Current Alzheimer Research - Volume 14, Issue 6, 2017

Background: The APOE4 allele is the strongest genetic risk factor for Alzheimer's disease (AD). It has been associated with an accumulation of amyloid-β (Aβ) in the brain, which is produced through the sequential cleavage of the amyloid-β precursor protein (AβPP) by β - and γ-secretases. Alternatively, AβPP is also cleaved by α -secretases such as A Disintegrin and Metalloproteinase Domain-containing Protein 10 (ADAM10). Objective: While several studies have investigated the impact of apoE on β- and γ-secretase, interactions between apoE and α-secretases have not been fully examined. We investigated the effect of each apoE isoform on ADAM10 in vitro and in human cortex samples. Method: ADAM10 activity and kinetics was assessed in cell-free assays and the biological activity of ADAM10 further investigated in 7WCHO cells over-expressing wild type AβPP through ELISA. Finally, ADAM10 expression and activity was observed in the soluble fraction of both control and Alzheimer's Disease human cortex samples through ELISA. Results: In a cell free assay, ADAM10 activity was found to be significantly lower in apoE4 samples compared to apoE2. 7WCHO cells over expressing wild type AβPP exposed to apoE4 demonstrated reduced formation of sAβPPα compared to other apoE isoforms. We also identified APOE and AD dependent changes in ADAM10 activity and expression in the soluble brain fraction of human brain cortex. Conclusion: Overall, our data demonstrates an apoE isoform-dependent effect on ADAM10 function and AβPP processing which may describe the elevated amyloid levels in the brains of AD subjects carrying the APOE4 allele.

Background: Gangliosides are enriched in the neuronal membranes. Gangliosides are shown to interact with amyloid-β proteins, leading to formation of amyloid fibrils in Alzheimer's disease (AD) brains. Several earlier studies indicated that the alterations of ganglioside metabolism could contribute the pathogenesis of AD. Methods: Gangliosides were isolated from the frontal lobes in five patients with AD and three control subjects. Gangliosides were assessed by high performance thin-layer chromatography (HPTLC) with resorcinol staining and immunostaining using mouse monoclonal antibodies against cholinergic neuronspecific (Chol-1α) gangliosides. Results: In all AD brains, not only the total sialic acid content but also a-series gangliosides, GM1 and GD1a, were dramatically reduced as compared with those in control subjects. These results are a hallmark of the pathogenesis in AD. In contrast, Chol-1α gangliosides, GT1aα and GQ1bα, which are specific markers of cholinergic neurons, were significantly increased in AD brains. Conclusion: The expression of Chol-1α gangliosides may be caused by a compensation to preserve the function of the cholinergic neuron and play an important role in cholinergic synaptic transmission.

Background: Phospholipids and their metabolisms are closely allied to nosogenesis and aggravation of Type 2 diabetes mellitus and cognitive impairment. The aim of this study is to characterize the plasma levels of phospholipids in type 2 diabetes patients and type 2 diabetes patients with mild cognitive impairment (MCI), and to identify potential biomarkers of type 2 diabetes patients with MCI. Methods: In this cross-sectional study, a total of 374 type 2 diabetes patients were prospectively enrolled. There were 103 patients with MCI and 271 patients without MCI. Plasma levels of lysophosphatidic acid (LPA) and phospholipids with solubility similar to that of LPA (PSS-LPA) were assayed. Results: Plasma LPA and PSS-LPA levels were significantly higher in patients with MCI than those without MCI (P = 0.007, P < 0.001). A logistic regression analysis indicates that elevated plasma PSSLPA was associated with increased risk of MCI in type 2 diabetic patients, with an OR of 1.87 (1.04-3.47) after additional adjustment for hyperlipidemia, hypertension, High-sensitivity C-reactive protein, hemoglobin A1c, Intima-media thickness, ankle brachial index, and brachial-ankle pulse wave velocity. In type 2 diabetic patients with MCI, there were negative correlations between plasma LPA, PSS-LPA and the MoCA scores (r =0.322, P < 0.01; r =0.349, P < 0.001). Furthermore, plasma PSS-LPA exhibited a fair diagnostic value for MCI, with an area under the curve of 0.86. Conclusion: The level of plasma PSS-LPA may be an important biomarker for diagnosis of MCI.

