Beta-amyloid Production Research Articles

Behavioral Improvements and its Molecular Mechanism of Ilex kudingcha C.J. Tseng on Animal Model of Alzheimer’s Disease

Alzheimer's disease (AD) is a common chronic neurodegenerative disease with well-defined pathophysiological mechanisms. Ilex kudingcha (IK) C.J. Tseng is commonly known as bitter tea or “Khom” tea in Vietnam. The present study was conducted to investigate the anti-dementia effect of IK using olfactory bulbectomized (OBX) mice. OBX mice were daily treated with IK extract (540 mg/kg) or reference drug, tacrine (2.5 mg/kg) 1 week before and continuously for 3 days after the OBX surgery. The object recognition test, modified Y maze test and fear conditioning test were employed to analyze non-spatial short-term, spatial short-term and long-term memories of the mice respectively. Administration of IK extract and tacrine attenuated these OBX-induced cognitive deficits in mice. The effects of IK and tacrine on spatial short-term memory impairment were reversed by scopolamine, a muscarinic receptor antagonist. The amyloid-beta (Aβ) production in adult transgenic Drosophila brain flies was also investigated by using Western blotting with APP-HA antibody. These results indicated that IK extract improves short-term and long-term memory disturbances in OBX mice and that muscarinic receptor may play a role on these actions. In addition, our result also showed that IK extract reduces the expression of amyloid precursor protein (APP) in brain of AD model using Drosophila melanogaster.

Sirtuin 1-dependent regulation of high mobility box 1 in hypoxia\u2013reoxygenated brain microvascular endothelial cells: roles in neuronal amyloidogenesis

Hypoxia–reperfusion injury is one of the major risk factors for neurodegeneration. However, it is unclear whether ischaemic damage in brain microvascular endothelial cells plays roles in neurodegeneration, particularly in the amyloidogenic changes contributing to the development of Alzheimer’s disease (AD) pathologies. Therefore, we investigated the roles of hypoxia–reoxygenation (H/R)-induced release of high mobility group box protein 1 (HMGB1), a risk molecule for AD pathogenesis in the ischaemic damaged brain, from human brain microvascular endothelial cells (HBMVECs) in neuronal amyloid-beta (Aβ) production. H/R increased nuclear–cytosolic translocation and secretion of HMGB1 in HBMVECs, along with increased permeability and HMGB1-dependent p-c-Jun activation. In addition, H/R increased the expression of Sirtuin 1 (Sirt1), coincident with an increase of intracellular Sirt1–HMGB1 binding in HBMVECs. H/R increased the acetylation of HMGB1 and extracellular secretion, which was significantly inhibited by Sirt1 overexpression. Furthermore, Sirt1 contributed to autophagy-mediated endogenous HMGB1 degradation. More importantly, treatment of neuronal cells with conditioned medium from H/R-stimulated HBMVECs (H/R-CM) activated their amyloidogenic pathways. The neuronal amyloidogenic changes (i.e. increased levels of extracellular Aβ40 and Aβ42) by H/R-CM from HBMVECs were further increased by Sirt1 inhibition, which was significantly suppressed by neutralization of the HMGB1 in H/R-CM. Collectively, our results suggest that HMGB1 derived from H/R-stimulated HBMVECs contributes to amyloidogenic pathways in neurons playing roles in the pathogenesis of AD, which are regulated by endothelial Sirt1.

Astrocyte cholesterol is essential for amyloid beta production

AbstractBackgroundSeveral variants of genes involved in cholesterol metabolism are risk factors for the development of Alzheimer’s disease (AD). We disrupted the master regulator of cellular cholesterol metabolism, SREBP2, and assessed the impacts of this disruption in neuron‐glia primary cell co‐cultures and in the 3xTg mouse model of AD.MethodGlial SREBP2 ablation was induced in neuron‐glia cultures by treatment of Aldh1l1‐CREERT2xSREBP2flox mixed primary cell cultures with 4OH tamoxifen. Amyloid precursor protein (APP) trafficking to lipid raft domains was quantified by dSTORM imaging. SREBP2 was ablated in the brains of 3xTg AD mice by crossing to an SREBP2‐flox and then a GFAP‐CRE. Aged (40 week old) mouse brains were then assessed for Aβ and pTau burden by ELISA.ResultDisruption of glial SREBP2 was sufficient to significantly alter localization of APP from α‐secretase rich disordered membrane regions to β‐ and γ‐secretase enriched lipid raft domains (Figure A). In 3xTg‐AD animals, SREBP2 ablation did not alter total levels of APP or Tau, but significantly reduced both Aβ 1‐42 peptide burden and P‐T181 Tau abundance in 40‐week hippocampus (Figure B).ConclusionDisruption of astrocyte‐mediated cholesterol metabolism is sufficient to robustly reduce Aβ and pTau burden in a mouse model of AD, which likely occurs in part through reduced APP localization to lipid rafts.

