Mechanisms Of Alzheimer's Disease Research Articles

Modeling resting state MEG functional connectivity of the prodromal phase of AD using The Virtual Brain

AbstractBackgroundComputational multi‐scale brain modeling has been found to be a useful tool for identifying potential disease mechanisms in Alzheimer's disease (AD) [1]. Importantly, structural and functional disruption patterns of AD continuum arise from a chain of degeneration effects which take place even from the preclinical phase of the disease, which characterization has the potential to enable early intervention to counteract and delay cognitive decline.MethodMagnetoencephalography (MEG), T1‐ and dw‐ magnetic resonance imaging (MRI) have been gathered from 20 healthy controls (HC) and 20 mild cognitive impaired (MCI), to characterize their resting‐state functional connectivity (rsFC), and structural connectivity (SC) profiles. Regarding MEG signal, source reconstruction was performed with linearly constrained minimum variance beamformer and the obtained neural MEG sources were anatomically parcellated according to the Desikan‐Killiany atlas. Resting state activity of the participants has been characterized considering two FC indices (i.e., PLV and AEC) among relevant areas of the Default Mode Network (DMN). Personalized simulations of the 40 subjects have been carried out using The Virtual Brain software and the matching between real and simulated rsFC is finally evaluated. For the MCIs two different degradation patterns are introduced in the model, one based on the gray matter volumes, and one that takes in account white matter integrity.ResultThe inclusion of both types of degeneration patterns in key areas of the DMN results in an increase of the matching between real and simulated rsFC for MCI patients; the inclusion of both simultaneously brought the best results.ConclusionThis study shows how the inclusion of quantifiable signatures of structural degeneration regarding gray matter volumes and white matter integrity in multi‐scale brain models reflects to a better matching between real and simulated MEG‐rsFC, when modeling MCI patients. This complements the already existing studies in the field and provides new insights towards a precise characterization of patient's MEG resting state networks during the early phases of AD. 1 ‐ L. Stefanovski et al., “Linking Molecular Pathways and Large‐Scale Computational Modeling to Assess Candidate Disease Mechanisms and Pharmacodynamics in Alzheimer’s Disease,” Front Comput Neurosci, vol. 13, p. 54, 2019.

Altered local gyrification index and corresponding functional connectivity in Alzheimer disease

AbstractBackgroundCortical gyrification is a promising surface anatomical marker to study Alzheimer disease, however, few studies combined the gyrification and functional connectivity together to explore the Potential mechanism in Alzheimer disease.MethodThe study consisted of three groups, healthy control(n=37), Mild cognitive impairment(n=39), and Alzheimer disease(n=30). Comparison between groups of gyrification was performed using ANOVA within CAT12 and SPM 12, age and cortical thickness were returned as covariates. After the LGI analyses, the surface areas with changed LGI were taken as seed regions for functional connectivity (FC) analyses. Comparison between groups of FCs was performed using ANOVA within dpabi 4.3 and RESTplus; age was returned as a covariate. False discovery rate (FDR)‐corrected and P < 0.05 was considered statistically significant.ResultCompared with NC and MCI group, we found significantly decreased LGI(local gyrification index) in left insula and right insula, and the changed LGI in bilateral insula was negatively correlated with disease onset age and positively correlated with global cognitive scores. The following functional connectivity analyses identified decreased functional connectivity between right insula and middle temporal gyrus. The decreased functional connectivities were correlated with disease duration, and global cognitive scores.ConclusionOur findings revealed abnormal LGI in bilateral insula and the connectivity between right insula and middle temporal gyrus maybe used as imaging metrics of Alzheimer disease.

