Alzheimer's Disease Process Research Articles

GPR40 Agonist Ameliorate Pathological Neuroinflammation of Alzheimer's Disease via the Modulation of Gut Microbiota and Immune System, a Mini-Review.

Alzheimer's disease (AD) is a central disease with high incidence, and its pathological process is closely associated with changes of some biological indicators in the periphery. Among them, the intestinal flora mainly causes a series of pathological changes such as inflammation through the immune system, which may contribute to the pathological process of AD. In this paper, we mainly focused the relationship between gut microbiota and immune system disorder in the neuropathology of AD, underlining the significance of the advanced mechanism of inflammatory response and providing a new direction for the treatment of AD.

Relation between Alpha-Synuclein and Core CSF Biomarkers of Alzheimer's Disease.

Background: Alzheimer’s disease (AD) is characterized by the presence of β-amyloid plaques and neurofibrillary tangles, while Lewy body dementia (LBD) is characterized by α-synuclein (α-syn) inclusions. Some authors examine α-syn protein in the neurodegeneration process of AD and propose to consider cerebrospinal fluid (CSF) α-syn as a possible additional biomarker to the so-called “core” of AD. Objective: To determine whether there is a correlation between α-syn levels and “core” AD biomarkers in patients with mild cognitive impairment (MCI). Materials and methods: In total, 81 patients in the early stages of MCI were selected from the outpatient dementia consultation in Alicante General Hospital. Using a cross-sectional case–control design, patients were analyzed in four groups: stable MCI (MCIs; n = 25), MCI due to AD (MCI-AD; n = 32), MCI due to LBD (MCI-LBD; n = 24) and a control group of patients with acute or chronic headache (Ctrl; n = 18). Correlation between CSF protein levels in the different groups was assessed by the Rho Spearman test. Results: We found positive correlations between T-tau protein and α-syn (ρ = 0.418; p value < 0.05) and p-tau181p and α-syn (ρ = 0.571; p value < 0.05) exclusively in the MCI-AD group. Conclusion: The correlation found between α-syn and tau proteins in the first stages of AD support the involvement of α-syn in the pathogenesis of AD. This result may have clinical and diagnostic implications, as well as help to apply the new concept of “precision medicine” in patients with MCI.

Peony seed oil ameliorates neuroinflammation-mediated cognitive deficits by suppressing microglial activation through inhibition of NF-κB pathway in presenilin 1/2 conditional double knockout mice.

Chronic neuroinflammation has been shown to exert adverse influences on the pathology of Alzheimer's disease (AD), associated with the release of abundant proinflammatory mediators by excessively activated microglia, causing synaptic dysfunction, neuronal degeneration, and memory deficits. Thus, the prevention of microglial activation-associated neuroinflammation is important target for deterring neurodegenerative disorders. Peony seed oil (PSO) is a new food resource, rich in α-linolenic acid, the precursor of long chain omega-3 polyunsaturated fatty acids, including docosahexaenoic acid and eicosapentaenoic acid, which exhibit anti-inflammatory properties by altering cell membrane phospholipid fatty acid compositions, disrupting lipid rafts, and inhibiting the activation of the proinflammatory transcription factor NF-κB. However, few studies have examined the anti-neuroinflammatory effects of PSO in AD, and the relevant molecular mechanisms remain unclear. Presenilin1/2 conditional double knockout (PS cDKO) mice display obvious AD-like phenotypes, such as neuroinflammatory responses, synaptic dysfunction, and cognitive deficits. Here, we assessed the potential neuroprotective effects of PSO against neuroinflammation-mediated cognitive deficits in PS cDKO using behavioral tests and molecular biologic analyses. Our study demonstrated that PSO suppressed microglial activation and neuroinflammation through the down-regulation of proinflammatory mediators, such as inducible NOS, COX-2, IL-1β, and TNF-α, in the prefrontal cortex and hippocampus of PS cDKO mice. Further, PSO significantly lessened memory impairment by reversing hyperphosphorylated tau and synaptic proteins deficits in PS cDKO mice. Importantly, PSO's therapeutic effects on cognitive deficits were due to inhibiting neuroinflammatory responses mediated by NF-κB signaling pathway. Taken together, PSO may represent an effective dietary supplementation to restrain the neurodegenerative processes of AD.