Alzheimer's Gone Viral: Could Herpes Simplex Virus Type-1 Be Stealing Your Memories?

Alzheimer's disease (AD) is one of the principal causes of disability and morbidity. It is one of the most expensive illnesses. Despite this, there are no significant data regarding its etiology and optimal treatment. This review concentrates on the viral hypothesis of AD. After a comprehensive PubMed literature search, we analyzed the studies associating herpes simplex virus type-1 (HSV1) infection to AD from the previous 10 years. Molecular mechanisms whereby HSV1 induces AD-related pathophysiology, including neuronal production and accumulation of amyloid-beta (amyloid-β), abnormal phosphorylation of tau proteins, impaired calcium homeostasis, and autophagy, are addressed. The virus also imitates the disease in other ways, showing increased neuroinflammation, oxidative stress, synaptic dysfunction, and neuronal apoptosis. Serological studies correlate HSV1 infection with AD and cognitive impairment. A causal link between HSV1 and AD raises the concept of a simple, efficient, and preventive treatment alternative. Anti-viral agents impede brain degeneration by preventing HSV1 spread and its replication, decreasing hyperphosphorylated tau and amyloid-β; thus providing an efficacious treatment for AD. We also mention brown algae, intravenous immunoglobulin (IVIG), and a synthetic drug, BAY57-1293, with anti-viral properties, as options for treating AD. We want to recommend future researchers to look for more affordable, non-invasive, and swifter techniques to identify HSV1 in the brain and assist in the early detection and prevention of AD.

Vitamin D exerts neuroprotection via SIRT1/nrf-2/ NF-kB signaling pathways against D-galactose-induced memory impairment in adult mice

Vitamin D (Vt. D) is one of the vital hormone having multiple functions in various tissues, including brain. Several evidences reported that Vt. D plays a significant part in memory and cognition as its inadequate amount may accelerate cognitive impairment. This study shows for the first time the antioxidant potential of Vt. D against D-Galactose (D-gal) induced oxidative stress mediated Alzheimer disease (AD) pathology in male adult albino mice. The result reveals that the mice exposed to D-gal (120 mg/kg) for eight weeks have pre-and post-synaptic dysfunction and impaired memory investigated through Morris water maze and Y-maze tests. This is followed by the suppressed Nuclear factor erythroid 2-related factor 2 (NRF2), Heme Oxygenase-1 (HO-1) and elevated expressions of Nuclear Factor kappa B (NF-kB), Tumor Necrosis Factor alpha (TNF-α) and Interleukin 1 beta (IL-1β) proteins in the brain homogenates evaluated through western blotting technique. On the other hand Vt. D (100 μg/kg) administration (three times a week for 4 weeks) activated Silent mating type information regulation 2 homolog 1 (SIRT1) and significantly improved both the neuronal synapse and memory, reduced oxidative stress by upregulating NRF-2 and HO-1 and downregulating NF-kB, TNF-α and IL-1β proteins expression. Most importantly, Vt. D significantly abrogate the amyloidogenic pathway of amyloid beta (Aβ) production against D-gal in the brains of adult male albino mice. These results reveal that Vt. D being an antioxidant agent plays a vital role in reducing the AD pathophysiology in D-gal induced animal model of aging, therefore act as a potential drug candidate in neurodegenerative diseases.

Cystatin C regulates the cytotoxicity of infection-induced endothelial-derived β-amyloid.

