Pathological Process Of Alzheimer's Disease Research Articles

Mechanisms of NLRP3 Inflammasome Activation: Its Role in the Treatment of Alzheimer’s Disease

Alzheimer's disease (AD) is a common neurodegenerative disease of progressive dementia which is characterized pathologically by extracellular neuritic plaques containing aggregated amyloid beta (Aβ) and intracellular hyperphosphorylated tau protein tangles in cerebrum. It has been confirmed that microglia-specific nucleotide-binding oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome-mediated chronic neuroinflammation plays a crucial role in the pathogenesis of AD. Stimulated by Aβ deposition, NLRP3 assembles and activates within microglia in the AD brain, leading to caspase-1 activation along with downstream interleukin (IL)-1β secretion, and subsequent inflammatory events. Activation of the NLRP3 inflammasome mediates microglia to exhibit inflammatory M1 phenotype, with high expression of caspase-1 and IL-1β. This leads to Aβ deposition and neuronal loss in the amyloid precursor protein (APP)/human presenilin-1 (PS1) mouse model of AD. However, NLRP3 or caspase-1 deletion in APP/PS1 mice promotes microglia to transform to an anti-inflammatory M2 phenotype, with decreased secretion of caspase-1 and IL-1β. It also results in improved cognition, enhanced Aβ clearance, and a lower cerebral inflammatory response. This result suggests that the NLRP3 inflammasome may be an appropriate target for reducing neuroinflammation and alleviating pathological processes in AD. In the present review, we summarize the generally accepted regulatory mechanisms of NLRP3 inflammasome activation, and explore its role in neuroinflammation. Furthermore, we speculate on the possible roles of microglia-specific NLRP3 activation in AD pathogenesis and consider potentialtherapeutic interventions targeting the NLRP3 inflammasome in AD.

The meaning of blood and cerebrospinal fluid biomarkers in early diagnosis of Alzheimer's disease

Introduction and purpose: Alzheimer's disease (AD) belongs to the group of neurodegenerative diseases and is the leading cause of dementia worldwide. Its development includes the impact of genetic, metabolic and environmental factors. Despite high prevalence of Alzheimer’s disease and dynamic development of medical science, there is currently no clinically proven causal treatment. The proposed therapies are only symptomatic. However, there is a wide set of substances known as biomarkers that are detected in the blood or in the cerebrospinal fluid (CSF) in the stages preceding full-blown Alzheimer's disease.Brief description of the state of knowledge: In order to obtain material for CSF examination, a lumbar puncture must be performed. It is an invasive procedure, with the risk of complications such as bleeding into the spinal cord, infection or even nerve damage. Obtaining a blood sample for testing specific indicators is less invasive and more widely available. Currently, the diagnostic significance of commonly known markers arising in the progress of the AD pathological process, such as amyloid β, tau protein and its phosphorylated form or β-secretase, is being investigated. As the knowledge on the pathogenesis of AD grows, further markers such as ubiquitin, micro RNA or plasma neurofilament light are tested.Conclusions: There is a collection of biomarkers that can perform a diagnostic function for Alzheimer's disease. Due to the advantages of blood and plasma testing, basing the diagnosis of early forms of AD on these tests seems to be particularly interesting. However, the use of biomarkers on a global scale requires further research and test standardization, as well as the development of guidelines for their interpretation.

MiR-149-5p inhibition reduces Alzheimer's disease β-amyloid generation in 293/APPsw cells by upregulating H4K16ac via KAT8.