Electrophysiological Markers of the Sense of Agency: Contributions of Temporal Proximity, Temporal Order and Action-Effect Congruency

Alzheimer's Disease (AD) is the first cause of dementia and represents a serious medical problem that severely affects social, sanitary, and economic aspects of life and its populations. Late-onset AD (age at onset >65 years) is the most frequent form. This is a complex disorder most likely caused by multiple genetic and environmental susceptibility factors. The pathophysiological process of AD is thought to begin many years before the appearance of dementia symptoms. This preclinical phase of AD would provide a critical opportunity for therapeutic intervention. In this chapter, we explore the relationship between AD neuropathology and neuronal bioenergetics in transgenic animal models of AD. We compare bioenergetic parameters obtained from isolated mitochondria and synaptosomes, addressing advantages and disadvantages of each biological preparation. Furthermore, we speculate that targeting synaptosomal bioenergetic defects could slow or prevent the neurodegenerative process and restore neuronal function.

Associations among vascular risk factors, neuroimaging biomarkers, and cognition: Preliminary analyses from the Multi-Ethnic Study of Atherosclerosis (MESA).

Little is known about how antecedent vascular risk factor (VRF) profiles impact late-life brain health. We examined baseline VRFs, and cognitive testing and neuroimaging measures (β-amyloid [Aβ] PET, MRI) in a diverse longitudinal cohort (N=159; 50% African-American, 50% White) from Wake Forest's Multi-Ethnic Study of Atherosclerosis Core. African-Americans exhibited greater baseline Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham stroke risk profile (FSRP), and atherosclerotic cardiovascular disease risk estimate (ASCVD) scores than Whites. We observed no significant racial differences in Aβ positivity, cortical thickness, or white matter hyperintensity (WMH) volume. Higher baseline VRF scores were associated with lower cortical thickness and greater WMH volume, and FSRP and CAIDE were associated with Aβ. Aβ was cross-sectionally associated with cognition, and all imaging biomarkers were associated with greater 6-year cognitive decline. Results suggest the convergence of multiple vascular and Alzheimer's processes underlying neurodegeneration and cognitive decline.

Involvement of cerebrovascular abnormalities in the pathogenesis and progression of Alzheimer's disease: an adrenergic approach.

Alzheimer’s disease (AD), as the most common neurodegenerative disease in elder population, is pathologically characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles composed of highly-phosphorylated tau protein and consequently progressive neurodegeneration. However, both Aβ and tau fails to cover the whole pathological process of AD, and most of the Aβ- or tau-based therapeutic strategies are all failed. Increasing lines of evidence from both clinical and preclinical studies have indicated that age-related cerebrovascular dysfunctions, including the changes in cerebrovascular microstructure, blood-brain barrier integrity, cerebrovascular reactivity and cerebral blood flow, accompany or even precede the development of AD-like pathologies. These findings may raise the possibility that cerebrovascular changes are likely pathogenic contributors to the onset and progression of AD. In this review, we provide an appraisal of the cerebrovascular alterations in AD and the relationship to cognitive impairment and AD pathologies. Moreover, the adrenergic mechanisms leading to cerebrovascular and AD pathologies were further discussed. The contributions of early cerebrovascular factors, especially through adrenergic mechanisms, should be considered and treasured in the diagnostic, preventative, and therapeutic approaches to address AD.

A network pharmacological approach to investigate the pharmacological effects of CZ2HF decoction on Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementia, which brings tremendous burden to the sufferers and society. However, ideal tactics are unavailable for AD. Our previous study has shown that CZ2HF, a Chinese herb preparation, mitigates cognitive impairment in AD rats; whereas, its detailed mechanism has not been elucidated. Public databases were applied to collect and identify the chemical ingredients of eight herbs in CZ2HF. Criteria of absorption, distribution, metabolism, and excretion was used to screen oral bio-availability and drug-likeness. STITCH database and Therapeutic Target Database were applied to decipher the relationship between compounds and genes related to AD. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology term analyses were used to identify the involved signaling pathways. Cytoscape was adopted to establish the networks The molecular docking was used to validate the interactions between the candidate compounds and their potential targets. 914 compounds were identified in eight herbal medicines of CZ2HF. Among them, 9 compounds and 28 genes were highly involved in the pathologic process of AD. Furthermore, the mechanism of CZ2HF to AD was based on its anti-inflammatory effects mainly through lipopolysaccharide-mediated signaling pathway and TNF signaling pathway. Core genes in this network were TNF, ICAM1, MMP9 and IL-10. This study predicts the active compounds in CZ2HF and uncovers their protein targets using holistic network pharmacology methods. It will provide a insight into the underlying mechanism of CZ2HF to AD from a multi-scale perspective.