Infection of rat pulmonary microvascular endothelial cells with the bacterium Pseudomonasaeruginosa induces the production and release of cytotoxic oligomeric tau and beta amyloid (Aβ). Here, we characterized these cytotoxic amyloids. Cytotoxic behavior and oligomeric tau were partially resistant to digestion with proteinase K, but cytotoxicity was abolished by various denaturants including phenol, diethylpyrocarbonate (DEPC), and 1,1,1,3,3,3-hexafluoro-2-isopropanol (HFIP). Ultracentrifugation for 8h at 150000g was required to remove cytotoxic activity from the supernatant. Ultracentrifugation, DEPC treatment, and immunodepletion using antibodies against Aβ also demonstrated that cytoprotective protein(s) are released from endothelial cells during P.aeruginosa infection. Mass spectrometry of endothelial cell culture media following P.aeruginosa infection allowed identification of multiple potential secreted modulators of Aβ, including cystatin C, gelsolin, and ApoJ/clusterin. Immunodepletion, co-immunoprecipitation, and ultracentrifugation determined that the cytoprotective factor released during infection of endothelial cells by P.aeruginosa is cystatin C, which appears to be in a complex with Aβ. Cytoprotective cystatin C may provide a novel therapeutic avenue for protection against the long-term consequences of infection with P.aeruginosa.

Amyloid beta regulates ER exit sites formation through O-GlcNAcylation triggered by disrupted calcium homeostasis.

Aberrant production of amyloid beta (Aβ) causes disruption of intracellular calcium homeostasis, a crucial factor in the pathogenesis of Alzheimer's disease. Calcium is required for the fusion and trafficking of vesicles. Previously, we demonstrated that Sec31A, a main component for coat protein complex II (COPII) vesicles at ER exit sites (ERES), is modulated by O-GlcNAcylation. O-GlcNAcylation, a unique and dynamic protein glycosylation process, modulates the formation of COPII vesicles. In this study, we observed that disrupted calcium levels affected the formation of COPII vesicles in ERES through calcium-triggered O-GlcNAcylation of Sec31A. Additionally, we found that Aβ impaired ERES through Aβ-disturbed calcium homeostasis and O-GlcNAcylation of Sec31A in neuronal cells. Furthermore, we identified that Aβ disrupted the ribbon-like structure of Golgi. Golgi fragmentation by Aβ was rescued by up-regulation of O-GlcNAcylaion levels using Thiamet G (ThiG), an O-GlcNAcase inhibitor. Additionally, we observed that the Golgi reassembly stacking proteins having a function in Golgi stacking showed attenuation at COPII vesicles following Aβ treatment. This study demonstrated that Aβ impaired Sec31A targeting to ERES through altered Sec31A O-GlcNAcylation triggered by disruption of intracellular calcium homeostasis. The findings of this study suggested that protection of ERES or Sec31 O-GlcNAcylation may offer a promising novel avenue for development of AD therapeutics.

Generation of a human induced pluripotent stem cell line (UEFi003-A) carrying heterozygous A673T variant in amyloid precursor protein associated with a reduced risk of Alzheimer's disease.

A673T mutation in the amyloid precursor protein (APP) is a rare variant associated with a reduced risk of late-onset Alzheimer's disease (AD) and age-related cognitive decline. The A673T mutation decreases beta-amyloid (Aβ) production and aggregation in neuronal cultures in vitro. Here we have identified a Finnish non-diseased male individual carrying a heterozygous A673T mutation, obtained a skin biopsy sample from him, and generated an iPSC line using commercially available integration-free Sendai virus-based kit. The established iPSC line retained the mutation, expressed pluripotency markers, had a normal karyotype, and differentiated into all three germ layers in vitro.

Abstract 14: Glyburide Treatment Improves Aortic Arch Pulse Wave Velocity In A Murine Model Of Alzheimer’S Disease