Alzheimer's disease (AD), the leading cause of age-related dementia, is characterized by abnormal β-amyloid accumulation. During learning, memory formation and consolidation, increased levels of histone H3 and H4 acetylation are observed. The present study reported significantly decreased level of H4K16ac in the plasma of patients with AD compared with healthy subjects via western blotting and reverse transcription-quantitative (RT-q)PCR. Lysine acetyltransferase 8 (KAT8) expression, the major lysine acetyltransferase responsible for the acetylation of H4K16, was significantly decreased in patients with AD compared with healthy subjects as determined via western blotting and RT-qPCR. The results indicated that aberrant expression patterns of H4K16ac and KAT8 might be associated with AD progression. Moreover, western blot analysis demonstrated that KAT8-overexpression cells displayed increased levels of H4K16ac, accompanied by higher levels of neuroprotective soluble amyloid precursor protein (sAPP)α and β-secretase (BACE)2, and decreased levels of sAPPβ and BACE1 compared with negative control and vector cells. In neurodegenerative disorders, microRNAs (miRNAs/miRs) are deregulated; however, the effect of miRNA dysregulation on histone acetylation is not completely understood. To the best of our knowledge, the present study identified a novel inhibitory interaction between miR-149-5p and KAT8 3'-UTR that contributed to the pathological alterations in an AD cell model for the first time, using bioinformatics and a dual-luciferase reporter assay. The western blotting results indicated that, compared with the inhibitor control group, miR-149-5p inhibitor markedly increased H4K16ac levels, which were significantly suppressed by co-transfection with KAT8 short hairpin (sh)RNA. KAT8 shRNA and miR-149-5p inhibitor co-transfection abolished the beneficial effects of miR-149-5p inhibitor. The results indicated that miR-149-5p regulated KAT8 and H4K16ac expression in an AD cell model, which may be associated with the pathological process of AD; therefore, miRNA may serve as a potential drug target for AD.

The Chemokine-like Receptor 1 Deficiency Improves Cognitive Deficits of AD Mice and Attenuates Tau Hyperphosphorylation via Regulating Tau Seeding.

Pathologic features of Alzheimer's disease (AD) include accumulation of amyloid β (Aβ) and hyperphosphorylated tau protein. We have shown previously that the chemokine-like receptor 1 (CMKLR1) is a functional receptor for Aβ, and CMKLR1 contributes to the uptake of Aβ. However, it is unclear whether CMKLR1 ameliorates or aggravates the process of AD. Here, we show that deletion of the gene coding for CMKLR1 significantly increased Aβ deposits in brains of both male and female amyloid β precursor protein/presenilin-1 mice. However, it markedly decreased the mortality of these mice. Behavioral studies found that CMKLR1 deficiency improved cognitive impairment of male and female amyloid β precursor protein/presenilin-1 mice and intracerebroventricular-streptozotocin injection AD mice. We further explored the effect of CMKLR1 on tau pathology. We found that CMKLR1 deficiency or inhibition attenuated the hyperphosphorylation of tau in brains of AD mice in vivo and in the neuronal cells in vitro The expression of CMKLR1 on the neurons affected tau phosphorylation by participating in tau seeding. Together, these results uncover a novel mechanism of CMKLR1 in the pathologic process of AD and suggest that inhibiting the promotion effect of CMKLR1 on tau seeding may provide a new strategy for the treatment of AD.SIGNIFICANCE STATEMENT Evidence suggests that inflammation is involved in the pathologic progression of AD. The chemokine-like receptor 1 (CMKLR1), belonging to the family of GPCRs, is able to bind and uptake amyloid β. We show here, for the first time, that, although CMKLR1 deficiency increased amyloid β deposits in AD mice, it reduced the mortality and improved the cognitive deficits of AD mice. We furthermore show that CMKLR1 deficiency or inhibition attenuated tau hyperphosphorylation in brains of AD model mice in vivo and in neuronal cells in vitro Finally, we first discovered that the expression of CMKLR1 on neurons affected tau phosphorylation by participating in tau seeding. These findings suggest that inhibition of CMKLR1 may provide a new strategy for the treatment of AD.

