfolded proteins in the mitochondrial matrix, resulting in the up-regulation of key genes involved in mitochondrial stabilization. To test whether mtUPR activation occurs in AD, we performed real-time quantitative PCR on postmortem frontal cortex samples from subjects classified as sporadic AD, familial AD linked to presenilin-1 mutations, or cognitively intact controls. Compared to controls, sporadic AD subjects exhibited a significant ~40-60% increase in expression levels of select genes activated by the mtUPR, including mitochondrial chaperones dnaja3, hspd1, and hspe1, mitochondrial proteases clpp and yme1l1, and txn2, a mitochondrial-specific oxidoreductase. Furthermore, levels of all six mtUPR genes were significantly up-regulated by ~70-90% in familial AD compared to controls, and these expression levels were significantly higher compared to sporadic AD. The increase in hspd1 (Hsp60) was validated by western blotting. These data support the concept that both sporadic and familial AD are characterized by mtUPR gene activation. Understanding the physiological consequences of this response may provide subcellular mechanistic clues to selective neuronal vulnerability or endogenous compensatory mechanisms during the progression of AD.

A Role for P-Glycoprotein in Clearance of Alzheimer Amyloid ? -Peptide from the Brain by Wei Wang, Angela M. Bodles-Brakhop, Steven W. Barger (615-620).
Most data indicates that Alzheimer's disease involves an accumulation of amyloid ? - peptide (A?) in the CNS and that sporadic cases arise from a deficiency in A? clearance. Considerable attention has been given to mechanisms by which A? might be transported between the brain and blood, and evidence suggests that p-glycoprotein, also known as the multi-drug resistance (MDR) protein (product of the ABCB1 gene), plays a role in A? transport across the blood-brain barrier (BBB). We tested this possibility through two approaches: First, wild-type and MDR1A-knockout mice were compared after intravenous injection of [125I]-labeled A?; after 60 min, homogenates of brain parenchyma were subjected to ?-counting of TCA-precipitable material, and histological sections of brain were subjected to autoradiography. Second, MDR1Aknockout mice were crossed with Tg2576 APP transgenic mice, a line that routinely accumulates A? in the brain; SDS and formic acid extracts of brain homogenates were assessed for A? levels by ELISA. Each of these approaches yielded data indicating that A? accumulates to a greater degree in mice lacking MDR1A. These findings confirm other reports linking p-glycoprotein to A? clearance across the BBB and have important implications for Alzheimer's disease genetics, pharmacology, and epidemiology.

Accumulation of intraneuronal amyloid-? peptide (A?) appears to be an early event in Alzheimer's disease (AD), suggesting its important role in the neurodegenerative process of AD. It is indicated that intracellular A? originates from a portion of A?, which is not secreted and consequently remains intracellular, or alternatively from the secreted A?, which is internalized into intracellular A? pool. A number of cell and transgenic animal models are established to study the pathological role of intracellular A?, and to screen for drugs against A? aggregation and associated toxicity. A? aggregates, particularly oligomers, may lead to synaptic dysfunction and neuronal loss. Screened from high-throughput methods, a number of cellpermeable agents reduce the aggregation of intracellular A? and antagonize its cytotoxicity by inhibiting the formation of A? oligomers in vivo. The multi-functional roles of A? in alternate pathways and associated clinical implications for AD treatment are also discussed.

Early ?-Amyloid-induced Synaptic Dysfunction Is Counteracted by Estrogen in Organotypic Hippocampal Cultures by Sara Merlo, Simona Federica Spampinato, Francisco Capani, Maria Angela Sortino (631-640).
In the present study we set up a model of slow progression of neuronal injury by exposing organotypic hippocampal cultures to a low concentration of Amyloid ? (25-35) peptide (A?, 2 ?M) to analyze the time-related effects of 17-? estradiol (17?-E2, 10 nM). Neuronal death occurs after 7 d and is prevented by addition of 17?-E2 24 h prior to, together with or 48 h after exposure to A?. This effect is mimicked by selective ER? agonist PPT (100 nM). Treatment with A? leads to early and transient (16-72 h) increase of pre- and post-synaptic proteins synaptophysin and PSD95, followed by a decrease coincident with neuronal death (7d), all prevented by 17?-E2. At 72 h of A? exposure, synaptic activity is increased, as by higher levels of glutamate and increased loading and unloading of FM 1-43-labeled synaptic vesicles. All these effects are also prevented by 17?-E2. These data point out beneficial effects of estrogen on early A?-induced synaptic disruption.

