inAlzheimer's Disease Research Articles

Identification of Molecular Correlations of GSDMD with Pyroptosis inAlzheimer's Disease.

An analysis of bioinformatics and cell experiments was performed to verify the relationship between gasdermin D (GSDMD), an executive protein of pyroptosis, and Alzheimer's disease (AD). The training set GSE33000 was utilized to identify differentially expressed genes (DEGs) in both the AD group and control group, as well as in the GSDMD protein high/low expression group. Subsequently, the weighted gene co-expression network analysis (WGCNA) and the least absolute shrinkage and selection operator (LASSO) regression analysis were conducted, followed by the selection of the key genes for the subsequent Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. The association between GSDMD and AD was assessed and confirmed in the training set GSE33000, as well as in the validation sets GSE5281 and GSE48350. Immunofluorescence (IF) was employed to detect the myelin basic protein (MBP), a distinctive protein found in the rat oligodendrocytes (OLN-93 cells). A range of concentrations (1-15 μmol/L) of β-amyloid 1-42 (Aβ1-42) were exposed to the cells, and the subsequent observations were made regarding cell morphology. Additionally, the assessments were conducted to evaluate the cell viability, the lactate dehydrogenase (LDH) release, the cell membrane permeability, and the GSDMD protein expression. A total of 7,492 DEGs were screened using GSE33000. Subsequently, WGCNA analysis identified 19 genes that exhibited the strongest correlation with clinical traits in AD. Additionally, LASSO regression analysis identified 13 key genes, including GSDMD, AFF1, and ATOH8. Furthermore, the investigation revealed that the key genes were associated with cellular inflammation based on GO and KEGG analyses. Moreover, the area under the curve (AUC) values for the key genes in the training and validation sets were determined to be 0.95 and 0.70, respectively. Significantly, GSDMD demonstrated elevated levels of expression in AD across both datasets. The positivity of MBP expression in cells exceeded 95%. As the concentration of Aβ1-42 action gradually escalated, the detrimental effects on cells progressively intensified, resulting in a gradual decline in cell survival rate, accompanied by an increase in lactate dehydrogenase release, cell membrane permeability, and GSDMD protein expression. The association between GSDMD and AD has been observed, and it has been found that Aβ1-42 can induce a significant upregulation of GSDMD in OLN-93 cells. This suggests that Aβ1-42 has the potential to induce cellular pyroptosis and can serve as a valuable cellular pyroptosis model for the study of AD.

Ferroptosis Signaling Pathways: Alzheimer's Disease.

The involvements of iron metabolism, lipid peroxidation, and oxidative stress in Alzheimer's disease (AD) development have recently received a lot of attention. We also observe that these pathogenic occurrences play a key role in regulating ferroptosis, a unique regulatory cell death that is iron-dependent, oxidative, and non-apoptotic. Iron is a crucial component that makes up a subunit of the oxidase responsible for lipid peroxidation. A family of non-heme iron enzymes known as lipoxygenases (LOXs) can cause ferroptosis by oxidising polyunsaturated fatty acids in cellular membranes (PUFAs). Toxic lipid hydroperoxides are produced in large part by the iron in LOX active sites. Deferoxamine and deferiprone, two iron chelators, could also treat ferroptosis by eliminating the crucial catalytic iron from LOXs. Phospholipids containing polyunsaturated fatty acids are the main substrates of lipid peroxidation in ferroptosis, which is favourably controlled by enzymes like ACSL4, LPCAT3, ALOXs, or POR. Selective stimulation of autophagic degradation pathways leads to an increase in iron accumulation and lipid peroxidation, which promotes ferroptosis. We highlighted recent advancements in our understanding of ferroptosis signaling routes in this study. One form of regulated necrotic cell death known as ferroptosis has been linked to a number of diseases, including cancer, neurological disorders, and ischemia/reperfusion injury. Cerebrospinal fluid (CSF) ferritin may be a good indicator of the amount of iron in the brain because it is the main protein that stores iron.

Structural Scaffolds as Anti- Alzheimer Agents.

