Reduced Amyloid Plaque Research Articles

Absolute Bioavailability, Tissue Distribution, and Excretion of Erinacine S in Hericium erinaceus Mycelia.

Erinacine S, so far known to have been produced only in Hericium erinaceus mycelia, has just recently been discovered and is able to reduce amyloid plaque growth and improve neurogenesis in aged brain of rats. However, few investigations have been conducted on the absorption, distribution, and excretion study of Erinacine S. This study aimed to investigate the absolute bioavailability, tissue distribution, and excretion of Erinacine S in H. Erinaceus mycelia in eight-week old Sprague-Dawley rats. After oral administration and intravenous administration of 2.395 g/kg body weight of the H. erinaceus mycelia extract (equivalent to 50 mg/kg body weight Erinacine S) and 5 mg/kg of Erinacine S, respectively, the absolute bioavailability was estimated as 15.13%. In addition, Erinacine S was extensively distributed in organs such as brain, heart, lung, liver, kidney, stomach, small intestine, and large intestine. The maximum concentration of Erinacine S was observed in the stomach, 2 h after the oral administration of H. erinaceus mycelia extract, whereas the maximum amount of Erinacine S found in other tissues were seen after 8 h. Total amount of unconverted Erinacine S eliminated in feces and urine in 24 h was 0.1% of the oral dosage administrated. This study is the first to show that Erinacine S can penetrate the blood–brain barrier of rats and thus support the development of H. erinaceus mycelia, for the treatment of neurological diseases.

Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer\u2019s disease model

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer’s disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.

Dietary Sargassum fusiforme improves memory and reduces amyloid plaque load in an Alzheimer\u2019s disease mouse model

Activation of liver X receptors (LXRs) by synthetic agonists was found to improve cognition in Alzheimer’s disease (AD) mice. However, these LXR agonists induce hypertriglyceridemia and hepatic steatosis, hampering their use in the clinic. We hypothesized that phytosterols as LXR agonists enhance cognition in AD without affecting plasma and hepatic triglycerides. Phytosterols previously reported to activate LXRs were tested in a luciferase-based LXR reporter assay. Using this assay, we found that phytosterols commonly present in a Western type diet in physiological concentrations do not activate LXRs. However, a lipid extract of the 24(S)-Saringosterol-containing seaweed Sargassum fusiforme did potently activate LXRβ. Dietary supplementation of crude Sargassum fusiforme or a Sargassum fusiforme-derived lipid extract to AD mice significantly improved short-term memory and reduced hippocampal Aβ plaque load by 81%. Notably, none of the side effects typically induced by full synthetic LXR agonists were observed. In contrast, administration of the synthetic LXRα activator, AZ876, did not improve cognition and resulted in the accumulation of lipid droplets in the liver. Administration of Sargassum fusiforme-derived 24(S)-Saringosterol to cultured neurons reduced the secretion of Aβ42. Moreover, conditioned medium from 24(S)-Saringosterol-treated astrocytes added to microglia increased phagocytosis of Aβ. Our data show that Sargassum fusiforme improves cognition and alleviates AD pathology. This may be explained at least partly by 24(S)-Saringosterol-mediated LXRβ activation.

Resveratrol improves cognition and decreases amyloid plaque formation in Tg6799 mice.

Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative disorder of the central nervous system that causes severe cognitive impairment. One of the most significant pathological features of AD is the accumulation of β‑amyloid (Aβ) peptide in the brain. Resveratrol (Res) is a polyphenol derived from peanuts, red grapes and other plants, which has received increasing attention due to its neuroprotective features. Tg6799 mice are transgenic mice with five familial AD (FAD) mutations that are also known as 5XFAD mice. The present study aimed to investigate the effects of Res on Tg6799 mice. The transgenic mice were randomly divided into the Res treatment group and the vehicle control group, and were treated with 0.5% Res solution (60mg/kg) or volume‑matched normal saline, respectively. Treatment was administered by oral gavage daily for 60 consecutive days. Res reduced amyloid plaque formation and the levels of Aβ42, and β‑secretase 1 levels were also significantly decreased. Furthermore, Res was able to reduce the expression of amyloid precursor protein and its cleavage products. The administration of Res to Tg6799 mice also improved their spatial working memory, as measured by the Y‑maze test, and rescued spatial memory deficits, as measured using the Morris water maze test; however, Res did not affect their motor function. In conclusion, this study suggested that Res may reduce Aβ‑induced neuronal damage, thus preventing memory loss.