Higher levels of the astrocytic marker CSF YKL40 are associated with better memory performance only in amyloid‐positive individuals with subjective cognitive decline

AbstractBackgroundIt is not clear whether neuroinflammation is a detrimental or a compensatory mechanism in Alzheimer’s disease (AD). Recent evidence suggests that increased levels of YKL40 are related to better memory performance in cognitively unimpaired older individuals with memory complaints. In this study, we aimed i) at replicating these previous findings and ii) extending to other markers by exploring the relationship between cognitive performance and cerebrospinal fluid (CSF) biomarkers of astrocytic (YKL40, GFAP and S100) and microglial (sTREM2) neuroinflammation‐related activation, and to explore whether this association is further modulated by amyloid status and presence of subjective cognitive decline (SCD) in a middle‐aged cohort of cognitively unimpaired individuals.MethodWe included data from 392 individuals from the ALFA+ cohort (mean age 61 years). CSF measures of amyloid pathology (Aβ42/40) pathology and YKL‐40, GFAP, S100 and sTREM2, were analyzed with the exploratory Roche NeuroToolKit assays, a panel of automated robust prototype immunoassays. Individuals were classified as amyloid positive (A+) or negative (A‐) using the Aβ42/40=0.071 cut‐off and as SCD or non‐SCD using the SCD‐Questionnaire. Memory and Executive cognitive composites were used as dependent variables in linear models using CSF biomarkers with covariates (age, sex, education) as predictors. Interaction terms with biomarker*Amyloid status*SCD status were also modeled.ResultOne hundred and thirty‐five individuals (34.4%) were A+ and 107 (27.3%) displayed SCD (Table 1). For Memory composite we found significant interactions for YKL40*Amyloid*SCD (p=0.04) and sTREM2* Amyloid *SCD (p=0.03). In stratified analyses by Aβ and SCD we observed that Memory performance was positively associated with YKL40 in Aβ+ that also display SCD (n=39, p=0.019, Figure 1). No significant associations were found in stratified analysis with sTREM2 (neither by Amyloid nor by SCD status). For GFAP and S100, no associations were observed nor for any analysis with the Executive composite.ConclusionAstrocytic (YKL40), but not microglial (sTREM2), activation was associated with better memory performance in those cognitively unimpaired individuals with evidence of Alzheimer’s pathophysiological changes and subjective cognitive decline. Thus, some specific neuroinflammation may be beneficial at the end of the AD preclinical stage, in which subjective SCD arise.

Protective Effects of Onjisaponin B in a Mouse Model of Alzheimer’s Disease via Enhancement of Hippocampal Neuroplasticity

Alzheimer’s disease mainly affects elderly population leading to impairment in cogitation. A lack of clear understanding of the mechanism of Alzheimer’s disease has led to a lack of definite therapeutic option. Herein we have explored the effect of Onjisaponin B derived from the traditional Chinese herbal medicinal plant Radix Polygalae in an animal model of Alzheimer’s disease. Onjisaponin B significantly reduced the severity of experimental Alzheimer’s disease in mice measured by learning abilities, spatial learning, memory, and recognition of novel objects via modulation of hippocampal neuroplasticity. Neuroplasticity was further confirmed by silver staining and expression of major proteins in the hippocampal synapse. Furthermore, Onjisaponin B remarkably altered the morphology of neuron dendrites in the CA1 region by increasing the numbers of apical and basal dendrites of neurons, and the length of neurons. In conclusion, Onjisaponin B might modulate neuroplasticity to attenuate Alzheimer’s disease.

Expression of Immune Related Genes and Possible Regulatory Mechanisms in Alzheimer’s Disease

Immune infiltration of peripheral natural killer (NK) cells in the brain has been observed in Alzheimer’s disease (AD). Immunity-related genes (IRGs) play an essential role in immune infiltration; however, the expression of IRGs and possible regulatory mechanisms involved in AD remain unclear. The peripheral blood mononuclear cells (PBMCs) single-cell RNA (scRNA) sequencing data from patients with AD were analyzed and PBMCs obtained from the ImmPort database were screened for cluster marker genes. IRG activity was calculated using the AUCell package. A bulk sequencing dataset of AD brain tissues was analyzed to explore common IRGs between PBMCs and the brain. Relevant regulatory transcription factors (TFs) were identified from the Human TFDB database. The protein-protein interaction network of key TFs were generated using the STRING database. Eight clusters were identified, including memory CD4 T, NKT, NK, B, DC, CD8 T cells, and platelets. NK cells were significantly decreased in patients with AD, while CD4 T cells were increased. NK and DC cells exhibited the highest IRG activity. GO and KEGG analyses of the scRNA and bulk sequencing data showed that the DEGs focused on the immune response. Seventy common IRGs were found in both peripheral NK cells and the brain. Seventeen TFs were associated with IRG expression, and the PPI network indicated that STAT3, IRF1, and REL were the hub TFs. In conclusion, we propose that peripheral NK cells may infiltrate the brain and contribute to neuroinflammatory changes in AD through bioinformatic analysis of scRNA and bulk sequencing data. Moreover, STAT3 may be involved in the transcriptional regulation of IRGs in NK cells.

