Current Alzheimer Research - Volume 16, Issue 7, 2019

Background: Various methodologies have been employed for the localization of amyloid plaques in numerous studies on Alzheimer’s disease. The majority of these stains are thought to label the plaques by virtue of their affinity for aggregated Aβ. However, plaques are known to contain numerous other components, including multivalent metals such as zinc. Objective: This investigates whether it is possible to localize the presence of zinc in parenchymal and vascular amyloid plaques in afflicted brains. To accomplish this, a novel fluorescent zinc chelator, HQO, was investigated to determine its mechanism of binding and to optimize a stain for the high contrast and resolution histological localization of amyloid plaques. Methods: A novel zinc chelator, HQ-O, was developed for localizing zinc within amyloid plaques. The histology involves incubating tissue sections in a dilute aqueous solution of HQ-O. Its compatibility with a variety of other fluorescent methodologies is described. Results: All amyloid plaques are stained in fine detail and appear bright green under blue light excitation. The staining of parenchymal plaques correlates closely with that seen following staining with antibodies to Aβ, however, the HQ-O sometimes also label additional globular structures within blood vessels. In situ mechanistic studies revealed that fluorescent plaque-like structures are only observed with HQ-O when synthetic Aβx-42 is aggregated in the presence of zinc. Conclusion: Zinc is intimately bound to all amyloid plaques, which was demonstrated by its histological localization using a novel fluorescent zinc chelator, HQ-O. Additionally, the tracer is also capable of labeling intravascular leucocytes due to their high zinc content.

Background: The incoming disease-modifying therapies against Alzheimer’s disease (AD) require reliable diagnostic markers to correctly enroll patients all over the world. CSF AD biomarkers, namely amyloid-β 42 (Aβ42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau181), showed good diagnostic accuracy in detecting AD pathology, but their real usefulness in daily clinical practice is still a matter of debate. Therefore, further validation in complex clinical settings, that is patients with different types of dementia, is needed to uphold their future worldwide adoption. Methods: We measured CSF AD biomarkers’ concentrations in a sample of 526 patients with a clinical diagnosis of dementia (277 with AD and 249 with Other Type of Dementia, OTD). Brain FDG-PET was also considered in a subsample of 54 patients with a mismatch between the clinical diagnosis and the CSF findings. Results: A p-tau181/Aβ42 ratio higher than 0.13 showed the best diagnostic performance in differentiating AD from OTD (86% accuracy index, 74% sensitivity, 81% specificity). In cases with a mismatch between clinical diagnosis and CSF findings, brain FDG-PET partially agreed with the p-tau181/Aβ42 ratio, thus determining an increase in CSF accuracy. Conclusion: The p-tau181/Aβ42 ratio alone might reliably detect AD pathology in heterogeneous samples of patients suffering from different types of dementia. It might constitute a simple, cost-effective and reproducible in vivo proxy of AD suitable to be adopted worldwide not only in daily clinical practice but also in future experimental trials, to avoid the enrolment of misdiagnosed AD patients.

Background: This study aimed to investigate the effect of long noncoding ribonucleic acids (RNAs) metastasis-associated lung adenocarcinoma transcript 1 (lnc-MALAT1) on regulating neuron apoptosis, neurite outgrowth and inflammation, and further explore its molecule mechanism in Alzheimer’s disease (AD). Methods: Control overexpression, lnc-MALAT1 overexpression, control shRNA, and lnc-MALAT1 shRNA were transfected into NGF-stimulated PC12 cellular AD model and cellular AD model from primary cerebral cortex neurons of rat embryo, which were established by Aβ1-42 insult. Rescue experiments were performed by transferring lnc-MALAT1 overexpression and lnc-MALAT1 overexpression & miR-125b overexpression plasmids. Neuron apoptosis, neurite outgrowth and inflammation were detected by Hoechst-PI/apoptosis marker expressions, and observations were made using microscope and RT-qPCR/Western blot assays. PTGS2, CDK5 and FOXQ1 expressions in rescue experiments were also determined. Results: In two AD models, lnc-MALAT1 overexpression inhibited neuron apoptosis, promoted neurite outgrowth, reduced IL-6 and TNF-α levels, and increased IL-10 level compared to control overexpression, while lnc-MALAT1 knockdown promoted neuron apoptosis, repressed neurite outgrowth, elevated IL-6 and TNF-α levels, but reduced IL-10 level compared to control shRNA. Additionally, lnc- MALAT1 reversely regulated miR-125b expression, while miR-125b did not influence the lnc- MALAT1 expression. Subsequently, rescue experiments revealed that miR-125b induced neuron apoptosis, inhibited neurite outgrowth and promoted inflammation, also increased PTGS2 and CDK5 expressions but decreased FOXQ1 expression in lnc-MALAT1 overexpression treated AD models. Conclusion: Lnc-MALAT1 might interact with miR-125b to inhibit neuron apoptosis and inflammation while promote neurite outgrowth in AD.