The possible protective effect of Gardenia Jasminoides extracts on the dentate gyrus changes in an Alzheimer-induced model in adult male albino rats: Histological and Immunohistochemical study

Introduction: Alzheimer's disease (AD) is the most common diagnosed form of senile dementias, a neurodegenerative disease resulting in cognitive impairment in the elderly. Geniposide, extracted of Gardenia Jasminoides, is widely used herb for brain diseases and reduce amyloid plaques deposition which is an intricate process in AD.Aim of the work: demonstrate the histological changes in the dentate gyrus of hippocampus in an Alzheimer-induced model and the possible neuroprotective effect of Gardenia Jasminoides extract.Materials and methods: Thirty six adult male albino rats(4-6 months) , weighing180-200g divided into 3 groups. Group I the control group, group II given aluminum chloride dissolved in distilled water, (300mg/kg/day) orally for one month. Group (III) given Geniposide in distilled water,at a dose of (100mg/kg/day) orally concomitant with aluminum chloride at the same dose and period of the previous group. Cognitive functions were assessed by the passive avoidance test. Temporal lobes processed for H&E , congo red stains. Immunohistochemical study for detection of (GFAP) and (INOS). Tau protein can be phosphorylated by glycogen synthase Kinase-3β(GSK-3 β). Western blot assay to investigate the total protein expression glycogen synthase Kinase-3β(GSK-3 β) . Comet assay to detect DNA damage.Results: Alzheimer-induced model group showed significantly impaired cognitive performance which was improved after treatment with Geniposide extract. Changes in the dentate gyrus apparent increase in immature neurons, disturbed granular cell layer, distortion of pyramidal cells that appeared with pyknotic nuclei. Positive immunoreaction for GFAP in astrocytes were also observed. The ultra structural study exhibited neurons with apoptotic features, heterochromatic nuclei and their cytoplasm contained dilated cisternae of rough endoplasmic reticulum. Gardenia extracts ameliorated histological alterations.Conclusion: Gardenia Jasminoides extracts significantly ameliorated the neuro- degenerative alterations induced in the Alzheimer model. Daily supplements of Gardenia Jasminoides extracts might be of benefit for the elderly people at risk of developing AD.

Repeated ultrasound treatment of tau transgenic mice clears neuronal tau by autophagy and improves behavioral functions.

Intracellular deposits of pathological tau are the hallmark of a broad spectrum of neurodegenerative disorders collectively known as tauopathies, with Alzheimer's disease, a secondary tauopathy, being further characterized by extracellular amyloid plaques. A major obstacle in developing effective treatments for tauopathies is the presence of the blood-brain barrier, which restricts the access of therapeutic agents to the brain. An emerging technology to overcome this limitation is the application of low-intensity ultrasound which, together with intravenously injected microbubbles, transiently opens the blood-brain barrier, thereby facilitating the delivery of therapeutic agents into the brain. Interestingly, even in the absence of therapeutic agents, ultrasound has previously been shown to reduce amyloid plaques and improve cognitive functions in amyloid-depositing mice through microglial clearance. Ultrasound has also been shown to facilitate the delivery of antibody fragments against pathological tau in P301L tau transgenic mice; however, the effect of ultrasound alone has not been thoroughly investigated in a tauopathy mouse model.Methods: Here, we performed repeated scanning ultrasound treatments over a period of 15 weeks in K369I tau transgenic mice with an early-onset tau-related motor and memory phenotype. We used immunohistochemical and biochemical methods to analyze the effect of ultrasound on the mice and determine the underlying mechanism of action, together with an analysis of their motor and memory functions following repeated ultrasound treatments.Results: Repeated ultrasound treatments significantly reduced tau pathology in the absence of histological damage. Associated impaired motor functions showed improvement towards the end of the treatment regime, with memory functions showing a trend towards improvement. In assessing potential clearance mechanisms, we ruled out a role for ubiquitination of tau, a prerequisite for proteasomal clearance. However, the treatment regime induced the autophagy pathway in neurons as reflected by an increase in the autophagosome membrane marker LC3II and a reduction in the autophagic flux marker p62, along with a decrease of mTOR activity and an increase in beclin 1 levels. Moreover, there was a significant increase in the interaction of tau and p62 in the ultrasound-treated mice, suggesting removal of tau by autophagosomes.Conclusions: Our findings indicate that a neuronal protein aggregate clearance mechanism induced by ultrasound-mediated blood-brain barrier opening operates for tau, further supporting the potential of low-intensity ultrasound to treat neurodegenerative disorders.