Biomarkers of neuroinflammation: Focus on monocyte chemotaxis

According to the amyloid cascade hypothesis, beta-amyloid (Abeta) aggregation represents the core pathogenic mechanism in Alzheimer's disease (AD). Neuroinflammation, as an inflammatory process confined to the CNS, plays a key role as well, fueling a response against Abeta, and eventually further damaging the surrounding neurons. Research currently points out at microglia cells as the central players of this game. However, an important role for periphery should be advocated, since peripheral blood monocytes cross the blood-brain barrier (BBB) attracted by Abeta and chemokines, and contribute to neuroinflammation by transforming into blood-born macrophages. Interestingly, this process of “neuroinvasion” from periphery represents the afferent arc of the inflammatory reflex, regulating a response against protein aggregates. The efferent arc is represented by a vagal cholinergic pathway projecting onto alpha7nAChR expressed by spleen mononuclear cells for shutting off the inflammasome and so modulating the process. In this talk we will focus on the role of peripheral monocytes, and in particular on the process of chemotaxis and neuroinvasion. Attention will be also given to the expression of the monocyte chemotactic systems, and among them, in particular, to the TSPO receptor (marker of activated microglia) and of the cognate biological ligand, the Diazepam Binding Inhibitor (DBI).

Uptake of A\u03b2 by OATPs might be a new pathophysiological mechanism of Alzheimer disease

BackgroundThe accumulation of neurotoxic amyloid-beta (Aβ) in the brain is a characteristic of Alzheimer's disease (AD), at the same time, it is possible alterations of liver function could affect brain Aβ levels through changes in blood Aβ concentration. Over the last decade, a number of reports have shown that P-glycoprotein (encoded by ABC1B1) actively mediates the efflux transport of Aβ peptides. However, the mechanism by which Aβ peptides enter the cells is not clear. In the preliminary study, we found that the protein expression of organic anion transporting Polypeptide 1a4 (OATP1B1) in the liver tissue of mice with AD was significantly higher than that in the normal mice. In contrast, the protein expression of Oatp1a4 in the brain significantly decreased in mice with AD. OATP1B1, an important drug transporter might be related to the pathophysiology of AD.ResultsIn this study, we established an OATP1B1-GFP-HEK293T cell model to confirm the OATP1B1 mediated transport of Aβ1-42. Compared to the control group of GFP-HEK293Tcells, the uptake of Aβ1-42 protein in the OATP1B1-GFP-HEK293T group increased significantly with the increase in concentration of Aβ1-42, and also increased significantly with an increase in the duration of incubation. Similar results were observed in the flow cytometry experiment, and the uptake of Aβ1-42in HEK293T-OATP1B1 cells was almost twice that in the control group. These results indicate that OATPs may act as an important “carrier” for the transport of Aβ1-42 from the blood to the tissues, including liver and brain.ConclusionsThis is a novel and interesting finding and OATP1B1 can be investigated as a new treatment target for AD.

Distinct types of amyloid-β oligomers displaying diverse neurotoxicity mechanisms in Alzheimer's disease.

Soluble oligomers of amyloid-β (Aβ) are recognized as key pernicious species in Alzheimer's disease (AD) that cause synaptic dysfunction and memory impairments. Numerous studies have identified various types of Aβ oligomers having heterogeneous peptide length, size distribution, structure, appearance, and toxicity. Here, we review the characteristics of soluble Aβ oligomers based on their morphology, size, and structural reactivity toward the conformation-specific antibodies and then describe their formation, localization, and cellular effects in AD brains, in vivo and in vitro. We also summarize the mechanistic pathways by which these soluble Aβ oligomers cause proteasomal impairment, calcium dyshomeostasis, inhibition of long-term potentiation, apoptosis, mitochondrial damage, and cognitive decline. These cellular events include three distinct molecular mechanisms: (i) high-affinity binding with the receptors for Aβ oligomers such as N-methyl- d-aspartate receptors, cellular prion protein, nerve growth factor, insulin receptors, and frizzled receptors; (ii) the interaction of Aβ oligomers with the lipid membranes; (iii) intraneuronal accumulation of Aβ by α7-nicotinic acetylcholine receptors, apolipoprotein E, and receptor for advanced glycation end products. These studies indicate that there is a pressing need to carefully examine the role of size, appearance, and the conformation of oligomers in identifying the specific mechanism of neurotoxicity that may uncoverpotential targets for designing AD therapeutics.

