Inflammation In Alzheimer's Disease Research Articles

Genetics ignite focus on microglial inflammation in Alzheimer's disease.

In the past five years, a series of large-scale genetic studies have revealed novel risk factors for Alzheimer’s disease (AD). Analyses of these risk factors have focused attention upon the role of immune processes in AD, specifically microglial function. In this review, we discuss interpretation of genetic studies. We then focus upon six genes implicated by AD genetics that impact microglial function: TREM2, CD33, CR1, ABCA7, SHIP1, and APOE. We review the literature regarding the biological functions of these six proteins and their putative role in AD pathogenesis. We then present a model for how these factors may interact to modulate microglial function in AD.

Molecular imaging of neuroinflammation in Alzheimer’s disease

Neuroinflammatory changes are observed in the brain of patients with Alzheimer’s disease (AD). Studies have shown the presence of activated microglia and astrocytes surrounding the amyloid plaques, along with the presence of cytokines and other mediators of inflammation. The role of inflammation in AD is not yet completely understood. More specifically, some inflammatory processes, such as the activation of microglia, may have detrimental or beneficial effects on the underlining neuropathology, by promoting inflammation and tissue damage or rather phagocytic activity and tissue repair. Imaging of neuroinflammation with positron emission tomography (PET) is the only technology that enables the visualization of microglia and astrocyte activation in the living human brain. PET studies with first- or second-generation radioligands binding to the 18-kDa translocator protein (TSPO) ([11C]-R-PK11195, [11C]DAA1106, [11C]PBR28, [18F]FEMPA, [18F]FEPPA) have shown some conflicting results, demonstrating on average a ~30 % higher TSPO availability in AD patients compared with controls, with a few studies showing no statistically significant difference between the two groups. Similar conflicting evidences have been shown when comparing subjects with mild cognitive impairment (MCI) and control subjects. Therefore, whether TSPO is a good marker for detecting in vivo microglia activation in AD is still a matter of debate. Imaging of MAO-B as a marker for astrocyte activation in AD is a valid alternative to TSPO imaging in the context of neuroinflammation. Only limited MAO-B imaging studies with [11C]l-deprenyl-D2 are available so far in AD and MCI, showing increased MAO-B binding in MCI patients compared with controls with a degree higher than that observed in AD. There are two unmet questions that are still under discussion. The first question is which neuroinflammatory process, microglia or astrocyte activation, occurs earlier in the natural course of AD from prodromal to dementia stage? Comparative studies using these two markers in MCI and AD could be important to clarify which marker can be used for earliest detection of neuroinflammatory changes in vivo. The second question is whether imaging of microglia or astrocytes per se is a useful marker of neuroinflammation associated with neurodegeneration. The development of new radioligands for other targets that are more directly associated with the pro- or anti-inflammatory activity of microglia could help in understanding the relevance of neuroinflammation in the pathological processes leading to neurodegeneration in AD. Molecular imaging with PET can be a useful tool to determine the nature and temporal evolution of inflammation in early stages of AD in relation to other pathological markers, such as deposition of amyloid plaques and tau as well as clinical presentation of the disease.

Increased Acetylation of Histone H4 at Lysine 12 (H4K12) in Monocytes of Transgenic Alzheimer’s Mice and in Human Patients

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-β (Aβ) plaque formation, tau pathology, neurodegeneration and inflammatory processes. Monocytes are involved in inflammation in AD and are recruited to the diseased brain. Recently it has been shown that aberrant epigenetic processes including acetylation are associated with the development of AD. The aim of the present study was to examine acetylation of histone H4 at lysine 12 (H4K12) in monocytes in two transgenic AD mouse models (the triple transgenic 3xTg and a model overexpressing amyloid-precursor protein APP with the Swedish-Dutch-Iowa mutations), and to compare with monocytes isolated from human patients with mild cognitive impairment (MCI) and AD. Mouse and human monocytes were selectively isolated with a positive (PluriSelect) respectively with a negative selection method (Miltenyi). Histones were extracted and acetylation of H4K12 was analyzed by a quantification fluorometric kit. Moreover, monocyte cytokine release was measured and cell death analyzed by FACS using incorporation of 7-AAD. Our data show a significant increase of monocytic H4K12 acetylation in both transgenic AD mouse models early during development of the plaque deposition in the brain. In line with these data we found significantly elevated acetylation of H4K12 in human patients with MCI but not in patients with AD. Further we observed that the monocytes of AD mice and of AD patients were significantly more vulnerable to cell damage (as seen by 7-AAD incorporation in FACS analysis) and displayed an enhanced release of pro-inflammatory cytokines (MIP2 and TNFα). Our findings indicate that epigenetic changes in peripheral monocytes are an early event in AD-pathology. Thus H4K12 acetylation may be considered as a novel biomarker for early changes in AD development.