Comparing different algorithms for the course of Alzheimer's disease using machine learning.

Alzheimer's disease (AD) is one of the most influential nervous system diseases in the world. It is accompanied by symptoms such as loss of memory, thinking, and language ability. This paper discusses the characteristic indexes of brain magnetic resonance imaging (MRI) in mild cognitive impairment (MCI) and AD. It applies the MRI characteristic indexes in machine learning to classify and predict the course of AD to select the best model for classification and prediction auxiliary diagnosis of AD. In this study, 560 eligible subjects numbered 0-15,000 in the AD Neuroimaging Initiative (ADNI) database were randomly selected. According to the ADNI diagnostic criteria, the subjects were divided into four groups: the cognitive normal (CN) group (n=140), 230 cases in the early MCI (EMCI) group, 110 cases in the late MCI (LMCI) group, and 80 patients in the AD group. Random forest (RF), decision tree (DT), support vector machine (SVM) algorithms were used to classify and predict the different disease progress of AD. Next, different MRI indexes were input into the three machine learning algorithms to predict CN-EMCI-LMCI-AD. We compared the prediction accuracy, sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve (AUC). This study found that CN-AD had the highest classification accuracy, followed by EMCI-AD, CN-LMCI, LMCI-AD, EMCI-LMCI, and CN-EMCI. In the prediction of CN-AD, the AUC of 0.92 of the RF classifier was higher than the AUCs of the SVM and DT classifiers. Of the three machine learning algorithms, RF was better than the SVM and DT at predicting different MRI features. The accuracy of RF, SVM, and DT was 73.8%, 60.7%, and 59.5%, respectively. The RF classifier had the best prediction effect on different disease processes of AD. Five MRI indexes (used as classification features) had the best prediction effects. CN-AD had the best classification effect. Overall, the classification accuracy of the RF classifier for CN-EMCI-LMCI-AD was higher than those of the other models. The RF classifier can be used to classify different stages of AD in the early stages of the disease to assist in diagnosing AD.

Exploration of potential circulating micro-RNA as biomarker for Alzheimer's disease

Alzheimer's disease (AD) is considered a progressive and devastating neurodegenerative disorder which primarily effects elders. Due to the course of the disease and the involvement of different gene loci with complex genetic studies, it is possible to calculate the relative risk of individuals at risk. In this study, our aim was to investigate the serum transcript levels of candidate microRNAs (miRNAs), including miR-138, miR-128, and miR-107 in patients with AD and compared with that of normal individuals. In this research work, during the diagnosis process of AD, 50 blood samples were obtained from patients and 50 samples were collected from healthy individuals. Then total RNA of each sample was extracted and the expression levels of miRNAs were measured by Real-time PCR method. Our analysis indicated that the relative expression of all three miRNAs decreased in AD patients compared to the healthy samples. There was statistically significant in transcript levels of miR-138 (P = 0.047) and miR-107 (P = 0.004), while the levels of miR-128 had no significant difference between two groups (P = 0.075). The receiver operating characteristic (ROC) curve analysis indicated the potential of all miRNAs as biomarkers in AD. In conclusion, miR-138 and miR-107 can be used as a diagnostic or predictive biomarker in AD. In the case of miR-128, more research is needed. We suggest further studies and evaluation of changes in the expression of these miRNAs in larger populations.

Role of the Extracellular Matrix in Alzheimer's Disease.

Alzheimer’s disease (AD) is a neurodegenerative disease with complex pathological characteristics, whose etiology and pathogenesis are still unclear. Over the past few decades, the role of the extracellular matrix (ECM) has gained importance in neurodegenerative disease. In this review, we describe the role of the ECM in AD, focusing on the aspects of synaptic transmission, amyloid-β-plaque generation and degradation, Tau-protein production, oxidative-stress response, and inflammatory response. The function of ECM in the pathological process of AD will inform future research on the etiology and pathogenesis of AD.

Ferroptosis, a Potential Therapeutic Target in Alzheimer's Disease.