Discovery of a novel small molecule PT109 with multi-targeted effects against Alzheimer's disease in vitro and in vivo

Alzheimer's disease (AD), which is characterized by impairment of cognitive functions, is a chronic neurodegenerative disease that mainly affects the elderly. Currently available anti-AD drugs can only offer limited symptom-relieving effects. “One-compound-Multitargeted Strategy” have been recognized as the promising way to win the war against AD. Herein we report a potential anti-AD agent PT109 with multi-functions. First, an 81-kinase screening was carried out and results showed that PT109 potently inhibited c-Jun N-terminal kinases and Serum and glucocorticoid-inducible kinase 1, which are the important signaling molecules involved in neurogenesis, neuroprotection and neuroinflammation and mildly inhibit glycogen synthase kinase-3β as well as protein kinase C gamma, both are involved in AD pathological processes. In addition, in vitro studies of immunofluorescent staining and Western blot showed that PT109 might promote the neurogenesis of C17.2 cells and induce synaptogenesis in primary cultured rat hippocampal neurons. We detected and confirmed the neuroprotective effect of PT109 in cultured HT22 cells by MTT assay, dehydrogenase assay, glutathione assay and reactive oxygen species assay. Furthermore, the results of Western blot, ELISA assay and immunofluorescent staining indicated that PT109 attenuated lipopolysaccharide-induced inflammation in BV2 cells and primary astrocytes. The results of Morris water maze and Step-through test indicated that PT109 improved the spatial learning ability in APP/PS1 mice. More importantly, the in vivo pharmacokinetic parameters indicated that PT109 had better medicinal properties. Taken together, our findings suggest that PT109 may be a promising candidate for treating AD through multiple targets although further studies are ought to be conducted.

Astaxanthin Ameliorated Parvalbumin-Positive Neuron Deficits and Alzheimer's Disease-Related Pathological Progression in the Hippocampus of AppNL-G-F/NL-G-F Mice.

Growing evidence suggests that oxidative stress due to amyloid β (Aβ) accumulation is involved in Alzheimer’s disease (AD) through the formation of amyloid plaque, which leads to hyperphosphorylation of tau, microglial activation, and cognitive deficits. The dysfunction or phenotypic loss of parvalbumin (PV)-positive neurons has been implicated in cognitive deficits. Astaxanthin is one of carotenoids and known as a highly potent antioxidant. We hypothesized that astaxanthin’s antioxidant effects may prevent the onset of cognitive deficits in AD by preventing AD pathological processes associated with oxidative stress. In the present study, we investigated the effects of astaxanthin intake on the cognitive and pathological progression of AD in a mouse model of AD. The AppNL-G-F/NL-G-F mice were fed with or without astaxanthin from 5-to-6 weeks old, and cognitive functions were evaluated using a Barnes maze test at 6 months old. PV-positive neurons were investigated in the hippocampus. Aβ42 deposits, accumulation of microglia, and phosphorylated tau (pTau) were immunohistochemically analyzed in the hippocampus. The hippocampal anti-oxidant status was also investigated. The Barnes maze test indicated that astaxanthin significantly ameliorated memory deficits. Astaxanthin reduced Aβ42 deposition and pTau-positive areal fraction, while it increased PV-positive neuron density and microglial accumulation per unit fraction of Aβ42 deposition in the hippocampus. Furthermore, astaxanthin increased total glutathione (GSH) levels, although 4-hydroxy-2,3-trans-nonenal (4-HNE) protein adduct levels (oxidative stress marker) remained high in the astaxanthin supplemented mice. The results indicated that astaxanthin ameliorated memory deficits and significantly reversed AD pathological processes (Aβ42 deposition, pTau formation, GSH decrease, and PV-positive neuronal deficits). The elevated GSH levels and resultant recovery of PV-positive neuron density, as well as microglial activation, may prevent these pathological processes.

The NLRP3 inflammasome as a bridge between neuro-inflammation in metabolic and neurodegenerative diseases.

Evidence increasingly suggests that type 2 diabetes mellitus (T2DM) is a risk factor for neurodegenerative diseases (NDDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD). These diseases share many pathological processes, including oxidative stress, local inflammation/neuroinflammation and chronic, low-grade (systemic) inflammation, which are exacerbated by aging, a common risk factor for T2DM and NDDs. Here, we focus on the link between chronic inflammation driven by peripheral metabolic disease and how this may impact neurodegeneration in AD and PD. We review the relationship between these common pathological processes in AD and PD from the perspective of the "pro-inflammatory" signaling of the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat- (LRR)-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complex. Since the need for effective disease-modifying therapies in T2DM, AD and PD is significant, the relationship between these diseases is important as a positive clinical impact on one may benefit the others. We briefly consider how novel strategies may target neuro-inflammation and provide potential therapies for AD and PD.