Dexmedetomidine Alleviates Lipopolysaccharide-Induced Hippocampal Neuronal Apoptosis via Inhibiting the p38 MAPK/c-Myc/CLIC4 Signaling Pathway in Rats.

Dexmedetomidine (DEX) has multiple biological effects. Here, we investigated the neuroprotective role and molecular mechanism of DEX against lipopolysaccharide (LPS)-induced hippocampal neuronal apoptosis. Sprague Dawley rats were intraperitoneally injected with LPS (10mg/kg) and/or DEX (30µg/kg). We found that DEX improved LPS-induced alterations of hippocampal microstructure (necrosis and neuronal loss in the CA1 and CA3 regions) and ultrastructure (mitochondrial damage). DEX also attenuated LPS-induced inflammation and hippocampal apoptosis by inhibiting the increase of interleukin-1β, interleukin-6, interleukin-18, and tumor necrosis factor-α levels and downregulating the expression of mitochondrial apoptosis pathway-related proteins. Moreover, DEX prevented the LPS-induced activation of the c-Myc/chloride intracellular channel 4 (CLIC4) pathway. DEX inhibited the p38 MAPK pathway, but not JNK and ERK. To further clarify whether DEX alleviated LPS-induced neuronal apoptosis through the p38 MAPK/c-Myc/CLIC4 pathway, we treated PC12 cells with p38 MAPK inhibitor SB203582 (10µM). DEX had the same effect as SB203582 in reducing the protein and mRNA expression of c-Myc and CLIC4. Furthermore, DEX and SB203582 diminished LPS-induced apoptosis, indicated by decreased Bax and Tom20 fluorescent double-stained cells, reduced annexin V-FITC/PI apoptosis rate, and reduced protein expression levels of Bax, cytochrome C, cleaved caspase-9, and cleaved caspase-3. Taken together, the findings indicate that DEX attenuates LPS-induced hippocampal neuronal apoptosis by regulating the p38 MAPK/c-Myc/CLIC4 signaling pathway. These findings provide new insights into the mechanism of Alzheimer's disease and depression and may help aid in drug development for these diseases.

Immunological and hormonal mechanisms in Alzheimer's disease.

Alzheimer’s disease (AD) is a disorder which is today treated and approached at the crossroad of two medical specialties – psychiatry and neurology. The insidious onset which can often mimic depressive disorders or other type of psychiatric disorders, the behavioral changes, the paranoid thoughts usually send people to the psychiatrist, while the brain changes observed on magnetic resonance imaging (MRI) scans and other imaging techniques may indicate the need for neurological monitoring also. The complex symptomatology and progression of this dementia requires a multidisciplinary approach and recent studies focused on adding a third perspective: a metabolic one. The common findings regarding type 2 diabetes and AD made some researchers to informally name it “the third type diabetes”. This mini review aims to highlight the mechanisms through which brain insulin resistance can lead to cognitive impairment and to make a short overview of the current findings which demonstrate why insulin may be a promising adjunctive treatment of Alzheimer’s dementia, for certain patients.

Genotype Load Modulates Amyloid Burden and Anxiety-Like Patterns in Male 3xTg-AD Survivors despite Similar Neuro-Immunoendocrine, Synaptic and Cognitive Impairments.