Objective: The aim of this study was to evaluate the diagnostic accuracy and clinical usability of a Dutch translation of the Test Your Memory (TYM) test in patients with mild cognitive impairment (MCI) and dementia as compared to the Mini-Mental State Examination (MMSE), in the setting of the memory clinic of a general hospital. Methods: Fourty-two participants referred to the memory clinic with memory problems and fourty-two healthy controls were assessed using the TYM and the MMSE. We evaluated the sensitivity, specificity and diagnostic accuracy of the TYM and MMSE. Both instruments were tested against recently established clinical diagnostic criteria of MCI, Alzheimer's disease (AD) and vascular dementia (VD). Results: The TYM demonstrated to be more sensitive in detecting dementia than the MMSE. The TYM also was better at discriminating between healthy controls and patients with MCI than the MMSE. Conclusion: Our data suggest that the TYM is more suitable as a practical tool for the early detection of dementia than the MMSE.

Background: Mild Cognitive Impairment (MCI) is a risk factor for Alzheimer’s disease (AD) and other forms of dementia. However, much heterogeneity concerning neuropsychological measures, prevalence and progression rates impedes distinct diagnosis and treatment implications. Objective: Aim of the present study was the identification of specific tests providing a high certainty for stable MCI and factors that precipitate instability of MCI in a community based sample examined at three measurement points. Method: 130 participants were tested annually with an extensive test battery including measures of memory, language, executive functions, intelligence and dementia screening tests. Exclusion criteria at baseline comprised, severe cognitive deficits (e.g. diagnosis of dementia, psychiatric or neurological disease). Possible predictors for stability or instability of MCI-diagnosis were analyzed using Regression and Receiver Operating Characteristic (ROC) curve analysis. Age, IQ and APOE status were tested for moderating effects on the interaction of test performances and group membership. Results: A high prevalence of MCI (49%) was observed at baseline with a reversion rate of 18% after two years. Stability of MCI was related to performances in four measures (VLMT: delayed recall, CERAD: recall drawings, CERAD: Boston Naming Test, Benton Visual Retention Test: number of mistakes). Conversion to MCI is associated with language functions. Reversion to ‘normal’ was primarily predicted by single domain impairment. There was no significant influence of demographic, medical or genetic variables. Conclusion: The results highlight the role of repeated measurements for a reliable identification of functional neuropsychological predictors and better diagnostic reliability. In cases of high uncertainty close monitoring over time is needed in order of estimating outcome.

Objective: To study the prevalence of cognitive impairment and dementia in communitydwelling Malays from Singapore; and to examine differences in prevalence among Chinese and Malays. Methods: Subjects (≥ 60 years) - drawn from the Malay component of the on-going multiethnic Epidemiology of Dementia in Singapore study - were screened using locally validated Abbreviated Mental Test and Progressive Forgetfulness Questionnaire. Subsequently, screen-positive participants underwent detailed neuropsychological assessments and neuroimaging. Cognitive impairment no dementia (CIND) and dementia were diagnosed based on accepted criteria. Results: A total of 966 Malay subjects were included, of whom 102 had CIND-mild, 135 CINDmoderate, and 27 dementia. The overall age-standardized prevalence of any cognitive impairment was 25.5%, including 2% of dementia. The prevalence of any cognitive impairment increased with age from 14·9% in those aged 60-64 years to 40.2% in age ≥80 years. Women had a higher prevalence of CIND and dementia than men. Compared to previously published data from EDIS on Chinese, Malay were nearly twice more likely to have any cognitive impairment (Odds ratios adjusted for age, demographic and cardiovascular risk factors, and ApoE4 carrier: 2.03, 95% confidence interval: 1.48-2.77). Conclusion: Among elderly Malays, the overall prevalence of any cognitive impairment was 25.5%. Even with a similar protocol of recruitment and assessment and adjusting for known risk factors, the prevalence of cognitive impairment was higher in Malays compared to Chinese. Further research is needed to unravel other factors that may underlie these ethnic differences in the occurrence of cognitive impairment.

Background: Impaired functional connectivity in the default mode network (DMN) is supposedly involved in Alzheimers disease (AD) progression. The posterior cingulate cortex (PCC) might be an imaging marker for monitoring AD progression. Objective: To investigate the alterations in the directed functional connectivity between the PCC and whole brain in patients with AD, patients with mild cognitive impairment (MCI), and healthy controls. Methods: A total of 116 enrolled participants were divided into three groups: AD (n=32), MCI (n=26), and controls (n=58). Using resting-state functional magnetic resonance imaging (rs-fMRI), the directed functional connectivity was studied using Granger causality analysis (GCA). Results: Almost all of the directed functional connections with significant differences were unidirectional. Compared with the NC group, the AD group showed enhanced directed connectivity from the whole brain to the PCC mainly for regions outside the DMN, and reduced connectivity from the PCC to the whole brain mainly for regions inside the DMN. Compared with the NC group, the MCI group showed enhanced directed connectivity from the PCC to the whole brain for the bilateral precuneus and postcentralgyrus, and reduced connectivity from the whole brain to the PCC for regions outside the DMN. Compared with the MCI group, the abnormal directed connectivity in the AD group was predominantly in the left hemisphere, possibly suggesting asymmetric characteristics. Conclusion: In patients with AD, the PCC in the DMN shows disorders in receiving and transmitting information, and these abnormalities are directional.