The Role of Inflammatory Mediators in the Pathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD), a neurodegenerative disorder associated with advanced age, is the most common cause of dementia globally. AD is characterised by cognitive dysfunction, deposition of amyloid plaques, neurofibrillary tangles and neuro-inflammation. Inflammation of the brain is a key pathological hallmark of AD. Thus, clinical and immunopathological evidence of AD could be potentially supported by inflammatory mediators, including cytokines, chemokines, the complement system, acute phase proteins and oxidative mediators. In particular, oxidative mediators may actively contribute to the progression of AD and on-going inflammation in the brain. This review provides an overview of the functions and activities of inflammatory mediators in AD. An improved understanding of inflammatory processes and their role in AD is needed to improve therapeutic research aims in the field of AD and similar diseases.

Involvement of inflammation in Alzheimer's disease pathogenesis and therapeutic potential of anti-inflammatory agents.

Alzheimer's disease (AD) is the most common form of dementia. It is characterized by beta-amyloid (Aβ) peptide fibrils, which are extracellular depositions of a specific protein, and is accompanied by extensive neuroinflammation. Various studies have demonstrated risk factors that can affect AD pathogenesis, and they include accumulation of Aβ, hyperphosphorylation of tau protein, and neuroinflammation. Among these detrimental factors, neuroinflammation has been highlighted by epidemiologic studies suggesting that use of anti-inflammatory drugs could significantly reduce the incidence of AD. Evidence suggests that astrocytes, microglia, and infiltrating immune cells from periphery might contribute to or modify the process of neuroinflammation and neurodegeneration in AD brains. In addition, recent data indicate that microRNAs may affect neuroinflammatory responses in the brain. This article focuses on supportive evidence that neuroinflammation plays a critical role in AD development. In addition, we depict putative therapeutic capacity of anti-inflammatory drugs for AD prevention or treatment. We also discuss pathogenic mechanisms by which astrocytes, microglia, T cells and microRNA participate in AD and the neuroprotective mechanisms of anti-inflammatory drugs.

Inflammation in Alzheimer's Disease and Molecular Genetics: Recent Update.

Alzheimer's disease (AD) is a complex age-related neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease. After three decades of genetic study in AD, dozens of loci harboring genetic variants influencing inflammatory pathways in AD patients has been identified through genome-wide association studies (GWAS). The most well-known GWAS risk factor that is responsible for immune response and inflammation in AD development should be APOE ε4 allele. However, a growing number of other GWAS risk AD candidate genes in inflammation have recently been discovered. In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2.

Oxidized cholesterol as the driving force behind the development of Alzheimer's disease.

Alzheimer’s disease (AD), the most common neurodegenerative disorder associated with dementia, is typified by the pathological accumulation of amyloid Aβ peptides and neurofibrillary tangles (NFT) within the brain. Considerable evidence indicates that many events contribute to AD progression, including oxidative stress, inflammation, and altered cholesterol metabolism. The brain’s high lipid content makes it particularly vulnerable to oxidative species, with the consequent enhancement of lipid peroxidation and cholesterol oxidation, and the subsequent formation of end products, mainly 4-hydroxynonenal and oxysterols, respectively from the two processes. The chronic inflammatory events observed in the AD brain include activation of microglia and astrocytes, together with enhancement of inflammatory molecule and free radical release. Along with glial cells, neurons themselves have been found to contribute to neuroinflammation in the AD brain, by serving as sources of inflammatory mediators. Oxidative stress is intimately associated with neuroinflammation, and a vicious circle has been found to connect oxidative stress and inflammation in AD. Alongside oxidative stress and inflammation, altered cholesterol metabolism and hypercholesterolemia also significantly contribute to neuronal damage and to progression of AD. Increasing evidence is now consolidating the hypothesis that oxidized cholesterol is the driving force behind the development of AD, and that oxysterols are the link connecting the disease to altered cholesterol metabolism in the brain and hypercholesterolemia; this is because of the ability of oxysterols, unlike cholesterol, to cross the blood brain barrier (BBB). The key role of oxysterols in AD pathogenesis has been strongly supported by research pointing to their involvement in modulating neuroinflammation, Aβ accumulation, and cell death. This review highlights the key role played by cholesterol and oxysterols in the brain in AD pathogenesis.