Understanding the cognitive and behavioral aspects of Alzheimer's disease- related dementia is surely a sturdy task to deal with. In recent years, a broad search for novel anti-Alzheimer agents has been continuously conducted. The malfunctioning of various neurotransmitter systems and the accumulation of abnormal proteins in the brain are the two key characteristics of this disorder. This is supported by a growing amount of evidence. Some Pharmacophoric groups/combinations exhibit potential neuroprotective activity. This study aims to compile the most recent and interesting target/target combinations/ pharmacophoric combinations to cure Alzheimer's disease. We concentrated our efforts to find the ability of certain pharmacophoric elements to interfere with various enzymatic and/or receptor systems or to work as neuroprotective agents. These pharmacophoric elements may be proved to be promising leads for future multi-target anti-Alzheimer drug discovery programs. Anticholinesterase drugs were mentioned as the best treatment thus far. Additionally, impairments in the serotonergic, GABAergic, noradrenergic, dopaminergic, and glutaminergic and a few other pathways have all been linked to memory, speech, behavioral and other alterations in Alzheimer's disease. This includes the study of workable pharmacophoric groups/combinations, receptors/ enzymatic systems and related hypotheses to find the promising therapeutic lead compounds which could work as future anti-Alzheimer drugs. We discuss future work that would improve our understanding of this Disease.

The Role of Thyroid Function inAlzheimer's Disease.

The thyroid gland is crucial for the regulation of metabolism, growth, and development of various tissues, organs, systems, including the central nervous system. Recent studies have implicated the role of thyroid dysfunction in the etiology of Alzheimer's disease (AD), while AD leads to a significant increase in the prevalence of thyroid dysfunction. In this review, we have analyzed the role of thyroid function in the pathophysiology of AD as well as its biomarkers. The present review aims to provide encouraging targets for early screening of AD risk factors and intervention strategies.

Advanced Nanoparticular Approaches to Combat Alzheimer's Disease.

Alzheimer's disease (AD) is a neurological disease that affects many of the world's rapidly ageing population. In the etiology of Alzheimer's disease (AD), the involvement of amyloid β (Aβ) plaque accumulation and oxidative stress in the brain have important roles. Various drugs have been proposed to prevent and treat AD, but delivering these therapeutic agents to the brain is difficult. Over the last decade, nanoparticle-mediated drug delivery represents one promising strategy to increase the CNS penetration of several therapeutic moieties successfully. Different nanocarriers are being investigated to treat and diagnose AD. NTDDS (nanotechnology-based drug delivery systems) can be used in various methods to improve patient compliance and treatment outcomes. However, literature analysis revealed that clinical activities, such as NTDDS application in Alzheimer's disease research lag behind despite extensive research. This review gives an account of the BBB and discusses the literature on some drugs, which are successfully encapsulated as nanoparticles for a future therapeutic approach. It also emphasizes the current clinical studies for Alzheimer's disease therapy.

Visual mental imagery in mild cognitive impairment: A pilot study

AbstractBackgroundVisual Mental Imagery (VMI), the ability of seeing with the mind eyes, has shown to be related with autobiographical memory deficits inAlzheimer's disease (AD) (El Haj et al., 2019). Hippocampus, affected by AD neuropathology since early stages, plays a pivotal contribution to the recollection of previous memories in service of VMI; however, little is known about VMI in Mild Cognitive Impairment (MCI). Basing on the current model of VMI and findings that the various processes and contents of VMI decline differently in physiological ageing (Piccardi et al. 2015), we investigated whether VMI is involved by MCI analyzing which processes and specific contents are compromised to evaluate the possible role of deficit in VMI as early neuropsychological marker of dementia.MethodTwelve amnestic‐MCI patients (mean age = 75.42, SD = 5.68; mean education=10.92, SD=4.17) and eleven healthy controls (HC) (mean age = 71.09, DS = 8.40; mean education = 13.18, SD = 4.64), matched for Age and Education, were enrolled. VMI was extensively assessed in all patients and controls by means of 1) an adapted version of The Complete Visual Mental Imagery Battery (CVMIB; Palermo et al., 2016), including tasks evaluating the generation, maintenance, inspection and transformation of different types of visual mental images (i.e. objects, buildings and faces), and 2) the O’Clock test (Grossi et al.,1994) that allows to disentangle the possible role of perceptive difficulties in the VMI task’s performance.ResultParametric and non‐parametric analyses revealed that MCI performed worse than HC in all CVMIB’s tasks except transformation (i.e. Mental Rotation and Folding tasks) and for the generation of VMI of faces. VMI deficits seem not attributable to perceptual difficulties due to the absence of deficits in the Perceptive task of the O’Clock Test (see Figure 1).ConclusionPresent preliminary results suggest that VMI is impaired since the early phase of cognitive decline and an extensive assessment of VMI, taking into account the different components and contents of VMI, may be used to better characterize MCI neuropsychological profile as well as early neuropsychological marker of dementia.