Brain hyperexcitability is a defining feature of AD, where aberrant neuronal activity may be both a cause and consequence of the pathology. Identifying novel targets to modulate cellular excitability is an important treatment strategy. We showed that inward rectifying, ATP-sensitive potassium (K ATP ) channels regulate excitability at the neurovascular unit to impact production and aggregation of amyloid-beta (Aβ), a hallmark of AD. Sulfonylureas such as glyburide (GLY) are antidiabetic medications that inhibit K ATP channels. We demonstrated that systemic treatment with GLY decreased Aβ production and plaque pathology by modulating vascular K ATP channel activity and neuronal excitability. Here, we investigated whether GLY alters cardiac function or pulse wave velocity (PWV) in APPswe, PSEN1dE9 (APP/PS1) mice, a model of Aβ overexpression.Female APP/PS1 mice at 8 months of age with established amyloid plaque pathology were treated for 1 month with GLY (subcutaneous, slow release 2.5mg pellet, ~30μg/GLY/day) or Placebo (n = 5, each group). After 1 month, transthoracic echocardiography was performed (Vevo 2100 LAZR, FUJIFILM/VisualSonics, Inc.; Toronto, Ca) with a 30 MHz linear array transducer. There were no differences in Placebo vs. GLY mice for heart rate, cardiac output, E/e’ ratio, ejection fraction, and fractional shortening. Arterial stiffness, measured as PWV in the aortic arch [Distance (D)/Time (T); D = mm from ascending to descending aorta and T = (R to ascending aorta foot) - (R to descending aorta foot) in ms], was lower in GLY treated mice (5 ± 1 vs. Placebo 9 ± 1 mm/ms; p < 0.04). Wild Type females at 9 months of age (n = 5) reveal similar cardiac function values as Placebo and GLY treated APP/PS1 mice, with a trend for lower PWV (6 ± 1 mm/ms) than the APP/PSI Placebo group. Thus, short-term treatment with GLY does not impact overall cardiac function. Moreover, improved vascular stiffness in GLY-treated APP/PS1 mice may contribute to improved neurovascular coupling independent of changes in Aβ aggregation, since arterial stiffness is associated with increased cerebrovascular pathology in clinical studies. SLM: Bright Focus Fdn, NIA K01AG050719, Donors Cure New Vision; SMD: T32AA007565; Hypertension & Vasc Res Ctr; NCATS UL1TR001420 (Vevo Core)

Mangosteen Pericarp and Its Bioactive Xanthones: Potential Therapeutic Value in Alzheimer's Disease, Parkinson's Disease, and Depression with Pharmacokinetic and Safety Profiles.

Alzheimer’s disease (AD), Parkinson’s disease (PD), and depression are growing burdens for society globally, partly due to a lack of effective treatments. Mangosteen (Garcinia mangostana L.,) pericarp (MP) and its xanthones may provide therapeutic advantages for these disorders. In this review, we discuss potential therapeutic value of MP-derived agents in AD, PD, and depression with their pharmacokinetic and safety profiles. MP-derived agents have shown multifunctional effects including neuroprotective, antioxidant, and anti-neuroinflammatory actions. In addition, they target specific disease pathologies, such as amyloid beta production and deposition as well as cholinergic dysfunction in AD; α-synuclein aggregation in PD; and modulation of monoamine disturbance in depression. Particularly, the xanthone derivatives, including α-mangostin and γ-mangostin, exhibit potent pharmacological actions. However, low oral bioavailability and poor brain penetration may limit their therapeutic applications. These challenges can be overcome in part by administering as a form of MP extract (MPE) or using specific carrier systems. MPE and α-mangostin are generally safe and well-tolerated in animals. Furthermore, mangosteen-based products are safe for humans. Therefore, MPE and its bioactive xanthones are promising candidates for the treatment of AD, PD, and depression. Further studies including clinical trials are essential to decipher their efficacy, and pharmacokinetic and safety profiles in these disorders.

A Pentacyclic Triterpene from Ligustrum lucidum Targets γ-Secretase

Amyloid-beta peptides generated by β-secretase- and γ-secretase-mediated successive cleavage of amyloid precursor protein are believed to play a causative role in Alzheimer's disease. Thus, reducing amyloid-beta generation by modulating γ-secretase remains a promising approach for Alzheimer's disease therapeutic development. Here, we screened fruit extracts of Ligustrum lucidum Ait. (Oleaceae) and identified active fractions that increase the C-terminal fragment of amyloid precursor protein and reduce amyloid-beta production in a neuronal cell line. These fractions contain a mixture of two isomeric pentacyclic triterpene natural products, 3-O-cis- or 3-O-trans-p-coumaroyl maslinic acid (OCMA), in different ratios. We further demonstrated that trans-OCMA specifically inhibits γ-secretase and decreases amyloid-beta levels without influencing cleavage of Notch. By using photoactivatable probes targeting the subsites residing in the γ-secretase active site, we demonstrated that trans-OCMA selectively affects the S1 subsite of the active site in this protease. Treatment of Alzheimer's disease transgenic model mice with trans-OCMA or an analogous carbamate derivative of a related pentacyclic triterpene natural product, oleanolic acid, rescued the impairment of synaptic plasticity. This work indicates that the naturally occurring compound trans-OCMA and its analogues could become a promising class of small molecules for Alzheimer's disease treatment.