Computational identification of potential multi-drug combinations for reduction of microglial inflammation in Alzheimer disease.

Like other neurodegenerative diseases, Alzheimer Disease (AD) has a prominent inflammatory component mediated by brain microglia. Reducing microglial inflammation could potentially halt or at least slow the neurodegenerative process. A major challenge in the development of treatments targeting brain inflammation is the sheer complexity of the molecular mechanisms that determine whether microglia become inflammatory or take on a more neuroprotective phenotype. The process is highly multifactorial, raising the possibility that a multi-target/multi-drug strategy could be more effective than conventional monotherapy. This study takes a computational approach in finding combinations of approved drugs that are potentially more effective than single drugs in reducing microglial inflammation in AD. This novel approach exploits the distinct advantages of two different computer programming languages, one imperative and the other declarative. Existing programs written in both languages implement the same model of microglial behavior, and the input/output relationships of both programs agree with each other and with data on microglia over an extensive test battery. Here the imperative program is used efficiently to screen the model for the most efficacious combinations of 10 drugs, while the declarative program is used to analyze in detail the mechanisms of action of the most efficacious combinations. Of the 1024 possible drug combinations, the simulated screen identifies only 7 that are able to move simulated microglia at least 50% of the way from a neurotoxic to a neuroprotective phenotype. Subsequent analysis shows that of the 7 most efficacious combinations, 2 stand out as superior both in strength and reliability. The model offers many experimentally testable and therapeutically relevant predictions concerning effective drug combinations and their mechanisms of action.

Immune attack: the role of inflammation in Alzheimer disease.

The past two decades of research into the pathogenesis of Alzheimer disease (AD) have been driven largely by the amyloid hypothesis; the neuroinflammation that is associated with AD has been assumed to be merely a response to pathophysiological events. However, new data from preclinical and clinical studies have established that immune system-mediated actions in fact contribute to and drive AD pathogenesis. These insights have suggested both novel and well-defined potential therapeutic targets for AD, including microglia and several cytokines. In addition, as inflammation in AD primarily concerns the innate immune system - unlike in 'typical' neuroinflammatory diseases such as multiple sclerosis and encephalitides - the concept of neuroinflammation in AD may need refinement.

Evaluation of inflammation-related genes polymorphisms in Mexican with Alzheimer's disease: a pilot study.

Amyloid peptide is able to promote the activation of microglia and astrocytes in Alzheimer’s disease (AD), and this stimulates the production of pro-inflammatory cytokines. Inflammation contributes to the process of neurodegeneration and therefore is a key factor in the development of AD. Some of the most important proteins involved in AD inflammation are: clusterin (CLU), complement receptor 1 (CR1), C reactive protein (CRP), tumor necrosis factor α (TNF-α), the interleukins 1α (IL-1α), 6 (IL-6), 10 (IL-10) and cyclooxygenase 2 (COX-2). In particular, COX-2 is encoded by the prostaglandin-endoperoxide synthase 2 gene (PTGS2). Since variations in the genes that encode these proteins may modify gene expression or function, it is important to investigate whether these variations may change the developing AD. The aim of this study was to determine whether the presence of polymorphisms in the genes encoding the aforementioned proteins is associated in Mexican patients with AD. Fourteen polymorphisms were genotyped in 96 subjects with AD and 100 controls; the differences in allele, genotype and haplotype frequencies were analyzed. Additionally, an ancestry analysis was conducted to exclude differences in genetic ancestry among groups as a confounding factor in the study. Significant differences in frequencies between AD and controls were found for the single-nucleotide polymorphism (SNP) rs20417 within the PTGS2 gene. Ancestry analysis revealed no significant differences in the ancestry of the compared groups, and the association was significant even after adjustment for ancestry and correction for multiple testing, which strengthens the validity of the results. We conclude that this polymorphism plays an important role in the development of the AD pathology and further studies are required, including their proteins.