The role of impairment of higher mental functions in suicidogenesis in the dementia caused by Alzheimer's disease

Background Dementia is the age-related disease. At the same time, the elderly age has one of the peaks in the number of suicides. Psychology of patients with demetia is characterized by the feeling of hopelessness, pessimism, awareness of own insolvency, dependence on others, that affects the risk of suicide. It is established that the highest risk of suicide in the early stages of dementia with the progression of cognitive deficit, the risk of suicide decreases. Aim To study the role of impairment of higher mental functions (perception, reasoning, attention, memory, emotions, will, speech) in the formation of suicidal behaviour in patients with dementia in Alzheimer's disease. Materials and methods There were examined 75 patients with dementia in Alzheimer's disease, 36 patients with a history of suicidal behavior composed the main group, and 39 patients without the signs of suicidal behavior composed control group. The study was carried out using clinical-anamnestic, psychopathological methods and mathematical statistical methods. Results The high risk of suicide in dementia caused by Alzheimer's disease is combined with the inhibition of thinking, the delusional ideas of self-blame and self-effacement (p ≤ 0.05); depressed mood, inner agitation, anxiety, feeling of despair, hopelessness, guilt, melancholia, apathy (p ≤ 0.05); effector-volitional disorders in the form of hypobulia, hypokinesia, hypomimia, decreased libido (p ≤ 0.05); speech disturbance in the form of bradylalia p ≤ 0.05; greater exhaustion and decreased attention (p ≤ 0.05). On the contrary, the following peculiarities of higher mental functions, namely thought disorder are referred to the anti-risk factors of suicide in dementia caused by Alzheimer's disease: the delusional ideas of relation and damage (p ≤ 0.05); emotions: the feeling of fear (p ≤ 0.05); effector-volitional sphere: parabulia and hyperkinesia (p ≤ 0.05). Conclusion On the basis of clinical and psychopathological study of patients with dementia in Alzheimer's disease, the specific impairment of higher mental functions and emotional-volitional spheres reasoning, memory, attention, perception, speech, emotions) are identified associated with high risk of suicide.

Patient Variables Associated with the Assignment of a Formal Dementia Diagnosis to Positively Screened Primary Care Patients.

Main objective was to analyze the associations of patient variables (depression, quality of life, anti-dementia drug treatment, knowledge about dementia) with the assignment of a formal diagnosis of dementia to community-dwelling primary care patients who have screened positive for dementia. DelpHi-MV (Dementia: life- and person-centered help in Mecklenburg-Western Pomerania) is a general practitioner based randomized controlled intervention trial. Present analyses are based on cross-sectional data of 319 positively screened patients (age 70+, living at home) who had not been formally diagnosed with dementia before the screening. The medical diagnoses (ICD-10) were retrieved from the patient's medical records. Depression (Geriatric Depression Scale; GDS), quality of life in Alzheimer's disease (Qol-AD), knowledge about dementia, and anti-dementia drug treatment were assessed after the screening test at the baseline examination. At the baseline examination, 171 out of 319 patients (54%) had been formally diagnosed with dementia after they have screened positive. Univariate comparisons showed no statistically significant differences between diagnosed and undiagnosed patients regarding depression (GDS≥6: 11% vs. 15%; p=0.396), quality of life (mean (SD): 2.8 (0.3) vs. 2.8 (0.4); p=0.833), and the knowledge about dementia (75% vs. 75%; p>0.999). Patients who had received a formal diagnosis were more often treated with anti-dementia drugs (20% vs. 11%; p=0.040). Multivariate analyses controlled for confounding variables confirmed these findings. Present findings do not support concerns that the assignment of a formal dementia diagnosis after screening is associated with potential harms. If confirmed in a prospective study, our data would suggest that patients may benefit from being formally diagnosed regarding anti-dementia drug treatment.