Background: CA1 subregion of the hippocampal formation is one of the primarily affected structures in AD, yet not much is known about proteome alterations in the extracellular milieu of this region. Objective: In this study, we aimed to identify the protein expression alterations throughout the pre-pathological, progression and pathological stages of AD mouse model. Methods: The CA1 region perfusates were collected by in-vivo intracerebral push-pull perfusion from transgenic 5XFAD mice and their non-transgenic littermates at 3, 6 and 12 wereβmonths of age. Morris water maze test and immunohistochemistry staining of A performed to determine the stages of the disease in this mouse model. The protein expression differences were analyzed by label-free shotgun proteomics analysis. Results: A total of 251, 213 and 238 proteins were identified in samples obtained from CA1 regions of mice at 3, 6 and 12 months of age, respectively. Of these, 68, 41 and 33 proteins showed statistical significance. Pathway analysis based on the unique and common proteins within the groups revealed that several pathways are dysregulated during different stages of AD. The alterations in glucose and lipid metabolisms respectively in pre-pathologic and progression stages of the disease, lead to imbalances in ROS production via diminished SOD level and impairment of neuronal integrity. Conclusion: We conclude that CA1 region-specific proteomic analysis of hippocampal degeneration may be useful in identifying the earliest as well as progressional changes that are associated with Alzheimer’s disease.

Background: Folate and vitamin B12 are well-known as essential nutrients that play key roles in the normal functions of the brain. Inflammatory processes play at least some role in the pathology of AD. Effective nutritional intervention approaches for improving cognitive deficits that reduce the peripheral inflammatory cytokine levels have garnered special attention. Objective: The present study aimed to determine whether supplementation with folic acid and vitamin B12, alone and in combination improves cognitive performance via reducing levels of peripheral inflammatory cytokines. Methods: 240 participants with MCI were randomly assigned in equal proportion to four treatment groups: folic acid alone, vitamin B12 alone, folic acid plus vitamin B12 or control without treatment daily for 6 months. Cognition was measured with WAIS-RC. The levels of inflammatory cytokines were measured using ELISA. Changes in cognitive function or blood biomarkers were analyzed by repeatedmeasure analysis of variance or mixed-effects models. This trial has been registered with trial number ChiCTR-ROC-16008305. Results: Compared with control group, the folic acid plus vitamin B12 group had significantly greater improvements in serum folate, homocysteine, vitamin B12 and IL-6, TNF-α, MCP-1. The folic acid plus vitamin B12 supplementation significantly changed the Full Scale IQ (effect size d = 0.169; P = 0.024), verbal IQ (effect size d = 0.146; P = 0.033), Information (d = 0.172; P = 0.019) and Digit Span (d = 0.187; P = 0.009) scores. Post hoc Turkey tests found that folic acid and vitamin B12 supplementation was significantly more effective than folic acid alone for all endpoints. Conclusions: The combination of oral folic acid plus vitamin B12 in MCI elderly for six months can significantly improve cognitive performance and reduce the levels of inflammatory cytokines in human peripheral blood. The combination of folic acid and vitamin B12 was significantly superior to either folic acid or vitamin B12 alone.