Activation of the factor XII-driven contact system in Alzheimer’s disease patient and mouse model plasma

Alzheimer's disease (AD) is characterized by accumulation of the β-amyloid peptide (Aβ), which likely contributes to disease via multiple mechanisms. Increasing evidence implicates inflammation in AD, the origins of which are not completely understood. We investigated whether circulating Aβ could initiate inflammation in AD via the plasma contact activation system. This proteolytic cascade is triggered by the activation of the plasma protein factor XII (FXII) and leads to kallikrein-mediated cleavage of high molecular-weight kininogen (HK) and release of proinflammatory bradykinin. Aβ has been shown to promote FXII-dependent cleavage of HK in vitro. In addition, increased cleavage of HK has been found in the cerebrospinal fluid of patients with AD. Here, we show increased activation of FXII, kallikrein activity, and HK cleavage in AD patient plasma. Increased contact system activation is also observed in AD mouse model plasma and in plasma from wild-type mice i.v. injected with Aβ42. Our results demonstrate that Aβ42-mediated contact system activation can occur in the AD circulation and suggest new pathogenic mechanisms, diagnostic tests, and therapies for AD.

Metabolomic research on the role of interleukin-4 in Alzheimer’s disease

Inflammation plays a prominent role in the pathogenesis of Alzheimer’s disease, affecting both brain and the peripheral system. Thus, modulation of inflammation in animal models of this neurodegenerative disorder may be of great interest to elucidate the pathological mechanisms underlying this inflammatory component. To this end, a metabolomic investigation on a triple transgenic mouse model obtained by crossing the APP/PS1 mice with interleukin-4 knockout mice (a model of impaired immune function) was performed for the first time. Serum samples from transgenic mice and wild type animals were analyzed by direct infusion mass spectrometry followed by multivariate statistics in order to identify altered metabolites. Subsequently, metabolic pathway analysis allowed the elucidation of potential pathological mechanisms associated with the development of Alzheimer-type disorders in response to interleukin-4 deficiency, such as impaired homeostasis of histamine, altered metabolism of amino acids (threonine, aspartate and tyrosine), deregulated urea cycle and increased production of eicosanoids. Therefore, this work demonstrates the potential of this triple transgenic model with modulated immunity for the study of pathological mechanisms associated with inflammation in Alzheimer’s disease.

Alzheimer's Disease: Exploring the Role of Inflammation and Implications for Treatment.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by both structural abnormalities and inflammation in the brain. While recent research has chiefly focused on the structural changes involved in AD, understanding the pathophysiology and associated inflammation of the AD brain helps to elucidate potential therapeutic and preventative options. By exploring the data supporting an inflammatory etiology of AD, we present a case for the use of existing evidence-based treatments addressing inflammation as promising options for treating and preventing AD. We present data demonstrating tumor necrosis factor alpha association with the inflammation of AD. We also discuss data supporting TNF alpha associated inflammation in traumatic brain injury, stroke, and spinal disc associated radiculopathy. We augment this previously unarticulated concept of a unifying pathophysiology of central nervous system disease, with reports of benefits of TNF alpha inhibition in many hundreds of patients with those diseases, including AD. We also assess the pathophysiologic and clinical trial evidence supporting the role of other inflammation resolving treatments in AD. In aggregate, the data from the several potentially effective therapeutic and preventative options contained within this report presents a clearer picture of next steps needed in research of treatment alternatives.

Preclinical Evaluation of miR-15/107 Family Members as Multifactorial Drug Targets for Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial, fatal neurodegenerative disorder characterized by the abnormal accumulation of Aβ and Tau deposits in the brain. There is no cure for AD, and failure at different clinical trials emphasizes the need for new treatments. In recent years, significant progress has been made toward the development of miRNA-based therapeutics for human disorders. This study was designed to evaluate the efficiency and potential safety of miRNA replacement therapy in AD, using miR-15/107 paralogues as candidate drug targets. We identified miR-16 as a potent inhibitor of amyloid precursor protein (APP) and BACE1 expression, Aβ peptide production, and Tau phosphorylation in cells. Brain delivery of miR-16 mimics in mice resulted in a reduction of AD-related genes APP, BACE1, and Tau in a region-dependent manner. We further identified Nicastrin, a γ-secretase component involved in Aβ generation, as a target of miR-16. Proteomics analysis identified a number of additional putative miR-16 targets in vivo, including α-Synuclein and Transferrin receptor 1. Top-ranking biological networks associated with miR-16 delivery included AD and oxidative stress. Collectively, our data suggest that miR-16 is a good candidate for future drug development by targeting simultaneously endogenous regulators of AD biomarkers (i.e., Aβ and Tau), inflammation, and oxidative stress.