Metabolomic-Driven Elucidation of Serum Disturbances Associated with Alzheimer's Disease and Mild Cognitive Impairment by Raúl González-Domínguez, Francisco Javier Rupérez, Tamara García-Barrera, Coral Barbas, José Luis Gómez-Ariza (641-653).
Numerous efforts have been made in the last years to discover potential biomarkers of Alzheimer's disease and its progression from mild cognitive impairment, considered as an intermediate phase in the development of Alzheimer's disease from normal aging. However, there is still a considerable lack of understanding about pathological mechanisms underlying to disease. In the present study, serum metabolomics based on ultra-high-performance liquid chromatographymass spectrometry was applied to investigate metabolic differences between subjects with Alzheimer's disease and mild cognitive impairment, as well as healthy controls. The most important findings can be associated with impaired metabolism of phospholipids and sphingolipids leading to membrane breakdown, wherein the nature of the fatty acids contained in the structure in terms of acyl chain length and degree of unsaturation appears to play a crucial role. Furthermore, several discriminant metabolites were found for the first time in relation to known pathological processes associated with Alzheimer's disease, such as the accumulation of acylcarnitines in relation to mitochondrial dysfunction, decreased levels of oleamide and monoglycerides as a result of defects in endocannabinoid system, or increased serum phenylacetylglutamine, which could reveal alterations in glutamine homeostasis. Therefore, these results represent a suitable approximation to understand the pathogenesis and progression of the disease. ?

Serum Levels of Progranulin Do Not Reflect Cerebrospinal Fluid Levels in Neurodegenerative Disease by Carlo Wilke, Frank Gillardon, Christian Deuschle, Evelyn Dubois, Markus A. Hobert, Jennifer Müller vom Hagen, Stefanie Krüger, Saskia Biskup, Cornelis Blauwendraat, Michael Hruscha, Stephan A. Kaeser, Peter Heutink, Walter Maetzler, Matthis Synofzik (654-662).
Altered progranulin levels play a major role in neurodegenerative diseases, like Alzheimer's dementia (AD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), even in the absence of GRN mutations. Increasing progranulin levels could hereby provide a novel treatment strategy. However, knowledge on progranulin regulation in neurodegenerative diseases remains limited. We here demonstrate that cerebrospinal fluid progranulin levels do not correlate with its serum levels in AD, FTD and ALS, indicating a differential regulation of its central and peripheral levels in neurodegeneration. Blood progranulin levels thus do not reliably predict central nervous progranulin levels and their response to future progranulin-increasing therapeutics.

Reducing amyloid-? (A?) accumulation is a promising strategy for developing Alzheimer's Disease (AD) therapeutics. We recently reported that a triphenylmethane food dye analog, Brilliant Blue G (BBG), is a dose-dependent modulator of in vitro amyloid-? aggregation and cytotoxicity in cell-based assays. Following up on this recent work, we sought to further evaluate this novel modulator in a therapeutically-relevant AD transgenic mouse model. BBG was orally administered to APPSwDI/NOS2-/- mice for three months in order to assess its biocompatibility, its permeability across the blood-brain barrier, and its efficacy at rescuing AD pathology. The results showed that BBG was well-tolerated, caused no significant weight change/unusual behavior, and was able to significantly cross the AD blood-brain barrier in APPSwDI/NOS2-/- mice. Immunohistochemical and electron microscopic analysis of the brain sections revealed that BBG was able to significantly prevent neuronal loss and reduce intracellular APP/A? in hippocampal neurons. This is the first report of 1) the effect of Brilliant Blue G on neuronal loss in a transgenic animal model of AD, 2) oral administration of BBG to affect a protein conformation/aggregation disease, and 3) electron microscopic ultrastructural analysis of AD pathology in APPSwDI/NOS2-/- mice.

Left Anterior Temporal Glucose Metabolism and not Amyloid-beta Load Predicts Naming Impairment in Alzheimer's Disease by Lars Frings, Timo S. Spehl, Michael Hüll, Philipp T. Meyer (678-681).
Naming impairment in Alzheimer's disease dementia (AD) is associated with atrophy of the left anterior temporal lobe (ATL). We aimed to elucidate if regional cerebral glucose metabolism, as a biomarker of synaptic dysfunction and neurodegeneration, of the left ATL predicts naming impairment, and if amyloid-beta (A?) deposition, a pathological hallmark of AD, contributes to the prediction.
Twenty-nine patients with AD underwent combined [11C]PIB and [18F]FDG PET examinations for assessment of A? load and regional cerebral glucose metabolism. An a priori defined region of interest was used for regional PET analyses of the left ATL. In linear stepwise regression analyses, glucose metabolism of the left ATL was the only significant predictor of naming performance, independent of sex, age, and education. Neither regional nor global A? load contributed to the prediction.
Left ATL glucose metabolism predicts naming impairment in AD. By contrast, A? deposition does not predict naming impairment.

Statistical Voxel-Based Methods and [18F]FDG PET Brain Imaging: Frontiers for the Diagnosis of AD by Francesca Gallivanone, Pasquale Anthony Della Rosa, Isabella Castiglioni (682-694).
Recommended guidelines for the diagnosis of dementia due to Alzheimer's Disease (AD) were revised in recent years, including Positron Emission Tomography (PET) as an in-vivo diagnostic imaging technique for the diagnosis of neurodegeneration. In particular PET, using 18Ffluorodeoxiglucouse ([18F]FDG), is able to detect very early changes of glucose consumption at the synaptic level, enabling to support both early and differential diagnosis of AD. In standard clinical practice, interpretation of [18F] FDG-PET images is usually achieved through qualitative assessment. Visual inspection although only reveals information visible at human eyes resolution, while information at a higher resolution is missed. Furthermore, qualitative assessment depends on the degree of expertise of the clinician, preventing from the definition of accurate and standardized imaging biomarkers. Automated and computerized image processing methods have been proposed to support the in-vivo assessment of brain PET studies. In particular, objective statistical image analyses, enabling the comparison of one patient's images to a group of control images have been shown to carry important advantages for detecting significant metabolic changes, including the availability of more objective, cross-center reliable metrics and the detectability of brain subtle functional changes, as occurring in prodromal AD. The purpose of the current review is to provide a systematic overview encompassing the frontiers recently reached by quantitative approaches for the statistical analysis of PET brain images in the study of AD, with a particular focus on Statistical Parametric Mapping. Main achievements, e.g. in terms of standardized biomarkers of AD as well as of sensitivity and specificity, will be discussed.