Cell death is a common phenomenon in the progression of Alzheimer’s disease (AD). However, the mechanism of triggering the death of neuronal cells remains unclear. Ferroptosis is an iron-dependent lipid peroxidation-driven cell death and emerging evidences have demonstrated the involvement of ferroptosis in the pathological process of AD. Moreover, several hallmarks of AD pathogenesis were consistent with the characteristics of ferroptosis, such as excess iron accumulation, elevated lipid peroxides, and reactive oxygen species (ROS), reduced glutathione (GSH), and glutathione peroxidase 4 (GPX4) levels. Besides, some ferroptosis inhibitors can relieve AD-related pathological symptoms in AD mice and exhibit potential clinical benefits in AD patients. Therefore, ferroptosis is gradually being considered as a distinct cell death mechanism in the pathogenesis of AD. However, direct evidence is still lacking. In this review, we summarize the features of ferroptosis in AD, its underlying mechanisms in AD pathology, and review the application of ferroptosis inhibitors in both AD clinical trials and mice/cell models, to provide valuable information for future treatment and prevention of this devastating disease.

Altered Biological Rhythm and Alzheimer's Disease: A Bidirectional Relationship.

Biological rhythms have become the research focus in recent years. Biological rhythm disruption is a common symptom of Alzheimer's disease (AD) patients, which is usually considered as the late consequence of AD. Recent studies have shown that biological rhythm disruption even occurs before the onset of clinical symptoms of AD. The causal relationship between AD and biological rhythm disruption is not clear. Delineating their relationship can help understand the disease mechanisms and make the early diagnosis of AD possible. This review integrates the research on the abnormal changes of the biological rhythm-related parameters in the clinical manifestations of AD patients and the roles of the biological rhythm disorders in AD. We will discuss the links between biological rhythms and AD, with the focus on the bidirectionality between biological rhythms and AD processes. Collectively, these updated research findings may provide the basis for further exploring the significance of rhythm in the diagnosis and treatment of AD.

Zuoguiwan Ameliorates Cognitive Deficits and Neuro-Inflammation in Streptozotocin-Induced Alzheimer’s Disease Rats

Introduction: Alzheimer’s disease is the most popular neurodegenerative disorder with no effective drugs to stop the progression. Zuoguiwan (ZGW), a traditional Chinese herbal medicine, has been applied in many diseases. Our study aimed to detect the function and mechanisms of ZGW in Alzheimer’s disease (AD). Methods: The rat models of AD were established by streptozotocin (STZ), and the function of ZGW on cognitive dysfunction was measured with the Morris water maze test. The concentration of pro-inflammatory mediators was accessed by enzyme-linked immunosorbent assay. The relative mRNA expression of ERβ was detected by real-time quantitative PCR. Results: The treatment with ZGW could suppress the cognitive impairment by the findings of escape latency and time spent in the target quadrant and the increased concentration of IL-1β, IL-6, and TNF-α induced by STZ. STZ might repress the mRNA levels of ERβ, and ZGW management weakened the declined mRNA expression of ERβ. ZGW might play a protective role in AD rats against the injury of STZ on cognition and neuro-inflammation by improving the mRNA expression of ERβ. Conclusion: The results indicated that ZGW might be a novel therapeutic strategy to slow the process of AD by modulating ERβ.

GPR120 Signaling Controls Amyloid-β Degrading Activity of Matrix Metalloproteinases.

Alzheimer's disease (AD) is characterized by the extensive deposition of amyloid-β peptide (Aβ) in the brain. Brain Aβ level is regulated by a balance between Aβ production and clearance. The clearance rate of Aβ is decreased in the brains of sporadic AD patients, indicating that the dysregulation of Aβ clearance mechanisms affects the pathologic process of AD. Astrocytes are among the most abundant cells in the brain and are implicated in the clearance of brain Aβ via their regulation of the blood-brain barrier, glymphatic system, and proteolytic degradation. The cellular morphology and activity of astrocytes are modulated by several molecules, including ω3 polyunsaturated fatty acids, such as docosahexaenoic acid, which is one of the most abundant lipids in the brain, via the G protein-coupled receptor GPR120/FFAR4. In this study, we analyzed the role of GPR120 signaling in the Aβ-degrading activity of astrocytes. Treatment with the selective antagonist upregulated the matrix metalloproteinase (MMP) inhibitor-sensitive Aβ-degrading activity in primary astrocytes. Moreover, the inhibition of GPR120 signaling increased the levels of Mmp2 and Mmp14 mRNAs, and decreased the expression levels of tissue inhibitor of metalloproteinases 3 (Timp3) and Timp4, suggesting that GPR120 negatively regulates the astrocyte-derived MMP network. Finally, the intracerebral injection of GPR120-specific antagonist substantially decreased the levels of TBS-soluble Aβ in male AD model mice, and this effect was canceled by the coinjection of an MMP inhibitor. These data indicate that astrocytic GPR120 signaling negatively regulates the Aβ-degrading activity of MMPs.SIGNIFICANCE STATEMENT The level of amyloid β (Aβ) in the brain is a crucial determinant of the development of Alzheimer's disease. Here we found that astrocytes, which are the most abundant cell type in the CNS, harbor degrading activity against Aβ, which is regulated by GPR120 signaling. GPR120 is involved in the inflammatory response and obesity in peripheral organs. However, the pathophysiological role of GPR120 in Alzheimer's disease remains unknown. We found that selective inhibition of GPR120 signaling in astrocytes increased the Aβ-degrading activity of matrix metalloproteases. Our results suggest that GPR120 in astrocytes is a novel therapeutic target for the development of anti-Aβ therapeutics.