Role of monocarboxylate transporter 4 in Alzheimer disease

The pathological process of Alzheimer disease (AD) is closely related to energy metabolism disorders. In the nervous system, monocarboxylate transporter 4 (MCT4) is expressed in the glial cell membrane and is responsible for transporting intracellular lactic acid. In this study, we found that MCT4 expression was elevated in the cerebrospinal fluid of patients with mild cognitive impairment. Two- and three-month-old APPswe/PS1dE9 (APP/PS1) mice and C57 mice were studied. The APP/PS1 mice began to show cognitive decline at 3 months of age and MCT4 in the hippocampus of 2- and 3-month old APP/PS1 mice was higher than that of C57 mice. This change is similar to that in people with mild cognitive impairment. Subsequently, MCT4 overexpression/siRNA lentiviral particles were used to establish stable primary astrocytes. Overexpression and knockdown of MCT4 had no significant effect on glial cell apoptosis. Transfected astrocytes were co-cultured with neurons. Overexpression of cytoplasmic MCT4 increased the expression of Aβ42, γ-secretase, and CD147 in the co-culture system; in addition, the growth ability of primary neurons decreased significantly, extracellular lactic acid increased, and neuronal apoptosis increased. In AD model mice, siMCT4 injection improved cognitive ability, reduced neuronal apoptosis, and reduced γ-secretase expression. Taken together, these results suggest that MCT4 is involved in energy metabolism during early pathological processes in AD, and suppression of MCT4 represents a new potential neuroprotective factor for AD.

Application of in Vivo Fluorescence Imaging and Metal Ion Detection for Investigation of Bis(ethylmaltolato) Oxidovanadium (IV) on Alzheimer's Disease

Alzheimer's disease (AD) is a major type of dementia in the elderly. Clinical medication at present can only relieve symptoms but has no therapeutical effect. Thus, it is urgent to develop an effective drug for the treatment of AD. In this study, 2-month-old triple transgenic AD model mice (3 × Tg-AD) was treated with 0.2 and 1.0 mM bis(ethylmaltolato) oxidovanadium IV (BEOV) in drinking water for 2 months respectively. The results of open field test, elevated plus-maze test and Y maze test showed that BEOV could significantly improve the exploratory ability, memory capacity and exercise ability and relieve the anxiety of 4-month-old 3 × Tg-AD mice. The dendritic spines of pyramidal neuron in neocortex were detected by in vivo two-photon imaging of YFP and AD-YFP mice (the offspring of 3 × Tg-AD and YFP mice). The numbers of dendritic spines increased in YFP mice but decreased in AD-YFP mice from 2.5-month-old to 3.5-month-old. Treatment with BEOV (1.0 mM) in the AD-YFP mice significantly increased the numbers of total dendritic spines, mushroom spines and thin spines, which suggested that BEOV could protect cortical neurons and reduce the loss of dendritic spines. The contents of metal ions in the brain of mice were further measured by inductively coupled plasma mass spectrometry (ICP-MS). The results showed that BEOV (1.0 mM) could significantly increase the contents of V and Se and decrease the contents of Fe, Zn, Hg, Pb, Bi and Ni in AD brains, implying that vanadium might synergize with selenium to regulate the contents of metal ions in AD mice. Summarily, BEOV could mediate the homeostasis of multiple metal ions in AD brain and protect cortical neurons by reducing the loss of dendritic spines, thus to interfere with the pathological process of AD. BEOV could alleviate the anxiety of AD mice and improve their exploratory ability and memory capacity. Pathogenic study revealed that BEOV could regulate the homeostasis of multiple metal ions and inhibit the loss of dendritic spines in the brain of AD mice, thus interfering with the pathological process of AD.

Genomic deletion of TLR2 induces aggravated white matter damage and deteriorated neurobehavioral functions in mouse models of Alzheimer's disease.