Background: Mild Parkinsonian Signs (MPS) have been associated with Mild Cognitive Impairment (MCI) types with conflicting results. Objective: To investigate the association of individual MPS with different MCI types using logistic ridge regression analysis, and to evaluate for each MCI type, the association of MPS with caudate atrophy, global cerebral atrophy, and the topographical location of White Matter Hyperintensities (WMH), and lacunes. Methods: A cross-sectional study was performed among 1,168 subjects with different types of MCI aged 45-97 (70,52 ± 9,41) years, who underwent brain MRI. WMH were assessed through two visual rating scales. The number and location of lacunes were also rated. Atrophy of the caudate nuclei and global cerebral atrophy were assessed through the bicaudate ratio, and the lateral ventricles to brain ratio, respectively. Apolipoprotein E (APOE) genotypes were also assessed. Using the items of the motor section of the Unified Parkinson’s Disease Rating Scale, tremor, rigidity, bradykinesia, and gait/balance/axial dysfunction were evaluated. Results: Bradykinesia, and gait/balance/axial dysfunction were the MPS more frequently encountered followed by rigidity, and tremor. MPS were present in both amnestic and non-amnestic MCI types, and were associated with WMH, lacunes, bicaudate ratio, and lateral ventricles to brain ratio. Conclusion: MPS are present in both amnestic and non-amnestic MCI types, particularly in those multiple domain, and carrying the APOE 4 allele. Cortical and subcortical vascular and atrophic processes contribute to MPS. Long prospective studies are needed to disentangle the contribution of MPS to the conversion from MCI to dementia.

Background: With the rapid aging process, an increasing number of individuals will be living with dementia worldwide. A good mastery of knowledge about Alzheimer's Disease (AD) by medical staff has been reported to improve the outcome of patients with AD, making it necessary to assess the level of AD knowledge among nursing staff and address their knowledge deficits in order to upgrade the quality of care and improve quality of life for AD patients. Objective: To assess the level of AD knowledge among nursing staff in Suzhou, using the Alzheimer's Disease Knowledge Scale (ADKS), and analyze its influencing factors. Methods: Nursing staff working in healthcare institutes such as hospitals, community centers, nursing homes, etc. in all the six districts of Suzhou City were selected by convenience sampling. A selfdesigned questionnaire was used to collect general information of the participants, including gender, age, education, professional title, workplace, AD-related training, contact with AD patients, experience in caring for AD patients, etc., and the ADKS scale was used to assess their level of AD knowledge. Results: A total of 1102 in-service nursing staff in Suzhou were included in the study. Univariate analysis showed that age, education, professional titles, bias towards AD patients, AD-related training, contact with AD patients, experience in caring for AD patients were the influencing factors of the total ADKS score; multivariate analysis indicated that age, bias towards AD patients, and contact with AD patients are independent influencing factors of the level of AD knowledge among nursing staff in Suzhou. Conclusion: Mastery of AD knowledge among the nursing staff in Suzhou is not satisfactory. It is urgent to change the nursing staff’s negative attitude towards AD and put into effect AD-related health education and training courses so that nursing staff can upgrade their level of AD knowledge and provide better care in order to improve the quality of life for AD patients.

Alzheimer’s disease is the world’s most common dementing illness. It is pathologically characterized by β-amyloid accumulation, extracellular senile plaques and intracellular neurofibrillary tangles formation, and neuronal necrosis and apoptosis. Neuroinflammation has been widely recognized as a crucial process that participates in AD pathogenesis. In this review, we briefly summarized the involvement of microglia in the neuroinflammatory process of Alzheimer’s disease. Its roles in the AD onset and progression are also discussed. Numerous molecules, including interleukins, tumor necrosis factor alpha, chemokines, inflammasomes, participate in the complex process of AD-related neuroinflammation and they are selectively discussed in this review. In the end of this paper from an inflammation- related perspective, we discussed some potential therapeutic choices.