A Short-Term Western Diet Impairs Cholesterol Homeostasis and Key Players of Beta Amyloid Metabolism in Brain of Middle Aged Rats.

Cholesterol homeostasis is crucial for brain functioning. Unhealthy nutrition can influence cerebral physiology, but the effect of western diets on brain cholesterol homeostasis, particularly at middle age, is unknown. Given the link between brain cholesterol alteration and beta amyloid production, the aim is to evaluate whether a diet rich in fat and fructose affects the protein network implicated in cholesterol synthesis and shuttling between glial cells and neurons, as well as crucial markers of beta amyloid metabolism. Middle aged rats are fed a high fat-high fructose (HFF) or a control diet for 4 weeks. Inflammatory markers and cholesterol levels significantly increase in hippocampus of HFF rats. A higher activation of 3-hydroxy 3-methylglutaryl coenzyme-A reductase, coupled with lower levels of apolipoprotein E, LXR-beta, and lipoproteins receptors is measured in hippocampus from HFF rats. The alteration of critical players of cholesterol homeostasis is associated with increased level of amyloid precursor protein, presenilin 1, and nicastrin, and decreased level of insulin degrading enzyme. Overall these data show that a western diet is associated with perturbation of cholesterol homeostasis in middle aged rats, mostly in hippocampus. This might trigger molecular events involved in the onset of neurodegenerative diseases.

Calcium Channel Blockers: A Possible Potential Therapeutic Strategy for the Treatment of Alzheimer's Dementia Patients with SARS-CoV-2 Infection.

Studies have shown that the calcium ion (Ca2+) plays important roles both in Alzheimer's dementia and SARS-CoV S-mediated fusion to host cell entry. An elevated level of intracellular calcium causes neuronal dysfunction, cell death, and apoptosis. Dysregulation of calcium has also been shown to increase the production of amyloid beta (Aβ) protein, the hallmark of Alzheimer's dementia. Reversely, deposition of Aβ is also responsible for calcium dysregulation. On the other hand, it has been well investigated that viruses can disturb host cell Ca2+ homeostasis as well as modulate signal transduction mechanisms. Viruses can also hijack the host cell calcium channels and pumps to release more intracellular Ca2+ to utilize for their life cycle. Even though evidence has not been reported on SARS-CoV-2 concerning Ca2+ regulation, however, it has been well established that Ca2+ is essential for viral entry, viral gene replication, and virion maturation and release. Recent reports suggest that SARS-CoV needs two Ca2+ ions to fuse with the host cell at the entry step. Furthermore, some calcium channel blockers (CCBs), such as nimodipine, memantine, etc., have been reported to be effective in the treatment of dementia in Alzheimer's disease (AD) as well as have shown inhibition in various virus infections.

Sleep is bi-directionally modified by amyloid beta oligomers.

Disrupted sleep is a major feature of Alzheimer's disease (AD), often arising years before symptoms of cognitive decline. Prolonged wakefulness exacerbates the production of amyloid-beta (Aβ) species, a major driver of AD progression, suggesting that sleep loss further accelerates AD through a vicious cycle. However, the mechanisms by which Aβ affects sleep are unknown. We demonstrate in zebrafish that Aβ acutely and reversibly enhances or suppresses sleep as a function of oligomer length. Genetic disruptions revealed that short Aβ oligomers induce acute wakefulness through Adrenergic receptor b2 (Adrb2) and Progesterone membrane receptor component 1 (Pgrmc1), while longer Aβ forms induce sleep through a pharmacologically tractable Prion Protein (PrP) signaling cascade. Our data indicate that Aβ can trigger a bi-directional sleep/wake switch. Alterations to the brain's Aβ oligomeric milieu, such as during the progression of AD, may therefore disrupt sleep via changes in acute signaling events.