Toll-like receptor-2 (TLR2), a member of the TLR family, plays an important role in the initiation and regulation of immune/inflammation response, which is a critical mechanism underlying Alzheimer’s disease (AD). To clarify the role of TLR2 in the pathological process of AD, in the present study, TLR2 knockout plus APPswe/PSEN1dE9 transgenic mice (AD-TLR2KO) were generated. Neurobehavioral tests and brain MRI scan were conducted on mice at the age of 12 months. Additionally, neuron loss was evaluated using NeuN staining. Amyloid β protein (Aβ), glial fibrillary acidic protein (GFAP), endogenous ligands for TLR2, and the activation of downstream signaling of TLR2 in mouse brains were detected by immunohistochemistry and Western blots. The results demonstrated that TLR2 deficit induced learning disabilities, decreased spontaneous activity, increased anxiety and depression, and led to white matter damage (WMD), brain atrophy, loss of neurons, and glial activation. Moreover, TLR2 deficit aggravated impaired neurobehavioral functions and WMD in AD mice, but did not affect the Aβ deposition in mouse brains. Our data indicate that the genomic deletion of TLR2 impairs neurobehavioral functions, induces WMD and brain atrophy, and increases the activation of astrocytes, which in turn aggravate the symptoms of AD through a non-Aβ mechanism.

Oral Immunization with Soybean Storage Protein Containing Amyloid-β 4-10 Prevents Spatial Learning Decline.

Amyloid-β (Aβ) plays a central role in the pathogenesis of Alzheimer’s disease (AD). Because AD pathologies begin two decades before the onset of dementia, prevention of Aβ amyloidosis has been proposed as a mean to block the pathological cascade. Here, we generate a transgenic plant-based vaccine, a soybean storage protein containing Aβ4–10, named Aβ+, for oral Aβ immunization. One mg of Aβ+ or control protein (Aβ–) was administered to TgCRND8 mice once a week from 9 weeks up to 58 weeks. Aβ+ immunization raised both anti-Aβ antibodies and cellular immune responses. Spatial learning decline was prevented in the Aβ+ immunized group in an extended reference memory version of Morris water maze test from 21 to 57 weeks. In Tris-buffered saline (TBS), sodium dodecyl sulfate (SDS), and formic acid (FA) serial extractions, all sets of Aβ species from Aβ monomer, low to high molecular weight Aβ oligomers, and Aβ smears had different solubility in TgCRND8 brains. Aβ oligomers decreased in TBS fractions, corresponding to an increase in high molecular weight Aβ oligomers in SDS extracts and Aβ smears in FA fraction of the Aβ+ treated group. There was significant inhibition of histological Aβ burden, especially in diffuse plaques, and suppression of microglial inflammation. Processing of amyloid-β protein precursor was not different between Aβ+ and Aβ– groups. No evidence of amyloid-related inflammatory angiopathy was observed. Thus, Aβ+ oral immunization could be a promising, cheap, and long-term safe disease-modifying therapy to prevent the pathological process in AD.

Inflammatory mechanisms in neurodegeneration.

This review discusses the profound connection between microglia, neuroinflammation, and Alzheimer's disease (AD). Theories have been postulated, tested, and modified over several decades. The findings have further bolstered the belief that microglia-mediated inflammation is both a product and contributor to AD pathology and progression. Distinct microglia phenotypes and their function, microglial recognition and response to protein aggregates in AD, and the overall role of microglia in AD are areas that have received considerable research attention and yielded significant results. The following article provides a historical perspective of microglia, a detailed discussion of multiple microglia phenotypes including dark microglia, and a review of a number of areas where microglia intersect with AD and other pathological neurological processes. The overall breadth of important discoveries achieved in these areas significantly strengthens the hypothesis that neuroinflammation plays a key role in AD. Future determination of the exact mechanisms by which microglia respond to, and attempt to mitigate, protein aggregation in AD may lead to new therapeutic strategies.

Targeting Inflammatory Pathways in Alzheimer's Disease: A Focus on Natural Products and Phytomedicines.