The wide heterogeneity and complexity of Alzheimer’s disease (AD) patients’ clinical profiles and increased mortality highlight the relevance of personalized-based interventions and the need for end-of-life/survival predictors. At the translational level, studying genetic and age interactions in a context of different levels of expression of AD-genetic-load can help to understand this heterogeneity better. In the present report, a singular cohort of long-lived (19-month-old survivors) heterozygous and homozygous male 3xTg-AD mice were studied to determine whether their AD-genotype load can modulate the brain and peripheral pathological burden, behavioral phenotypes, and neuro-immunoendocrine status, compared to age-matched non-transgenic controls. The results indicated increased amyloid precursor protein (APP) levels in a genetic-load-dependent manner but convergent synaptophysin and choline acetyltransferase brain levels. Cognitive impairment and HPA-axis hyperactivation were salient traits in both 3xTg-AD survivor groups. In contrast, genetic load elicited different anxiety-like profiles, with hypoactive homozygous, while heterozygous resembled controls in some traits and risk assessment. Complex neuro-immunoendocrine crosstalk was also observed. Bodyweight loss and splenic, renal, and hepatic histopathological injury scores provided evidence of the systemic features of AD, despite similar peripheral organs’ oxidative stress. The present study provides an interesting translational scenario to study further genetic-load and age-dependent vulnerability/compensatory mechanisms in Alzheimer’s disease.

Plasma lipidome is dysregulated in Alzheimer\u2019s disease and is associated with disease risk genes

Lipidomics research could provide insights of pathobiological mechanisms in Alzheimer’s disease. This study explores a battery of plasma lipids that can differentiate Alzheimer’s disease (AD) patients from healthy controls and determines whether lipid profiles correlate with genetic risk for AD. AD plasma samples were collected from the Sydney Memory and Ageing Study (MAS) Sydney, Australia (aged range 75–97 years; 51.2% male). Untargeted lipidomics analysis was performed by liquid chromatography coupled–mass spectrometry (LC–MS/MS). We found that several lipid species from nine lipid classes, particularly sphingomyelins (SMs), cholesterol esters (ChEs), phosphatidylcholines (PCs), phosphatidylethanolamines (PIs), phosphatidylinositols (PIs), and triglycerides (TGs) are dysregulated in AD patients and may help discriminate them from healthy controls. However, when the lipid species were grouped together into lipid subgroups, only the DG group was significantly higher in AD. ChEs, SMs, and TGs resulted in good classification accuracy using the Glmnet algorithm (elastic net penalization for the generalized linear model [glm]) with more than 80% AUC. In general, group lipids and the lipid subclasses LPC and PE had less classification accuracy compared to the other subclasses. We also found significant increases in SMs, PIs, and the LPE/PE ratio in human U251 astroglioma cell lines exposed to pathophysiological concentrations of oligomeric Aβ42. This suggests that oligomeric Aβ42 plays a contributory, if not causal role, in mediating changes in lipid profiles in AD that can be detected in the periphery. In addition, we evaluated the association of plasma lipid profiles with AD-related single nucleotide polymorphisms (SNPs) and polygenic risk scores (PRS) of AD. We found that FERMT2 and MS4A6A showed a significantly differential association with lipids in all lipid classes across disease and control groups. ABCA7 had a differential association with more than half of the DG lipids (52.63%) and PI lipids (57.14%), respectively. Additionally, 43.4% of lipids in the SM class were differentially associated with CLU. More than 30% of lipids in ChE, PE, and TG classes had differential associations with separate genes (ChE-PICALM, SLC24A4, and SORL1; PE-CLU and CR1; TG-BINI) between AD and control group. These data may provide renewed insights into the pathobiology of AD and the feasibility of identifying individuals with greater AD risk.

New insights into mechanisms of Alzheimer's disease revealed by a dynamic functional magnetic resonance imaging study.

New insights into mechanisms of Alzheimer's disease revealed by a dynamic functional magnetic resonance imaging study.

β-Asarone Ameliorates β-Amyloid-Induced Neurotoxicity in PC12 Cells by Activating P13K/Akt/Nrf2 Signaling Pathway.