Functional Biomedical Images of Alzheimer's Disease a Green's Functionbased Empirical Mode Decomposition Study by S. Al-Baddai, A. Neubauer, A.M. Tomé, V. Vigneron, D. Salas-Gonzalez, J.M. Górriz, C.G. Puntonet, E.W. Lang, the Alzheimer';s Disease Neuroimaging Initiative (695-707).
Positron emission tomography (PET) provides a functional imaging modality to detect signs of dementias in human brains. Two-dimensional empirical mode decomposition (2D-EMD) provides means to analyze such images. It decomposes the latter into characteristic modes which represent textures on different spatial scales. These textures provide informative features for subsequent classification purposes. The study proposes a new EMD variant which relies on a Green's function based estimation method including a tension parameter to fast and reliably estimate the envelope hypersurfaces interpolating extremal points of the twodimensional intensity distrubution of the images. The new method represents a fast and stable bi-dimensional EMD which speeds up computations roughly 100-fold. In combination with proper classifiers these exploratory feature extraction techniques can form a computer aided diagnosis (CAD) system to assist clinicians in identifying various diseases from functional images alone. PET images of subjects suffering from Alzheimer's disease are taken to illustrate this ability.

The TT allele of rs405509 synergizes with APOE ?4 in the impairment of cognition and its underlying default mode network in non-demented elderly by Chao Ma, Yangjun Zhang, Xin Li, Yaojing Chen, Junying Zhang, Zhen Liu, Kewei Chen, Zhanjun Zhang (708-717).
Background: Evidence demonstrates that the T allele of the single-nucleotide polymorphism rs405509 as the apolipoprotein E (APOE) promoter is a risk factor for Alzheimer's disease (AD). However, it is unclear the APOE-rs405509 interaction effect on brain spontaneous activity. Methods: We analyzed the interaction of the rs405509 TT allele and the APOE ?4 allele on cognitive performances measured using neuropsychological tests and brain default mode network (DMN) defined by independent component analysis using based on resting-state functional magnetic resonance imaging data among the non-demented elderly people. Results: Significant interaction was found between rs405509 and APOE on general mental status, memory and attention (p<0.05). Functional network analysis showed a significantly APOE-rs405509 interaction on anterior cingulate gyrus, medial frontal region and precuneus at anterior and posterior DMN (False Discovery Rate p<0.05). Additionally, significant correlations were found between cognitive performance and DMN connectivity (p<0.05). Conclusion: The data indicates that the APOE-rs405509 interaction impairs elderly's cognitive performance through brain functional network.

Prevalence and associated factors of sarcopenia in elderly subjects with amnestic mild cognitive impairment or Alzheimer disease. by Taiki Sugimoto, Rei Ono, Shunsuke Murata, Naoki Saji, Yasumoto Matsui, Shunpei Niida, Kenji Toba, Takashi Sakurai (718-726).
Background: To date, very little is known about the nature of sarcopenia in subjects with cognitive impairment. The aims of this study were firstly to clarify the prevalence of sarcopenia at various stages of cognitive impairment, and secondly to examine factors related to sarcopenia in men and women with cognitive impairment. Method: The subjects were 418 outpatients (normal cognition; NC: 35, amnestic mild cognitive impairment; aMCI: 40, Alzheimer disease; AD: 343) who attended the Memory Clinic at the National Center for Geriatrics and Gerontology of Japan during the period from October 2010 to July 2014. Cognitive status, vitality, depressive mood, body mass index, hand grip strength, timed up and go test, skeletal muscle mass and serum levels of 25-hydroxyvitamin D, albumin and creatinine were assessed. Sarcopenia was defined as the presence of both poor muscle function (low physical performance or low muscle strength) and low muscle mass. We performed the univariate and multivariate logistic regression analyses to explore factors associated with sarcopenia. Results: The overall prevalence of sarcopenia was 21.1% (NC = 8.6%, aMCI = 12.5%, AD = 23.3%). In both sexes, factors associated with sarcopenia were age (P < .01), body mass index (P < .001) and vitality (P < .05). In women, serum level of 25-hydroxyvitamin D was associated with sarcopenia (P < .05). Conclusion: Low vitality could be a dementia-specific risk factor for sarcopenia. Prevention of sarcopenia in patients with cognitive impairment should be approached from physical and psychologic points of view.