Studies of the brains of Alzheimer's disease (AD) patients have revealed key neuropathological features, such as the deposition of aggregates of insoluble amyloid-β (Aβ) peptides and neurofibrillary tangles (NFTs). These pathological protein deposits, including Aβ peptides (which form senile plaques) and hyperphosphorylated tau (which aggregates into NFTs), have been assumed to be 'the cause of AD'. Aβ has been extensively targeted to develop an effective disease-modifying therapy, but with limited clinical success. Emerging therapies are also now targeting further pathological processes in AD, including neuroinflammation. This review focuses on the inflammatory and oxidative stress-related changes that occur in AD, and discusses some emerging anti-inflammatory natural products and phytomedicines. Many of the promising compounds are cytokine-suppressive anti-inflammatory drugs (CSAIDs), which target the proinflammatory AP1 and nuclear factor-κB signalling pathways and inhibit the expression of many proinflammatory cytokines, such as interleukin (IL)-1, IL-6, tumour necrosis factor-α, or nitric oxide produced by inducible nitric oxide synthase. However, many of these phytomedicines have not been tested in rigorous clinical trials in AD patients. It is not yet clear if the active compounds reach an effective concentration in the brain (due to limited bioavailability) or if they can slow down AD progression in long-term trials. The authors suggest that it is crucial for both the pharmacological and complementary medicine industries to conduct and fund those studies to significantly advance the field.

Complement C3a receptor antagonist attenuates tau hyperphosphorylation via glycogen synthase kinase 3β signaling pathways

Neurofibrillary tangles aggregated from hyperphosphorylated tau protein are the main pathological feature of Alzheimer's disease (AD). Complement C3 (or C3a) is the core component of the complement system and is associated with AD pathological processes. However, it remains unclear whether C3a or the C3a receptor has any effect on tau phosphorylation. In this study, we found that exposure of SH-SY5Y cells to okadaic acid (OA) decreased cell viabilities and induced tau hyperphosphorylation. These effects were alleviated by C3a receptor antagonist SB290157 and were further validated by C3a receptor siRNA in OA-treated SH-SY5Y cells. In addition, our results demonstrated that SB290157 markedly inhibited the activities of glycogen synthase kinase 3β (GSK3β), but had no effect on protein phosphatase 2A C subunit (PP2Ac) and cyclin-dependent kinases 5 (CDK5). Our findings here indicate the unique role of the C3a receptor in regulating tau phosphorylation via GSK3β signaling pathways and suggest that the C3a receptor may be a viable target for treating AD.

Seeding and Cross-Seeding Aggregations of Aβ40 and Its N-Terminal-Truncated Peptide Aβ11-40.

In the amyloid plaques of Alzheimer's disease (AD) patients, a large number of N-terminal-truncated amyloid β (Aβ) peptides such as Aβ11-40 have been identified in addition to the full-length Aβ peptides. However, little is known about the roles of the N-terminal-truncated peptides in AD pathological process. Herein, seeding and cross-seeding aggregations of Aβ40 and its N-terminal-truncated Aβ11-40 were investigated in the solution and on the surfaces of chips with immobilized seeds by extensive biophysical and biological analyses. The results showed that Aβ40 and Aβ11-40 aggregates could seed both homologous and heterologous aggregations of the two monomers. However, the capability and characteristics of the seeding (homologous aggregation) and cross-seeding (heterologous aggregation) were significantly different. Aβ40 seeds showed stronger acceleration effects on the aggregations than Aβ11-40 seeds and induced β-sheet-rich fibrous aggregates of similar cytotoxicities for the two monomers. This indicates that Aβ40 and Aβ11-40 had similar aggregation pathways in the seeding and cross-seeding on Aβ40 seeds. By contrast, Aβ11-40 seeds led to different aggregation pathways of Aβ40 and Aβ11-40. Pure Aβ11-40 aggregates had higher toxicity than Aβ40 aggregates, and as seeds, Aβ11-40 seeds induced Aβ40 to form aggregates of higher cytotoxicity. However, homologous Aβ11-40 aggregates induced by Aβ11-40 seeds showed lower cytotoxicity than pure Aβ11-40 aggregates. The results suggest that Aβ11-40 plays an important role in the pathological process of AD.