Accumulation of β-amyloid (Aβ) causes oxidative stress, which is the major pathological mechanism in Alzheimer’s disease (AD). β-asarone could reduce Aβ-induced oxidative stress and neuronal damage, but the molecular mechanism remains elusive. In this study, we used an Aβ-stimulated PC12 cell model to explore the neuroprotective effects and potential mechanisms of β-asarone. The results showed that β-asarone could improve cell viability and weaken cell damage and apoptosis. β-asarone could also decrease the level of ROS and MDA; increase the level of SOD, CAT, and GSH-PX; and ameliorate the mitochondrial membrane potential. Furthermore, β-asarone could promote the expression of Nrf2 and HO-1 by upregulating the level of PI3K/Akt phosphorylation. In conclusion, β-asarone could exert neuroprotective effects by modulating the P13K/Akt/Nrf2 signaling pathway. β-asarone might be a promising therapy for AD.

Age and gender differences for the behavioral phenotypes of 3xTg alzheimer's disease mice

The triple transgenic Alzheimer’s disease (3xTg-AD) strain is a common mouse model used for studying the pathology and mechanism of Alzheimer’s disease (AD). The 3xTg-AD strain exhibits two hallmarks of AD, amyloid beta (Aβ) and neurofibrillary tangles. Several studies using different gender and age of 3xTg-AD mice to investigate their behavior phenotypes under the influence of various treatments have reported mixed results. Therefore, a comprehensive investigation on the optimal gender, age, and training paradigms used for behavioral studies of 3xTg-AD is necessary. In the present study, we investigated the behavioral phenotypes for the two genders of 3xTg-AD mice at 3, 6, 9, and 12 months old and compared the results with age-, gender-matched C57BL/6N control strain. All mice were subjected to tail flick, pinprick, open field, elevated plus maze, passive avoidance, and trace fear conditioning (TFC) tests to evaluate their sensory, locomotor, anxiety, and learning/memory functions. The results showed that TFC on male 3xTg-AD mice is optimal for studying the memory performance in AD. The sensory and locomotor functions of 3xTg-AD mice for two genders appear to be normal before 6 months, decline in fear memory afterwards. The differences between control and 3xTg-AD male mice in contextual and cued memory are robust, thus they are ideal for evaluating the effect of a treatment. Since it is costly and time consuming to obtain wildtype littermates as controls, C57BL/6N strain is suggested to be used as control mice because their baseline performance of sensorimotor functions are similar to that of 3xTg-AD mice.

Probable Causes of Alzheimer’s Disease

A three-part mechanism is proposed for the induction of Alzheimer’s disease: (1) decreased blood lactic acid; (2) increased blood ceramide and adipokines; (3) decreased blood folic acid. The age-related nature of these mechanisms comes from age-associated decreased muscle mass, increased visceral fat and changes in diet. This mechanism also explains why many people do not develop Alzheimer’s disease. Simple changes in lifestyle and diet can prevent Alzheimer’s disease. Alzheimer’s disease is caused by a cascade of events that culminates in damage to the blood–brain barrier and damage to neurons. The blood–brain barrier keeps toxic molecules out of the brain and retains essential molecules in the brain. Lactic acid is a nutrient to the brain and is produced by exercise. Damage to endothelial cells and pericytes by inadequate lactic acid leads to blood–brain barrier damage and brain damage. Inadequate folate intake and oxidative stress induced by activation of transient receptor potential cation channels and endothelial nitric oxide synthase damage the blood–brain barrier. NAD depletion due to inadequate intake of nicotinamide and alterations in the kynurenine pathway damages neurons. Changes in microRNA levels may be the terminal events that cause neuronal death leading to Alzheimer’s disease. A new mechanism of Alzheimer’s disease induction is presented involving lactic acid, ceramide, IL-1β, tumor necrosis factor α, folate, nicotinamide, kynurenine metabolites and microRNA.

Molecular mechanisms in Alzheimer's disease and the impact of physical exercise with advancements in therapeutic approaches.