Peripheral versus Central Index ofMetabolic Dysfunction and Associations with Clinical and Pathological Outcomes inAlzheimer's Disease.

Insulin-like growth factor binding protein 2 (IGFBP-2) regulates blood glucose levels, facilitates hippocampal synaptic plasticity and may have a predictive value for Alzheimer's disease (AD) diagnosis. IGFBP-2 levels were studied in plasma in 566 subjects and in cerebrospinal fluid (CSF) in 245 subjects across the AD spectrum from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Variants in the IGFBP-2 gene were examined. Linear mixed modeling in SPSS tested main effects of IGFBP-2 and interactions with APOE4 on neurocognitive indices and biomarkers. Voxel-wise regression was used to gauge IGFBP-2 and regional grey matter and glucose metabolism associations. Each point increase in IGFBP-2 corresponded to a three times greater likelihood of having mild cognitive impairment (MCI) or AD. IGFBP-2 showed beneficial associations with respect to cognitive scores in individuals with two APOE4 alleles. Higher IGFBP-2 predicted higher insulin resistance, but not CSF amyloid or tau. Voxel-wise analyses showed that plasma IGFBP-2 predicted lower grey matter volume and FDG metabolism in a large area spanning the frontal, temporal, and occipital lobes. CSF IGFBP-2 levels showed similar voxel-wise analysis results, but were uniquely associated with CSF amyloid and tau. Analysis of single nucleotide polymorphisms (SNPs) in IGFBP-2 showed that subjects carrying risk alleles versus common alleles had increased risk of AD and lower memory scores. Voxel-wise analyses of these SNPs also implicated the hippocampus and prefrontal cortex. IGFBP-2 is associated with AD risk and outcomes; plasma IGFBP-2 provides stronger predictive power for brain outcomes, while CSF IGFBP-2 provides improved predictive accuracy for AD CSF biomarkers.

Epigenetics and DNA methylomic profiling in Alzheimer's disease and other neurodegenerative diseases.

Recent studies have suggested a role for epigenetic mechanisms in the complex etiology of various neurodegenerative diseases. In this review, we discuss advances that have been made toward understanding the role of epigenetic processes in neurodegenerative disorders, with aparticular focus on Alzheimer's disease, where themostextensive studies have been undertaken to date. We provide a brief overview of DNA modifications, followed by a summarization of studies of DNA modifications inAlzheimer's disease and other neurodegenerative diseases.

Stress-Induced Synaptic Dysfunction andNeurotransmitter Release inAlzheimer's Disease: Can Neurotransmitters and Neuromodulators bePotential Therapeutic Targets?

The communication between neurons at synaptic junctions is an intriguing process that monitors the transmission of various electro-chemical signals in the central nervous system. Albeit any aberration in the mechanisms associated with transmission of these signals leads to loss of synaptic contacts in both the neocortex and hippocampus thereby causing insidious cognitive decline and memory dysfunction. Compelling evidence suggests that soluble amyloid-β (Aβ) and hyperphosphorylated tau serve as toxins in the dysfunction of synaptic plasticity and aberrant neurotransmitter (NT) release at synapses consequently causing acognitive decline in Alzheimer's disease (AD). Further, an imbalance between excitatory and inhibitory neurotransmission systems induced by impaired redox signaling and altered mitochondrial integrity is also amenable for such abnormalities. Defective NT release at the synaptic junction causes several detrimental effects associated with altered activity of synaptic proteins, transcription factors, Ca2+ homeostasis, and other molecules critical for neuronal plasticity. These detrimental effects further disrupt the normal homeostasis of neuronal cells and thereby causing synaptic loss. Moreover, the precise mechanistic role played by impaired NTs and neuromodulators (NMs) and altered redox signaling in synaptic dysfunction remains mysterious, and their possible interlink still needs to be investigated. Therefore, this review elucidates the intricate role played by both defective NTs/NMs and altered redox signaling in synaptopathy. Further, the involvement of numerous pharmacological approaches to compensate neurotransmission imbalance has also been discussed, which may be considered as apotential therapeutic approach in synaptopathy associated with AD.