Milrinone Ameliorates the Neuroinflammation and Memory Function of Alzheimer's Disease in an APP/PS1 Mouse Model.

PurposeAlzheimer’s disease (AD) is a complex neurodegenerative disorder, which is characterized by memory loss and cognitive deficits. The neuroprotective role of milrinone on the injury of spinal cord or cerebral ischemia-reperfusion has been confirmed. However, the accurate function of milrinone on AD pathogeny is still unclear.MethodsAPP/PS1 transgenic mouse was used to explore the role of milrinone in behaviour tests, and the effects on histopathologic features of AD such as the formation of neuronal amyloid-β (Aβ) plaque, microglial activation, tau protein hyperphosphorylation, oxidative stress, and neuroinflammation. Lipopolysaccharide (LPS)/Aβ-treated BV-2 cells were used to understand the anti-inflammation mechanism of milrinone on AD in vitro.ResultsOur in vivo results showed that milrinone ameliorates the memory functions of AD mice. Meanwhile, milrinone reduced Aβ deposits, repressed microglial activation and tau protein hyperphosphorylation, attenuated the oxidative stress, and decreased the levels of inflammatory cytokines. The in vitro results demonstrated that milrinone could inhibit the secretion of interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α via regulation of NLRP3 inflammasomes and TLR4/MyD88/NF-κB signalling pathway.ConclusionOverall, milrinone could ameliorate the memory loss and cognitive deficits through repressing the multiple pathological processes of AD, suggesting that milrinone may be an underlying and effective drug for treating AD clinically.

Insights into the cross-amyloid aggregation of Aβ40 and its N-terminal truncated peptide Aβ11-40 affected by epigallocatechin gallate

Inhibition of protein misfolding and aggregation is a great challenge in the field of biochemical and biopharmaceutical engineering. Alzheimer's disease (AD) is a protein-misfolding disease, and the interactions between 40-amino-acid-residue β-amyloid peptide (Aβ40) and its N-terminal truncated peptide Aβ11-40 demonstrate that Aβ11-40 may play an important role in the pathological process of AD. However, the effect of inhibitors on Aβ11-40 aggregation and on the cross-amyloid aggregation (co-assembly) between Aβ40 and Aβ11-40 has never been studied. Herein, coaggregation and seeding interactions between Aβ40 and Aβ11-40 as well as the effect of epigallocatechin gallate (EGCG), a small molecule inhibitor, on the cross-amyloid aggregation have been investigated by extensive analyses. It is found that Aβ11-40 participates in the aggregation of Aβ40 and leads to the formation of coaggregates that contain less β-sheet structures than pure Aβ40 aggregates. The aggregation kinetics along with morphologies and secondary structures of the coaggregates are also significantly affected by the Aβ40/Aβ11-40 ratio. EGCG accelerates the nucleation of Aβ40 but retards that of Aβ11-40 by affecting their elongation and secondary nucleation processes in solution and on solid surfaces. Meanwhile, EGCG makes the conformations of the seeding-induced Aβ aggregates more compact, especially for the homologous seedings. Isothermal titration calorimetry measurement indicates that hydrophobic interactions mainly contribute to the inhibition of the two Aβ isoforms by EGCG. The findings of this research have provided new insights into Aβ aggregation and the effect of an important inhibitor and the results would benefit in the development of potent inhibitors against co-assembly of different amyloid proteins.

Methylation factor MRPL15 identified as a potential biological target in Alzheimer's disease.