Oligomeric Amyloid-β Peptide on Sialylic Lewisx-Selectin Bonding at Cerebral Endothelial Surface.

IntroductionAlzheimer’s disease (AD) is a chronic neurodegenerative disorder, which affects approximately 10% of the population aged 65 and 40% of people over the age 80. Currently, AD is on the list of diseases with no effective treatment. Thus, the study of molecular and cellular mechanisms of AD progression is of high scientific and practical importance. In fact, dysfunction of the blood-brain barrier (BBB) plays an important role in the onset and progression of the disease. Increased deposition of amyloid b peptide (Aβ) in cerebral vasculature and enhanced transmigration of monocytes across the BBB are frequently observed in AD brains and are some of the pathological hallmarks of the diseases. Since the transmigration of monocytes across the BBB is both a mechanical and a biochemical process, the expression of adhesion molecules and mechanical properties of endothelial cells are the critical factors that require investigation.MethodsBecause of recent advances in the biological applications of atomic force microscopy (AFM), we applied AFM with cantilever tips bio-functionalized by sLex in combination with the advanced immunofluorescent microscopy (QIM) to study the direct effects of Aβ42 oligomers on the selectins expression, actin polymerization, and cellular mechanical and adhesion properties in cerebral endothelial cells (mouse bEnd3 line and primary human CECs) and find a possible way to attenuate these effects.ResultsQIM results showed that Aβ42 increased the expressions of P-selectin on the cell surface and enhanced actin polymerization. Consistent with our QIM results, AFM data showed that Aβ42 increased the probability of cell adhesion with sLex-coated cantilever and cell stiffness. These effects were counteracted by lovstatin, a cholesterol-lowering drug. Surprisingly, the apparent rupture force of sLex-selectin bonding was significantly lower after treatment with Aβ42, as compared with the control (i.e. no treatment). Similar results were also obtained when cells were treated with latruculin A (F-actin-disrupting drug). These results suggest that the decrease in the apparent rupture force of sLex-selectin bonding is the consequence of the dissociation of adhesion between the cytoskeleton and the bilayer membrane induced by Aβ42. The major causes of excess mortality in the first group were neoplams (30.6%), hypertension (23.8%), and myocardial infarction (22.6%). The effects of radiation influenced mortality in the second group were 2–2.5 times lower than the first group.ConclusionThe studies of the effects of Aβ42 on the adhesion properties of cerebral endothelial cells and how pharmacological agents (e.g. statin) counteract these effects should prove to provide insights into the mechanism of inflammation in Alzheimer’s brains and the design of therapeutic treatments of the disease.

The CCAAT/enhancer-binding protein delta/miR135a/thrombospondin 1 axis mediates PGE2-induced angiogenesis in Alzheimer's disease

In Alzheimer's disease (AD), large populations of endothelial cells undergo angiogenesis due to brain hypoxia and inflammation. Substantial evidence from epidemiologic, pathologic, and clinical reports suggests that vascular factors are critical for the pathogenesis of AD. However, the precise mechanistic correlation between inflammation and angiogenesis in AD has not been well elucidated. Prostaglandin E2 (PGE2), a key factor of the inflammatory response, has been known to promote angiogenesis. In this study, we demonstrated that PGE2 acts through EP4 receptor and protein kinase A to modulate CCAAT/enhancer-binding protein delta (CEBPD) abundance in astrocytes. Attenuated vessel formation was observed in the brains of AppTg/Cebpd−/− mice. We showed that miR135a was responsive to the induction of CEBPD and further negatively regulated thrombospondin 1 (THBS1) transcription by directly targeting its 3′-untranslated region (3′UTR) in astrocytes. Furthermore, conditioned media from astrocytes expressing miR135a promoted Human umbilical vein endothelial cells (HUVECs) tube-like formation, which correlated with the effects of PGE2 on angiogenesis. Our results indicated that CEBPD contributes to the repression of THBS1 transcription by activating the expression of miR135a in astrocytes following PGE2 treatment. We provided new evidence that astrocytic CEBPD increases angiogenesis during AD pathogenesis. This discovery supports the negative influence of CEBPD activation in astrocytes with respect to AD pathogenesis and implies that the CEBPD/miR135a/THBS1 axis could be a therapeutic target of AD.

Bioenergetic dysfunction and inflammation in Alzheimer's disease: a possible connection.