Olive Biophenols Reduces Alzheimer's Pathology in SH-SY5Y Cells and APPswe Mice.

Alzheimer’s disease (AD) is a major neurodegenerative disease, associated with the hallmark proteinacious constituent called amyloid beta (Aβ) of senile plaques. Moreover, it is already established that metals (particularly copper, zinc and iron) have a key role in the pathogenesis of AD. In order to reduce the Aβ plaque burden and overcome the side effects from the synthetic inhibitors, the current study was designed to focus on direct inhibition of with or without metal-induced Aβ fibril formation and aggregation by using olive biophenols. Exposure of neuroblastoma (SH-SY5Y) cells with Aβ42 resulted in decrease of cell viability and morphological changes might be due to severe increase in the reactive oxygen species (ROS). The pre-treated SH-SY5Y cells with olive biophenols were able to attenuate cell death caused by Aβ42, copper- Aβ42, and [laevodihydroxyphenylalanine (l-DOPA)] l-DOPA-Aβ42-induced toxicity after 24 h of treatment. Oleuropein, verbascoside and rutin were the major anti-amyloidogenic compounds. Transgenic mice (APPswe/PS1dE9) received 50 mg/kg of oleuropein containing olive leaf extracts (OLE) or control diet from 7 to 23 weeks of age. Treatment mice (OLE) were showed significantly reduced amyloid plaque deposition (p < 0.001) in cortex and hippocampus as compared to control mice. Our findings provide a basis for considering natural and low cost biophenols from olive as a promising candidate drug against AD. Further studies warrant to validate and determine the anti-amyloid mechanism, bioavailability as well as permeability of olive biophenols against blood brain barrier in AD.

Sitagliptin protects the cognition function of the Alzheimer’s disease mice through activating glucagon-like peptide-1 and BDNF-TrkB signalings

BackgroundSitagliptin is an anti-diabetic drug and its effects on Alzheimer’s disease (AD) remain controversial. This study aimed to investigate the protective effect of sitagliptin on the cognition in AD and its underlying molecular mechanism. MethodsThe APP/PS1 (a model of AD) mice received daily gastric gavage administration of sitagliptin (20 mg/kg) for 8 weeks. Then animals were subjected to behavioral experiment or sacrificed to histological staining and protein level analysis. ResultsThe MWM test showed that sitagliptin treatment significantly reduced the escape latency times in APP/PS1 mice in the learning phase (day 3–5) and elongated the time spent in the target quadrant in the probe test. Sitagliptin significantly reduced amyloid plaque deposition and elevated the spine density and the protein levels of synaptoneurosome GluA1- and GluA2-containing AMPA receptor (GluA1R and GluA2R) in the brain of the APP/PS1 mice. Sitagliptin treatment significantly up-regulated the brain BNDF protein and phosphorylation of tyrosine receptor kinase B (TrkB). Furthermore, exendin-(9–39) (a glucagon-like peptide-1 [GLP-1] receptor antagonist) and K252a (a Trk tyrosine kinase inhibitor) treatment significantly abolished the cognitive protective effect of sitagliptin in the MWM test. ConclusionSitagliptin treatment effectively protected the cognition function of the AD mice by regulating synaptic plasticity, at least partially, through activating GLP-1 and BDNF-TrkB signalings.

The protective effect of betulinic acid on microvascular responsivity and protein expression in alzheimer disease induced by cerebral micro-injection of beta-amyloid and streptozotocin.