Background: DNA topoisomerase IIβ (topo IIβ) plays a crucial role in neural differentiation and axonogenesis. Inhibition of topo IIβ activity in vitro and in vivo results in shorter axons and increased DNA damage. These molecular events also involve in Alzheimer's disease (AD); however, the role of topo IIβ in the pathogenesis of AD remains to be elucidated. Objectives: We aimed to investigate the role of topo IIβ association with Nuclear receptor related 1 protein (Nurr1) in the onset of AD. Methods: In vitro AD model was established by the incubation of fibrillar amyloid-β 1-42 (Aβ1-42) for 48 hours with cultured cerebellar granule neurons (CGNs) isolated from post-natal eight-day rats. The regulatory role of topo IIβ on the transcription of Nurr1 was analyzed in topo IIβ silenced CGNs, and also topo IIβ silenced and overexpressed in a neurally-differentiated human mesenchymal (hMSC) cell line. Results: Aβ1-42 fibrils led to the upregulation of Presenilin1 and Cofilin1 genes as measured at mRNA levels and hyperphosphorylation of tau protein, all are distinctive characteristics of AD pathology. A significant decrease in topo IIβ expression at mRNA and protein levels and Nurr1 at mRNA level was also observed. In both cell types, Nurr1 expression was dramatically down-regulated due to topo IIβ deficiency, and was increased in topo IIβ overexpressing hMSCs. Conclusion: Our findings suggest that topo IIβ could be a down-stream target of signaling pathways contributing to AD-like pathology. However, further studies must be carried out in vivo to elucidate the precise association topo IIβ with AD.

Background: Whether exercise could delay the cognitive function decline and structural changes in Alzheimer's disease (AD) are not fully understood. Methods: 6-month-old male APP/PS1 double transgenic mice ran four months and then the effects of exercise on the cognitive function and the white matter of AD were investigated. Results: The mean escape latency of the excercised group was significantly shortened when compared to that of the sedentary group. The percentage of time in target quadrant and the target zone frequency of the exercised group were significantly increased when compared to the sedentary group. The white matter volume, the myelinated fiber volume and axon volume in the white matter of the exercised group were significantly increased when compared to the sedentary group. Conclusion: Exercise could improve the cognitive function in AD, and the effects of exercise on the white matter of AD might be one of the structural bases for the protective effect of exercise on the cognitive function of AD. The exercise-induced protection of the white matter in AD might be due to the fact that the exercise prevented the demyelination of the myelinated fibers in the white matter of AD.

Background: Immunization against beta-amyloid (Aβ) reduces cerebral Aβ deposits and improves cognitive capacities in transgenic mouse models, and thus has been considered a promising disease-modifying therapeutic approach for Alzheimer's disease (AD). Although clinical trials in AD patients have yielded evidence for clearance of parenchymal Aβ plaques, Aβ increases in blood vessels of treated patients. We hypothesize that an age-related decline in the mechanisms that clear Aβ from the brain might be at least in part responsible for the failure to purge and re-distribute Aβ. The expulsion of Aβ via the blood-brain barrier is mediated by specialized transport proteins such as P-glycoprotein (P-gp, ABCB1/MDR1). Objective: The objective of this study is to investigate the influence of the absence of P-gp at the bloodbrain barrier on the effectiveness of Aβ peptide immunization in APP/PS1+/- P-gp ko mice. Methods: Male APP/PS1+/- P-gp wt (n = 8) and APP/PS1+/- P-gp ko (n = 8) mice were actively immunized with human Aβ 42. After behavioral testing animals were sacrificed at the age of 395 days (+/- 5 days) and antibody titres against Aβ were measured. Brains were dissected and soluble/insoluble cerebral Aβ was quantified, additionally the number of amyloid plaques and severity of amyloid angiopathy were evaluated. Results: In immunized mice with intact P-gp, our results showed a significant reduction of soluble and insoluble Aβ 40 and Aβ 42. Furthermore, immunization significantly reduced Aβ plaque burden. In contrast, immunized APP/PS1+/- P-gp ko mice lacking functional P-gp did not show a reduction of Aβ 40 or Aβ42 accumulation in the brain except for the soluble form of Aβ 42. Furthermore, after active immunization these mice displayed a stronger intracerebral amyloid angiopathy. Conclusion: The results show that the absence of P-gp results in a significant disturbance of Aβ removal from the brain and increased intraparenchymal cerebral amyloid angiopathy after immunization against Aβ. Our data indicate that the selective up-regulation of P-gp could enhance the efficacy of Aβ immunization in the treatment or prevention of AD.