Alzheimer's disease (AD) is one of the most common, severe neurodegenerative brain disorder characterized by the accumulation of amyloid-beta plaques, neurofibrillary tangles in the brain causing neural disintegration, synaptic dysfunction, and neuronal death leading to dementia. Although many US-FDA-approved drugs like Donepezil, Rivastigmine, Galantamine are available in the market, their consumption reduces only the symptoms of the disease but fails in potency to cure the disease. This disease affects many individuals with aging. Combating the disease tends to be very expensive. This review focuses on biochemical mechanisms in the neuron both at normal and AD state with relevance to the tau hypothesis, amyloid hypothesis, the risk factors influencing dementia, oxidative stress, and neuroinflammation altogether integrated with neurodegeneration. A brief survey is carried out on available biomarkers in the diagnosis of the disease, drugs used for the treatment, and the challenges in approaching therapeutic targets in inhibiting the disease pathologies. This review conjointly assesses the demerits with the inefficiency of drugs to reach targets, their side effects, and toxicity. Optimistically, this review directs on the advantageous strategies in using nanotechnology-based drug delivery systems to cross the blood-brain barrier for improving the efficacy of drugs combined with a novel neuronal stem cell therapy approach. Determinately, this review aims at the natural, non-therapeutic healing impact of physical exercise on different model organisms and the effect of safe neuromodulation treatments using repetitive Transcranial Magnetic Stimulation (rTMS), transcranial Electrical Stimulation (tES) in humans to control the disease pathologies prominent in enhancing the synaptic function.

Longitudinal changes in the control mechanisms for blood pressure and cerebral blood flow in Alzheimer's disease: Secondary results of a randomized controlled trial.

Dynamic cerebral autoregulation (dCA) and baroreflex sensitivity (BRS) are key mechanisms involved in the homeostasis of blood pressure (BP) and cerebral blood flow. We assessed changes in these mechanisms in Alzheimer's disease (AD) during a 1.5 year follow-up. In this secondary analysis of a randomized controlled trial we measured beat-to-beat BP, heart rate, and cerebral blood flow velocity at baseline, 0.5 and 1.5 years, during: rest (spontaneous oscillations), repeated sit-stand maneuvers (induced oscillations), an orthostatic challenge, and hypo- and hypercapnia. dCA was estimated using transfer function analysis and the autoregulatory index on spontaneous and induced oscillations. BRS was estimated by calculating the heart rate response to BP changes during induced oscillations. Linear mixed models were used to assess changes over time. 56 patients were included (mean age:73±6 years, 57% female). BRS did not change over time. dCA parameters showed small changes after 0.5 years, suggestive of a reduction in efficiency (e.g. higher gain [linear mixed effect model: B=0.09, SE=0.03, P= 0.008] and lower phase [B=-9.7, SE= 3.2, P= 0.004] in the very low frequency domain, and lower autoregulatory index during induced oscillations [B=-0.69, SE=0.26, P= 0.010]). These changes did not show further progression after 1.5 years of follow-up. In this sample of patients with dementia due to AD we found no evidence that dCA or BRS become impaired during AD progression. This paves the way for further studies that investigate the safety and benefits of antihypertensive treatment in patients with AD.

An Insight in Pathophysiological Mechanism of Alzheimer's Disease and its Management Using Plant Natural Products

An Insight in Pathophysiological Mechanism of Alzheimer's Disease and its Management Using Plant Natural Products

Effect of Combined Electroacupuncture and Selegiline Treatment in Alzheimer's Disease: An Animal Model.

The complexity of pathological mechanisms in Alzheimer’s disease (AD) poses significant challenges to the development of corresponding drugs. Symptom-specific pharmacological interventions and alternative treatments provide promising treatment possibilities. Therefore, we considered a combination of selegiline (SEL) and electroacupuncture (EA). We used an animal model with AD to investigate the effect of a combination of these treatments on cognitive function. 5XFAD mice received a week of SEL treatment and 2 weeks of EA. Novel object recognition and Y-maze tests were subsequently performed to assess their cognitive functions. To determine the molecular action of the combination treatment, Western blots, Aβ1-42 enzyme-linked immunosorbent assays (ELISA), and micro-positron-emission tomography were also performed to assess pathological markers and processes. The results were assessed based on the difference between untreated transgenic, SEL-treated, and SEL- and EA-treated groups of mice. Mice in the combined treatment group demonstrated significantly better cognitive functions, and lesser neuroinflammation than the comparative groups. In addition, mice treated with a combination of SEL and EA did not demonstrate a direct modulation of insoluble Aβ but demonstrated greater glucose metabolism. Our findings demonstrated that SEL combined with EA treatment was associated with better cognitive functioning due to inhibition of neuroinflammation and increased glucose metabolism relative to the comparative groups in a mouse model with AD.