Alzheimer's disease (AD) is mainly caused by accumulation of β-amyloid (Aβ) in vessels or parenchyma of the brain. Accordingly, natural compounds such as betulinic acid (BA) might improve the AD signs by increase in blood flow and through reduction in amyloid plaques. Intra-hippocampal injection of BA (0.2 and 0.4μmol/L /10μL DMSO /rat) was done at intervals of 180 and 10min before co-microinjection of 0.1μmol/L Aβ dissolved in PBS (5μL/rat, hippocampi) and 1.5mg/kg Streptozotocin dissolved in aCSF (10μL/rat, lateral ventricles). Cerebro-vascular responsivity tested by Laser Doppler, BBB leakage, Elisa assays of cytokines (TNF-α and IL-10), and Western blot analysis of proteins (BDNF and AchE) in the hippocampus were assessed 1month after the injections. Microvascular reaction and BBB function were significantly impaired in AD rats, which were improved via BA pretreatment. BA could increase BDNF expression and decrease cytokine levels in the hippocampus of AD rats (especially 0.1μmol/L Aβ: 0.4μmol/L BA); however, no significant changes were detected in the blotting of AchE among the groups. Betulinic acid could have a role in AD through protecting microcirculation, alleviating inflammation, and up-regulating BDNF expression which is clearer toward 1:4 molar ratios of Aβ to BA.

IVIG Delays Onset in a Mouse Model of Gerstmann-Sträussler-Scheinker Disease

Our previous studies showed that intravenous immunoglobulin (IVIG) contained anti-Aβ autoantibodies that might be able to treat Alzheimer's disease (AD). Recently, we identified and characterized naturally occurring autoantibodies against PrP from IVIG. Although autoantibodies in IVIG blocked PrP fibril formation and PrP neurotoxicity in vitro, it remained unknown whether IVIG could reduce amyloid plaque pathology in vivo and be used to effectively treat animals with prion diseases. In this study, we used Gerstmann-Sträussler-Scheinker (GSS)-Tg (PrP-A116V) transgenic mice to test IVIG efficacy since amyloid plaque formation played an important role in GSS pathogenesis. Here, we provided strong evidence that demonstrates how IVIG could significantly delay disease onset, elongate survival, and improve clinical phenotype in Tg (PrP-A116V) mice. Additionally, in treated animals, IVIG could markedly inhibit PrP amyloid plaque formation and attenuate neuronal apoptosis at the age of 120days in mice. Our results indicate that IVIG may be a potential, effective therapeutic treatment for GSS and other prion diseases.

7B2 chaperone knockout in APP model mice results in reduced plaque burden

Impairment of neuronal proteostasis is a hallmark of Alzheimer’s and other neurodegenerative diseases. However, the underlying molecular mechanisms leading to pathogenic protein aggregation, and the role of secretory chaperone proteins in this process, are poorly understood. We have previously shown that the neural-and endocrine-specific secretory chaperone 7B2 potently blocks in vitro fibrillation of Aβ42. To determine whether 7B2 can function as a chaperone in vivo, we measured plaque formation and performed behavioral assays in 7B2-deficient mice in an hAPPswe/PS1dE9 Alzheimer’s model mouse background. Surprisingly, immunocytochemical analysis of cortical levels of thioflavin S- and Aβ-reactive plaques showed that APP mice with a partial or complete lack of 7B2 expression exhibited a significantly lower number and burden of thioflavin S-reactive, as well as Aβ-immunoreactive, plaques. However, 7B2 knockout did not affect total brain levels of either soluble or insoluble Aβ. While hAPP model mice performed poorly in the Morris water maze, their brain 7B2 levels did not impact performance. Since 7B2 loss reduced amyloid plaque burden, we conclude that brain 7B2 can impact Aβ disposition in a manner that facilitates plaque formation. These results are reminiscent of prior findings in hAPP model mice lacking the ubiquitous secretory chaperone clusterin.

Dihydropyridines Allosterically Modulate Hsp90 Providing a Novel Mechanism for Heat Shock Protein Co-induction and Neuroprotection.