The Combination of Functional and Structural MRI Is a Potential Screening Tool in Alzheimer's Disease.

Introduction: This study aimed to survey the discrimination power of parameters from cerebrospinal fluid (CSF) biomarkers, fluorodeoxyglucose uptake on PET (FDG-PET), structural magnetic resonance imaging (MRI), and functional MRI in high- and low-risk subjects or in converters and stable subjects of normal and mild cognitive impairment (MCI) statuses.Methods: We used baseline resting-state functional MRI (rfMRI) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset to analyze functional networks and recorded subjects’ characteristics and results of the CSF study, FDG-PET, and structural MRI from the ADNI website. All parameters were evaluated based on the between-group difference among normal (NC), MCI, and Alzheimer’s disease (AD) groups. The parameters other than CSF results were included to study the difference between high- and low-AD-risk subjects in NC or MCI groups, based on CSF results. On the basis of two-year follow-up conditions, all parameters were compared between stable subjects and converters in NC and MCI.Results: CSF biomarkers, FDG-PET, structural MRI, and functional MRI are all able to differentiate AD from MCI or NC but not between MCI and NC. As compared with low-AD-risk subjects, high-risk subjects present decreased FDG-PET in both MCI and NC groups but structural MRI change only in MCI status and rfMRI alteration only in NC status. As compared with stable subjects, converters have decreased FDG-PET, functional network changes, and structural changes in both MCI and NC groups.Conclusion: The combination of functional and structural MRI is a safer screening tool but with similar power as FDG-PET to reflect CSF change in the AD pathological process and to identify high-risk subjects and converters in NC and MCI.

Effects of Androgens on the Amyloid-β Protein in Alzheimer's Disease.

Age-related androgen depletion has been implicated in compromised neuroprotection and is involved in the pathogenesis of neurodegenerative disease, including Alzheimer's disease (AD), the leading cause of dementia. Emerging data revealed that reduction of both serum and brain androgen levels in males is associated with increased amyloid-β (Aβ) accumulation, a putative cause of AD. It has been demonstrated that androgens can function as the endogenous negative regulators of Aβ. However, the mechanisms by which androgens regulate Aβ production, degradation, and clearance, as well as the Aβ-induced pathological process in AD, are still elusive. This review emphasizes the contributions of androgen to Aβ metabolism and toxicity in AD and thus may provide novel strategies for prevention and therapeutics.

Streptocyclinones A and B ameliorate Alzheimer's disease pathological processes in vitro

Alzheimer's disease (AD) is a pathology characterized by the abnormal accumulation of amyloid-beta (Aβ) and hyperphosphorylated tau. Oxidative stress and neuroinflammation are also strongly related to this disease. The ability of two new glycosylated angucyclinones, streptocyclinones A and B (1 and 2), isolated from Streptomyces sp to improve AD hallmarks was evaluated. Compounds were able to protect SH-SY5Y neuroblastoma cells from H2O2-induced oxidative injury by activating the nuclear factor E2-related factor (Nrf2). Their capacity to modulate neuroinflammation was tested in lipopolysaccharide-activated BV2 microglial cells. Compounds reduced the release of pro-inflammatory factors, inhibited the activation of NFκB and mitogen activated kinases (MAPK), and induced the translocation of Nrf2 to the nucleus of microglial cells. A trans-well co-culture was established to determine the effect of microglia treated with streptocyclinones on the survival of SH-SY5Y cells. The cell viability of neuroblastoma cells increased when the compounds were added to BV2 cells. SH-SY5Y-TMHT441 cells were used to determine the effect of compounds on tau phosphorylation. Both compounds reduced tau hyperphophorylation by targeting MAPK kinases. Moreover, streptocyclinone B (2) was able to inhibit the activity of β-secretase 1 and decrease the release of reactive oxygen species in BV2 cells stimulated with Aβ. With the same co-culture trans-well system, the treatment of Aβ-stimulated microglia with compound 2 augmented the viability of SH-SY5Y-TMHT441 cells. The results presented in this work provide evidences of the multitarget activities displayed by these new Streptomyces compounds, making them good candidates for further studies in the treatment of AD.