Background: Amyloid peptide precursor (APP) as the precursor protein of peptide betaamyloid (β-amyloid, Aβ), which is thought to play a central role in the pathogenesis of Alzheimer's disease (AD), also has an important effect on the development and progression of AD. Through knocking-in APP gene in animals, numerous transgenic AD models have been set up for the investigation of the mechanisms behind AD pathogenesis and the screening of anti-AD drugs. However, there are some limitations to these models and here is a need for such an AD model that is economic as well as has satisfactory genetic homology with human. Methods: We generated a new AD transgenic model by knocking a mutant human APP gene (APPsw) in zebrafish with appb promoter of zebrafish to drive the expression of APPsw. Results: Fluorescent image and immunochemistry stain showed and RT-PCR and western blot assay confirmed that APPsw was successfully expressed in the brain, heart, eyes and vasculature of the transgenic zebrafish. Behavioral observation demonstrated that the transgenic zebrafish had AD-like symptoms. Histopathological observation found that there were cerebral β-amyloidosis and angiopathy (CAA), which induced neuron loss and enlarged pervascular space. Conclusion: These results suggest that APPsw transgenic zebrafish well simulate the pathological characters of AD and can be used as an economic AD transgenic model. Furthermore, the new model suggested that APP can express in microvasculatures and cause the Aβ generation and deposition in cerebral vessel which further destroys cerebral vascular structure resulting in the development and/or the progress of AD.

Background: Alzheimer´s disease (AD) is a serious and complex neurodegenerative disease. Currently, there are about 44 million people suffering from AD all over the world and this number is expected to rapidly grow due to demographic changes. The disease can be treated both pharmacologically and non-pharmacologically. Unfortunately, it cannot be cured yet. Nevertheless, the drugs for the treatment of AD are quite expensive, have different side effects and only delay symptoms of this disease. Therefore researchers suggest the use of various non-pharmacological therapies. Apart from relatively popular in western world such as physical activities, cognitive training or healthy diet, Chinese medicine starts to be practiced in Europe. Objective: The purpose of this mini-review is to discuss the concept of Chinese medicine and explore its most common and effective forms in the treatment of AD. Methods: This was done by conducting a literature search in the world´s acknowledged databases such as Web of Science, Scopus, PubMed and Springer. Results: Five randomized controlled clinical trial studies were analyzed and their findings were discussed. Conclusion: The authors of this mini-review list the key benefits (e.g., positive results of the reviewed randomized clinical trials studies for the improvement of cognitive decline in AD) and limitations (e.g., low awareness of benefits of TCM in Europe) of Chinese medicine therapy for the treatment of AD.

Many stroke patients have pre-existing cognitive impairment. Plasma amyloid β peptides (Aβ) - possible biomarkers of Alzheimer’s pathology - induce vascular dysfunction. Our objective was to evaluate factors influencing plasma Aβ 1-40 and Aβ 1-42 peptides in a cohort of stroke patients. In the Biostroke study (ClinicalTrials.gov Identifier: NCT00763217), we collected vascular risk factors, neuroimaging features and biological tests including Aβ 1-40 and Aβ 1-42. We used the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) to systematically assess the pre-existing cognitive status. Of 403 patients (371 ischemia), 25 met criteria for pre-existing dementia, 142 for pre-existing cognitive decline-no-dementia, and 236 had no PCoI. Aβ 1-42 was independently associated with PCoI (odds ratio 0.973; 95% confidence interval: 0.950-0.996; p=0.024). Factors associated with plasma Aβ 1- 40 were age, smoking and diabetes mellitus. After exclusion of hemorrhagic strokes, the results remained unchanged, but blood samples taken less than 12 hours after onset were associated with lower plasma Aβ 1-40. Our results support a dissociated response of the 2 plasma Aβ peptides in stroke patients, plasma Aβ 1-40 being involved in vascular aspects whereas Aβ 1-42 might be involved in neurodegenerative processes.