The Correlation between Inflammatory Biomarkers and Polygenic Risk Score inAlzheimer's Disease.

Plasma biomarkers to aid the early diagnosis of Alzheimer's disease (AD) or to monitor disease progression have long been sought and continue to be widely studied. Biomarkers that correlate with AD polygenic risk score, a measure of the polygenic architecture of the disease and highly predictive of AD status, would be excellent candidates. Therefore, we undertook a preliminary study to assess the association of plasma inflammatory biomarkers with an overall AD polygenic risk score as well as with an inflammation-specific AD polygenic risk score in a sample set of 93 AD cases. We measured five complement biomarkers [complement receptor 1 (CR1), clusterin, complement component 9 (C9), C1 inhibitor (C1inh), terminal complement complex (TCC)] and the benchmark inflammatory marker C-reactive protein (CRP). Plasma clusterin level showed an association with overall AD polygenic risk score, while clusterin, C1inh, and CRP levels each displayed some association with the inflammatory-specific AD polygenic risk score. The results suggest that elevated plasma levels of inflammatory biomarkers, including complement proteins, associate with polygenic risk scores in AD, further strengthening the link between genetic and biomarker disease predictors and indicating a potential role for these markers in disease prediction and patient stratification in AD.

Uncovering the Neural Bases of Cognitive and Affective Empathy Deficits inAlzheimer's Disease and the Behavioral-Variant of Frontotemporal Dementia.

Loss of empathy is a core presenting feature of the behavioral-variant of frontotemporal dementia (bvFTD), resulting in socioemotional difficulties and behavioral transgressions. In contrast, interpersonal functioning remains relatively intact in Alzheimer's disease (AD), despite marked cognitive decline. The neural substrates mediating these patterns of loss and sparing in social functioning remain unclear, yet are relevant for our understanding of the social brain. We investigated cognitive versus affective aspects of empathy using the Interpersonal Reactivity Index (IRI) in 25 AD and 24 bvFTD patients and contrasted their performance with 22 age- and education-matched controls. Cognitive empathy was comparably compromised in AD and bvFTD, whereas affective empathy was impaired exclusively in bvFTD. While controlling for overall cognitive dysfunction ameliorated perspective-taking deficits in AD, empathy loss persisted across cognitive and affective domains in bvFTD. Voxel-based morphometry analyses revealed divergent neural substrates of empathy loss in each patient group. Perspective-taking deficits correlated with predominantly left-sided temporoparietal atrophy in AD, whereas widespread bilateral frontoinsular, temporal, parietal, and occipital atrophy was implicated in bvFTD. Reduced empathic concern in bvFTD was associated with atrophy in the left orbitofrontal, inferior frontal, and insular cortices, and the bilateral mid-cingulate gyrus. Our findings suggest that social cognitive deficits in AD arise largely as a consequence of global cognitive dysfunction, rather than a loss of empathy per se. In contrast, loss of empathy in bvFTD reflects the deterioration of a distributed network of frontoinsular and temporal structures that appear crucial for monitoring and processing social information.

The Disconnection Hypothesis inAlzheimer's Disease Studied Through Multimodal Magnetic Resonance Imaging: Structural, Perfusion, and Diffusion Tensor Imaging.