Alzheimer’s disease (AD) is the most common form of dementia. However, the molecular basis of the development and progression of AD is still unclear. To elucidate the molecular processes related to AD, we obtained the expression profiles and analyzed the differentially expressed genes (DEGs). The genes potentially involved in the AD process were identified by PPI network and STEM analysis. The molecular mechanisms related to the recognition of AD were determined by GSEA and enrichment analysis. The differences from immune cells in AD were calculated. The methylation factors were identified by methylation difference analysis. Among them, MRPL15 was identified as suitable for diagnosing AD. Its expression trend had been verified in GSE5281. Importantly, MRPL15 was also a methylation factor. In addition, macrophages and neutrophils were up-regulated in AD patients. This was consistent with previous immune inflammation responses identified as being involved in the development of AD. The results of the present study revealed the genetic changes and molecular mechanisms involved in the process of the development and deterioration of AD patients. The potential AD risk genes and potential biological targets were identified. It provided evidence that immune inflammation and immune cells play an important role in AD.

Neuroinflammation in Alzheimer's Disease.

Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.

052 APOE-ε4 is associated with impaired sleep-dependent memory consolidation in healthy carriers

Abstract Introduction The Apolipoprotein E (APOE)-ε4 genotype is a marker of susceptibility for late-onset Alzheimer’s disease (AD). Sleep disturbances may accelerate the aging process and increase the risk for future development of cognitive impairment and dementia. Given that the pathophysiological process of AD can predate its clinical manifestations by years or even decades, the aim of this study was to assess the role of the APOε4 allele on sleep-dependent memory consolidation in cognitively healthy adults. Methods 16 healthy APOE-ε4 carriers (mean age=49.9±13.7) and 32 healthy non-carriers (age=45.7±12.9) were included in the main analysis. Baseline screening included the Epworth Sleepiness Scale, Morningness-Eveningness scale, Wechsler Adult Intelligence Scale (WAIS) and Beck Depression Inventory (BDI), as well as a baseline polysomnogram (PSG), which also served as an adaptation night. Participants subsequently underwent an overnight testing session, which included computer sessions of the Psychomotor Vigilance Task (PVT) and the declarative Verbal Paired-Associates Task (VPA) in the evening followed by a full night PSG and repeat PVT and VPA sessions in the morning. For further reference, we added an age matched group of 16 non-carriers with newly diagnosed obstructive sleep apnea (OSA, age=48.1±15.1), who underwent the same study procedures. Results APOE-ε4 carriers had higher BDI (p=0.04) and ESS (p=0.01) scores than non-carriers. There were no significant group differences for sleep macrostructure. Evening VPA performance was similar for both groups (p=0.77). The following morning, APOE-ε4 carriers improved by 7.5±6.4 % from the evening before, compared to 13.5±7.0% for the healthy non-carriers (p=0.005). OSA subjects improved by 5.0± 8.1%, which was similar to APOE-ε4 carriers (p=0.34). Conclusion To our knowledge, this is the first study to reveal that healthy APOE-ε4 carriers while showing similar initial learning (encoding) on a declarative memory task compared to healthy controls, exhibit a deficit in sleep-dependent memory consolidation, similar to patients with obstructive sleep apnea. Consequently, this study provides evidence that impaired sleep-related memory processes could be an important harbinger in otherwise healthy individuals, who are at high risk for AD. Support (if any) NIH grant # K23HL103850 (Ina Djonlagic) and American Sleep Medicine Foundation grant #54-JF-10 (Ina Djonlagic)

Role of methionine sulfoxide reductase in Alzheimer's disease

Cellular oxidative damage has been implicated as one of the factors in Alzheimer's disease (AD) pathogenesis. One of the enzyme systems preventing protein oxidation in mammalian cells is the methionine sulfoxide reductase (MSR) system; MSR system is comprised of MSRA and MSRB, which reduce oxidized methionine residues (Met(O)) present in proteins back to methionine. Further, the MSR system scavenges reactive oxygen species (ROS), by permitting methionine residues in proteins to function as catalytic antioxidants. There is growing evidence from many studies on the affect of altered MSRA levels on AD progression in different animal models and, also that oxidized Met 35 will promote aggregation of toxic forms of Aß. Our research aims to further understand the role of MSRA and Met35 in the pathogenic processes of AD. For our studies we have used, AD transgenic mice, J20 APP-Tg that overexpresses Aß to analyze MSR levels and, variants of commercially available Aß (1-42) to assess the effect of methionine oxidation. Our preliminary results indicate that the level of MSRA was decreased in the transgenic mice as compared to the wild type mice. We have also observed in Aß peptide aggregation experiments, oxidized Met35 Aβformed high molecular weight fibrillar aggregates compared to the WT- Aβ and, if Met is replaced with norleucine (Nle) only monomers were formed. These results suggest that MSRA plays a role in Aß aggregation and these studies provide a potential therapeutic target for AD.