Differential Hyperphosphorylation of Tau-S199, -T231 and -S396 in Organotypic Brain Slices of Alzheimer Mice. A Model to Study Early Tau Hyperphosphorylation Using Okadaic Acid.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the brain, characterized by extracellular aggregation of beta-amyloid (Aβ) and hyperphosphorylation of tau causing intraneuronal neurofibrillary tangles (NFTs). There is urgent need to study the interactions between Aβ and tau, especially to solve the question of the pathological cascade. In the present study, we aim to develop a model of organotypic brain slices in which both plaque and tau pathology can be examined. Organotypic brain slices (150 μm thick, coronal, at the hippocampal level) from adult (9 month) wildtype (WT, C57BL/6N) and transgenic AD mice (TG, APP_SweDI) were cultured for 2 weeks. To induce tau hyperphosphorylation 100 nM okadaic acid (OA), 10 μM wortmannin (WM) or both were added to the slices. Hyperphosphorylation of tau was tested at tau-S199, tau-T231 and tau-S396 using Western blot. Our data show that in TG mice with plaques a 50 kDa fragment of tau-S396 was hyperphosphorylated and that OA induced hyperphosphorylation of tau-S199. In WT mice (without plaques) OA caused hyperphosphorylation of a 50 kDa and a 38 kDa tau-T231 form and a 25 kDa sdftau-S396 fragment. The N-methyl-D-aspartate (NMDA) antagonist MK801 (1 μM) did not block these effects. Immunohistochemistry showed diffuse increased tau-S396 and tau-T231-like immunoreactivities at the hippocampal level but no formation of NFTs. Confocal microscopy indicated, that pTau-T231 was preferentially located in cytoplasma surrounding nuclei whereas pTau-S396 was found mainly in nerve fibers and strongly associated with plaques. In conclusion we provide a novel in vitro model to study both plaque and tau hyperphosphorylation but not NFTs, which could be useful to study pathological processes in AD and to screen for drugs.

Melatonin protects against Aβ-induced neurotoxicity in primary neurons via miR-132/PTEN/AKT/FOXO3a pathway.

Alzheimer's disease (AD) is a kind of neurodegenerative disorder associated with age. Investigations suggest that amyliod-β (Aβ) is implicated in the pathogenesis of AD. The accumulation of Aβ in the brain causes oxidative stress and synaptic toxicity, leads to synaptic dysfunction and neuronal death. Previous investigations suggest that melatonin an endogenous hormone can counteract Aβ-induced neurotoxicity. However, the molecular mechanisms of Aβ-induced toxicity and melatonin treatment remain elusive. Studies indicate that microRNA-132 is crucial for neuronal survival and plays a key role in the pathological process of AD. Moreover, PTEN and FOXO3a two key targets of miR-132 are upregulated in the AD brain. Here, we exposed the primary cultured cortical neurons with Aβ25-35 and treated with melatonin. Our investigations demonstrated that Aβ25-35 exposure significantly decreased the expression of miR-132 and elevated the expression of PTEN and FOXO3a. Whereas, melatonin treatment could rescue the expression of miR-132 and downregulate the level of PTEN and FOXO3a. Moreover, melatonin blocked the nuclear translocation of FOXO3a and thereby suppressed its pro-apoptotic pathways. In addition, our investigations suggested that the over-expression of miR-132 could block Aβ-induced neurotoxicity. We also found that VO-OHpic (PTEN inhibitor) could counteract Aβ-induced neuronal damage, and LY294002 (AKT inhibitor) suppressed the protective effect of melatonin. Together, these results indicate that melatonin exerts its neuroprotective effect in Aβ-induced neurotoxicity via miR-132/PTEN/AKT/FOXO3a pathway. © 2018 BioFactors, 44(6):609-618, 2018.