According to the so-called disconnection hypothesis, the loss of synaptic inputs from the medial temporal lobes (MTL) in Alzheimer's disease (AD) may lead to reduced activity of target neurons in cortical areas and, consequently, to decreased cerebral blood flow (CBF) in those areas. The aim of this study was to assess whether hypoperfusion in parietotemporal and frontal cortices of patients with mild cognitive impairment who converted to AD (MCI-c) and patients with mild AD is associated with atrophy in the MTL and/or microstructural changes in the white matter (WM) tracts connecting these areas. We assessed these relationships by investigating correlations between CBF in hypoperfused areas, mean cortical thickness in atrophied regions of the MTL, and fractional anisotropy (FA) in WM tracts. In the MCI-c group, a strong correlation was observed between CBF of the superior parietal gyri and FA in the parahippocampal tracts (left: r = 0.90, p < 0.0001; right: r = 0.597, p = 0.024), and between FA in the right parahippocampal tract and the right precuneus (r = 0.551, p = 0.041). No significant correlations between CBF in hypoperfused regions and FA in the WM tract were observed in the AD group. These results suggest an association between perfusion deficits and altered WM tracts in prodromal AD, while microvasculature impairments may have a greater influence in more advanced stages. We did not find correlations between cortical thinning in the medial temporal lobes and decreased FA in the WM tracts of the limbic system in either group.

Truncation and Activation of Dual Specificity Tyrosine Phosphorylation-regulated Kinase 1A by Calpain I: A MOLECULAR MECHANISM LINKED TO TAU PATHOLOGY IN ALZHEIMER DISEASE

Hyperphosphorylation and dysregulation of exon 10 splicing of Tau are pivotally involved in pathogenesis of Alzheimer disease (AD) and/or other tauopathies. Alternative splicing of Tau exon 10, which encodes the second microtubule-binding repeat, generates Tau isoforms containing three and four microtubule-binding repeats, termed 3R-Taus and 4R-Taus, respectively. Dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) lies at the Down syndrome critical region of chromosome 21. Overexpression of this kinase may contribute to the early Tau pathology in Down syndrome via phosphorylation of Tau and dysregulation of Tau exon 10. Here, we report that Dyrk1A was truncated at the C terminus and was associated with overactivation of calpain I in AD brain. Calpain I proteolyzed Dyrk1A in vitro first at the C terminus and further at the N terminus and enhanced its kinase activity toward Tau via increased Vmax but not Km. C-terminal truncation of Dyrk1A resulted in stronger activity than its full-length protein in promotion of exon 10 exclusion and phosphorylation of Tau. Dyrk1A was truncated in kainic acid-induced excitotoxic mouse brains and coincided with an increase in 3R-Tau expression and phosphorylation of Tau via calpain activation. Moreover, truncation of Dyrk1A was correlated with an increase in the ratio of 3R-Tau/4R-Tau and Tau hyperphosphorylation in AD brain. Collectively, these findings suggest that truncation/activation of Dyrk1A by Ca(2+)/calpain I might contribute to Tau pathology via promotion of exon 10 exclusion and hyperphosphorylation of Tau in AD brain.

2878 – Oral-motor speech disorders inalzheimer's disease

Objectives Aim of the study is to evaluate the oral-motor speech disorders in Alzheimer's disease as compared to the speech disorders occurring in the physiological process of aging. Methods We examined 22 patients with Alzheimer's disease (AD) at the age of 68 to 90 years. The control group (C) consisted of 22 people. The test has 5 parts: dialogic speech, descriptive speech, naming, repeating and speaking automated verbal sequences. Results Statistically significant differences between AD and C groups in the number of correct and incorrect answers were found. The greatest difference was found between AD and C groups in the descriptive speech. During the repetition of monosyllabic and polysyllabic words in AD occurred significantly more often the articulation errors on repeated speech productions of the same utterance. Conclusions The results confirmed the presence of oral-motor speech disorders in Alzheimer's disease. It was stated articulation errors, periphrases and jams. These errors occur in the structure of lexical-semantic and phonological system of the language. No abnormalities were noted in the area of grammar.