Long-term Exercise Training Prevents Anxious-depressive-like Behavior In Transgenic Alzheimer Rats

PURPOSE: This study examined the effects of long-term treadmill exercise training on the anxious-depressive-like behavioral phenotype of transgenic Alzheimer rats in the early stage of Alzheimer's disease (AD) development and provided evidence that exercise alleviated fear-avoidance behavior deficits. METHODS: 2-month-old Male TgF344-AD and wild-type (WT) rats were separated into WT (n = 9), AD (n = 8), and AD + treadmill exercise (Exe) groups (n = 12). Following 8 months of exercise, the passive avoidance test, Barnes maze task, novel object recognition test, and object location test were used to measure learning and memory function. The open field test, elevated plus maze, sucrose preference test, and forced swim test were conducted to measure anxious-depressive-like behavior of AD rats. Immunofluorescence staining, Western blot analysis, enzyme-linked immunosorbent assay (ELISA) analysis, and related assay kits were used to measure levels of inflammatory cytokines, oxidative stress, amyloid-beta production, and tau hyperphosphorylation. RESULTS: Behavioral tests indicated that AD rats aged 12-months did not exhibit spatial learning and memory deficits, but did display anxious-depressive-like behaviors (open field, Center time: P = 0.008; Center entries: P = 0.009; Line crossings: P = 0.001). Long-term exercise significantly prevented anxious-depressive-like behaviors in AD rats (Center time: P = 0.016; Center entries: P = 0.004; Line crossings: P = 0.033). In addition, AD animals displayed enhanced Aβ deposition (P < 0.001), Tau hyperphosphorylation (P < 0.001), microglial activation (P <0.001), inflammatory cytokine release (P < 0.05), and oxidative damage (P < 0.05) that was attenuated significantly after long-term exercise training ( P < 0.05). CONCLUSIONS: Long-term exercise training ameliorated anxious-depressive-like behaviors and improved fear-avoidance behavior in transgenic AD rats, supporting exercise training as an effective strategy to prevent or reduce anxiety, depression and fear-avoidance behavior deficits in the early stages of AD pathogenesis.

Understanding the Pathophysiology of Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA), one of the main types of cerebral small vessel disease, is a major cause of spontaneous intracerebral haemorrhage and an important contributor to cognitive decline in elderly patients. Despite the number of experimental in vitro studies and animal models, the pathophysiology of CAA is still largely unknown. Although several pathogenic mechanisms including an unbalance between production and clearance of amyloid beta (Aβ) protein as well as ‘the prion hypothesis’ have been invoked as possible disease triggers, they do not explain completely the disease pathogenesis. This incomplete disease knowledge limits the implementation of treatments able to prevent or halt the clinical progression. The continuous increase of CAA patients makes imperative the development of suitable experimental in vitro or animal models to identify disease biomarkers and new pharmacological treatments that could be administered in the early disease stages to prevent irreversible changes and disease progression.

Alzheimer's Disease: Parsing the Pathways Leading to the Disease Based on the Spirochete/Biofilm Hypothesis

A pathway which highlighted spirochetes (Borrelia burgdorferi and dental treponemes) that made biofilms which led to Alzheimer’s disease has recently been promulgated. All the Alzheimer’s disease, on which this pathway was based, had been specifically confirmed both clinically and pathologically. This current work will show putative and plausible individual pathways that were studied. First and foremost, intracellular spirochetes make biofilms and concurrently make beta amyloid; this has been shown in vitro in pure culture and in vivo. The beta amyloid together with tau protein leads to hyperphosphorylated tau that leads to neurofibrillary tangles and dendrite disintegration. Extracellular biofilms lead to activation of the innate immune system (similar to other chronic diseases), and this together with its major pathway (MyD88) leads to the production of beta amyloid. Many drugs and environmental states interact with that pathway and generally lead to further disease progression. (These drugs such as haloperidol, and environmental states such as hyperosmolality have been known to cause worsening of the disease.) Few things lead to reversal of the pathway, though L-serine stands out among them. All these pathways would not even exist or be activated were the spirochetes not present. The above hypothesis is based on observed findings from patients with Alzheimer’s disease and from pathways known to be generated from those findings.