Inflammation is observed in Alzheimer’s disease (AD) subject brains. Inflammation-relevant genes are increasingly implicated in AD genetic studies, and inflammatory cytokines to some extent even function as peripheral biomarkers. What underlies AD inflammation is unclear, but no “foreign” agent has been implicated. This suggests that internally produced damage-associated molecular pattern (DAMPs) molecules may drive inflammation in AD. A more complete characterization and understanding of AD-relevant DAMPs could advance our understanding of AD and suggest novel therapeutic strategies. In this review, we consider the possibility that mitochondria, intracellular organelles that resemble bacteria in many ways, trigger and maintain chronic inflammation in AD subjects. Data supporting the possible nexus between AD-associated bioenergetic dysfunction are discussed.

Amyloid-beta-activated human microglial cells through ER-resident proteins.

Microglial activation in the central nervous system is a key event in the neuroinflammation that accompanies neurodegenerative diseases such as Alzheimer's disease (AD). Among cytokines involved in microglial activation, amyloid β (Aβ) peptide is known to be a key molecule in the induction of diverse inflammatory products, which may lead to chronic inflammation in AD. However, proteomic studies of microglia in AD are limited due to lack of proper cell or animal model systems. In this study, we performed a proteomic analysis of Aβ-stimulated human microglial cells using SILAC (stable isotope labeling with amino acids in cell culture) combined with LC-MS/MS. Results showed that 60 proteins increased or decreased their abundance by 1.5 fold or greater. Among these, ER-resident proteins such as SERPINH1, PDIA6, PDIA3, and PPIB were revealed to be key molecular biomarkers of human microglial activation by validation of the proteomic results by immunostaining, PCR, ELISA, and Western blot. Taken together, our data suggest that ER proteins play an essential role in human microglial activation by Aβ and may be important molecular therapeutic targets for treatment of AD.

Natural compounds and plant extracts as therapeutics against chronic inflammation in Alzheimer's disease--a translational perspective.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by deposition of amyloid beta, neurofibrillary tangles, astrogliosis and microgliosis, leading to neuronal dysfunction and loss in the brain. Bio- and histochemical evidence suggests a pivotal role of central and peripheral inflammation in its aetiopathology, linked to the production of free radicals. Numerous epidemiological studies support that the long-term use of non-steroidal antiinflammatory drugs is preventive against AD, but these medications do not slow down the progression of the disease in already diagnosed patients. There are a number of studies focusing on traditional herbal medicines and small molecules (usually plant secondary metabolites) as potential anti-inflammatory drugs, particulary in respect to cytokine suppression. For instance, ω-3 polyunsaturated fatty acids and a number of polyphenolic phytochemicals have been shown to be effective against inflammation in animal and cell models. Some of these plant secondary metabolites have also been shown to possess antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects. This review will provide an overview the effects of catechins/proanthocyanidins from green tea, curcumin from turmeric, extracts enriched in bacosides from Brahmi (Bacopa monnieri), flavone glycosides from Ginkgo biloba, and ω-3 polyunsaturated fatty acids. They do not only counteract one pathophysiological aspect of AD in numerous in vitro and in vivo studies of models of AD, but also ameliorate several of the above mentioned pathologies. The evidence suggests that increased consumption of these compounds might lead to a safe strategy to delay the onset of AD. The continuing investigation of the potential of these substances is necessary as they are promising to yield a possible remedy for this pervasive disease.

Astrocytes and neuroinflammation in Alzheimer's disease.

Increased production of amyloid β-peptide (Aβ) and altered processing of tau in Alzheimer's disease (AD) are associated with synaptic dysfunction, neuronal death and cognitive and behavioural deficits. Neuroinflammation is also a prominent feature of AD brain and considerable evidence indicates that inflammatory events play a significant role in modulating the progression of AD. The role of microglia in AD inflammation has long been acknowledged. Substantial evidence now demonstrates that astrocyte-mediated inflammatory responses also influence pathology development, synapse health and neurodegeneration in AD. Several anti-inflammatory therapies targeting astrocytes show significant benefit in models of disease, particularly with respect to tau-associated neurodegeneration. However, the effectiveness of these approaches is complex, since modulating inflammatory pathways often has opposing effects on the development of tau and amyloid pathology, and is dependent on the precise phenotype and activities of astrocytes in different cellular environments. An increased understanding of interactions between astrocytes and neurons under different conditions is required for the development of safe and effective astrocyte-based therapies for AD and related neurodegenerative diseases.