A conformational B-Z DNA study monitored with phosphatemethylated DNA as a model for epigenetic dynamics focused on 5-(hydroxy)methylcytosine

This study was directed on the B- into Z-DNA isomerization with alternating CG sequences monitored with artificial DNA model-systems based on methylation of the phosphate backbone. The chemical concept for this transition wherein shielding of the oxygen anions of the backbone phosphates plays an essential role, resulted in the preparation of the phosphatemethylated d(CpG). Even on this primitive level of only two base pair long, the B-Z conformational aspects of this self-complementary duplex could be described in solution with nuclear magnetic resonance (NMR) and circular dichroism (CD) measurements. The exclusivity of this choice became clear after synthesizing phosphatemethylated DNA with longer alternating CG fragments. It could be shown that conflicting conformational effects of the CG and GC fragments resulted in an overall B structure of the phosphatemethylated tetramer d(CPGPCPG). From our model considerations, it is clear that the internal stress introduced by the alternating CG sequences will be promoted by a complete shielding of the phosphate backbone. Elimination of this effect may be realized by a site-specific phosphate shielding. The role of the anti-syn isomerization of G in the CG fragments is clarified by methylation of the phosphate group. This anti-syn transition is absent in corresponding methylphosphonates, suggesting an exclusive role for base-backbone coordination via hydrogen bonding. In addition, we propose that the B- into Z-DNA interconversion may offer a mechanistic view for differences in dynamics between cytosine and its epigenetic derivative 5-methylcytosine. This mechanism has been extended to the demethylation of 5-methylcytosine and the exchange of information between the new epigenetic base, 5-hydroxymethylcytosine and the DNA backbone via an intramolecular phosphorylation. The role of 5-hydroxymethylcytosine in Alzheimer disease has been briefly discussed. In our opinion, this study can be considered as a new dynamic concept for epigenetics based on the dynamics of the B-Z transition in natural and phosphatemethylated DNA.

Astrocytes Secrete Exosomes Enriched with Proapoptotic Ceramide and Prostate Apoptosis Response 4 (PAR-4): POTENTIAL MECHANISM OF APOPTOSIS INDUCTION IN ALZHEIMER DISEASE (AD)

Amyloid protein is well known to induce neuronal cell death, whereas only little is known about its effect on astrocytes. We found that amyloid peptides activated caspase 3 and induced apoptosis in primary cultured astrocytes, which was prevented by caspase 3 inhibition. Apoptosis was also prevented by shRNA-mediated down-regulation of PAR-4, a protein sensitizing cells to the sphingolipid ceramide. Consistent with a potentially proapoptotic effect of PAR-4 and ceramide, astrocytes surrounding amyloid plaques in brain sections of the 5xFAD mouse (and Alzheimer disease patient brain) showed caspase 3 activation and were apoptotic when co-expressing PAR-4 and ceramide. Apoptosis was not observed in astrocytes with deficient neutral sphingomyelinase 2 (nSMase2), indicating that ceramide generated by nSMase2 is critical for amyloid-induced apoptosis. Antibodies against PAR-4 and ceramide prevented amyloid-induced apoptosis in vitro and in vivo, suggesting that apoptosis was mediated by exogenous PAR-4 and ceramide, potentially associated with secreted lipid vesicles. This was confirmed by the analysis of lipid vesicles from conditioned medium showing that amyloid peptide induced the secretion of PAR-4 and C18 ceramide-enriched exosomes. Exosomes were not secreted by nSMase2-deficient astrocytes, indicating that ceramide generated by nSMase2 is critical for exosome secretion. Consistent with the ceramide composition in amyloid-induced exosomes, exogenously added C18 ceramide restored PAR-4-containing exosome secretion in nSMase2-deficient astrocytes. Moreover, isolated PAR-4/ceramide-enriched exosomes were taken up by astrocytes and induced apoptosis in the absence of amyloid peptide. Taken together, we report a novel mechanism of apoptosis induction by PAR-4/ceramide-enriched exosomes, which may critically contribute to Alzheimer disease.

S4-01-01: Identification of subgroups of Alzheimer disease

S4-01-01: Identification of subgroups of Alzheimer disease

S.12.02 Vaccination against beta-amyloid inAlzheimer's disease

S.12.02 Vaccination against beta-amyloid inAlzheimer's disease