Cyclical amyloid beta-astrocyte activity induces oxidative stress in Alzheimer’s disease

Glial cell involvement in Alzheimer’s disease (AD) is multi-faceted. The role of astrocytes in AD pathology, both as a causative agent of amyloid-beta (Aβ) production as well as a casualty of dysfunction resulting from the presence of Aβ has been well-delineated. In this review, we explore the influence of oxidative stress in astrocytes and the subsequent effect on Aβ levels in the brain from a perspective of intracellular calcium homeostasis and NADPH oxidase activity. The response of astrocytes to the presence of Aβ, as well astrocytic and microglial interaction and inflammatory cytokine release is also discussed, highlighting a cyclical behaviour of these cells in contributing to AD pathogenesis.

Protective Effects of Compounds from Cimicifuga dahurica against Amyloid Beta Production in Vitro and Scopolamine-Induced Memory Impairment in Vivo.

Cimicifuga dahurica has traditionally been used as an antipyretic, analgesic, and anti-inflammatory agent and as a treatment for uterine and anal prolapse. This study has investigated the potential beneficial effects of this medicinal plant and its components on Alzheimer's disease (AD) with a focus on amyloid beta (Aβ) production and scopolamine-induced memory impairment in mice. An ethanol extract from C. dahurica roots decreased Aβ production in APP-CHO cells [Chinese hamster ovarian (CHO) cells stably expressing amyloid precursor protein (APP)], as determined by an enzyme-linked immunosorbent assay and Western blot analysis. Then, the compounds isolated from C. dahurica were tested for their antiamyloidogenic activities. Four compounds (1-4) efficiently interrupted Aβ generation by suppressing the level of β-secretase in APP-CHO cells. Moreover, the in vivo experimental results demonstrated that compound 4 improved the cognitive performances of mice with scopolamine-induced disruption on behavioral tests and the expression of memory-related proteins. Taken together, these results suggest that C. dahurica and its constituents are potential agents for preventing or alleviating the symptoms of AD.

Reducing the progression of Alzheimer’s disease in Down syndrome patients with micro-dose lithium

Alzheimer’s disease (AD) is a pervasive and progressive neurodegenerative disorder characterized by a gradual decline in memory, leading to significant impairments in cognition, language, and social functioning. An early-onset variant of the disease is a substantial source of morbidity in individuals with trisomy 21, the main cause of Down syndrome (DS), with clinical evidence of the disease seen in roughly one-half of those 50 years and older. Current pharmacologic therapies are limited to a handful of medications that offer only modest improvement in cognition and overall functioning. There is growing consensus in the literature that lithium salts, well-established as efficacious in the treatment of select affective disorders, may also provide neuroprotection from the development and progression of AD by targeting multiple processes implicated in the disease. These include beta-amyloid production, tau hyperphosphorylation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. While complex, inhibition of glycogen synthase kinase 3 (GSK-3) appears to be the primary mechanism by which lithium exerts its disease-modifying effects. Reduced rates of dementia have been described in bipolar patients chronically treated with lithium. Additionally, “micro-dose” lithium (300 µg daily in one study) demonstrated stabilization of cognitive decline in AD patients with mild cognitive impairment. With encouraging data suggesting that lithium confers a clinically significant benefit in AD by impeding accumulation of the aberrant proteins central to the putative pathogenesis, it follows to reason that a population with a genetic predisposition rooted in this disease mechanism may benefit from it. After a thorough review of the literature and currently active clinical trials, no studies have looked at using lithium to slow or prevent the development of Alzheimer’s disease in the Down syndrome population. Because those with DS have such reliably high rates of developing AD, many 20–30 years younger than those in the general population, they represent an exemplary subject population to investigate the effect that lithium has on progression to disease. Furthermore, the specific factors that make those with Down syndrome prone to developing AD, including enhanced ability to synthesize beta-amyloid, mitochondrial dysfunction, and elevated oxidative stress, correlate quite well with the model by which lithium is thought to disrupt Alzheimer’s pathogenesis, making the DS population ideally suited to study this intervention. Demonstrating reduced progression of Alzheimer’s pathology with micro-dose lithium in those with trisomy 21 could function to reinforce our current understanding of the pathogenetic mechanism underlying early-onset AD, and ultimately, establish a preventative treatment for the disease.