Chaperones play a pivotal role in protein homeostasis, but with age their ability to clear aggregated and damaged protein from cells declines. Tau pathology is a driver of a variety of neurodegenerative disease and in Alzheimer's disease (AD) it appears to be precipitated by the formation of amyloid-β (Aβ) aggregates. Aβ-peptide appears to trigger Tau hyperphosphorylation, formation of neurofibrillary tangles and neurotoxicity. Recently, dihydropyridine derivatives were shown to upregulate the heat shock response (HSR) and provide a neuroprotective effect in an APPxPS1 AD mouse model. The HSR response was only seen in diseased cells and consequently these compounds were defined as co-inducers since they upregulate chaperones and co-chaperones only when a pathological state is present. We show for compounds tested herein, that they target predominantly the C-terminal domain of Hsp90, but show some requirement for its middle-domain, and that binding stimulates the chaperones ATPase activity. We identify the site for LA1011 binding and confirm its identification by mutagenesis. We conclude, that binding compromises Hsp90's ability to chaperone, by modulating its ATPase activity, which consequently induces the HSR in diseased cells. Collectively, this represents the mechanism by which the normalization of neurofibrillary tangles, preservation of neurons, reduced tau pathology, reduced amyloid plaque, and increased dendritic spine density in the APPxPS1 Alzheimer's mouse model is initiated. Such dihydropyridine derivatives therefore represent potential pharmaceutical candidates for the therapy of neurodegenerative disease, such as AD.

Huatuo Zaizao pill ameliorates cognitive impairment of APP/PS1 transgenic mice by improving synaptic plasticity and reducing A\u03b2 deposition

BackgroundIt is well known that Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory deficits and cognitive decline. Amyloid-β (Aβ) deposition and synaptic dysfunction play important roles in the pathophysiology of Alzheimer’s disease (AD). The Huatuo Zaizao pill (HT) is a Traditional Chinese Medicine (TCM) that has been used clinically for many years in China, mainly for post-stroke rehabilitation and cognitive decline; however, the mechanism of cognitive function is not clear. In this study, we investigated the effect of HT on hippocampal synaptic function, Amyloid-β (Aβ) deposition in APP/PS1 AD transgenic mice.MethodSix-month-old APP/PS1 transgenic (Tg) mice were randomly divided into control, HT-treated, and memantine (MEM)-treated groups. Then, these groups were orally administered vehicle (for the control), HT (0.25 g/kg) and MEM (5 mg/kg) respectively for 4 weeks. The Morris water maze, Novel Object Recognition, and Open field tests were used to assess cognitive behavioral changes. We evaluated the effects of HT on neuronal excitability, membrane ion channel activity, and synaptic plasticity in acute hippocampal slices by combining electrophysiological extracellular tests. Synaptic morphology in the hippocampus was investigated by electron microscopy. Western blotting was used to assess synaptic-associated protein and Aβ production and degrading levels. Immunofluorescence staining was used to determine the relative integrated density.ResultsHT can ameliorate hippocampus-dependent memory deficits and improve synaptic dysfunction by reversing LTP impairment in APP/PS1 transgenic mice. Moreover, HT reduces amyloid plaque deposition by regulating α-secretase and γ-secretase levels.ConclusionHT can improve the learning and memory function of APP/PS1 transgenic mice by improving synaptic function and reducing amyloid plaque deposition.

Stereological Investigation of the Effects of Treadmill Running Exercise on the Hippocampal Neurons in Middle-Aged APP/PS1 Transgenic Mice.

The risk of cognitive decline during Alzheimer's disease (AD) can be reduced if physical activity is maintained; however, the specific neural events underlying this beneficial effect are still uncertain. To quantitatively investigate the neural events underlying the effect of running exercise on middle-aged AD subjects, 12-month-old male APP/PS1 mice were randomly assigned to a control group or running group, and age-matched non-transgenic littermates were used as a wild-type group. AD running group mice were subjected to a treadmill running protocol (regular and moderate intensity) for four months. Spatial learning and memory abilities were assessed using the Morris water maze. Hippocampal amyloid plaques were observed using Thioflavin S staining and immunohistochemistry. Hippocampal volume, number of neurons, and number of newborn cells (BrdU+ cells) in the hippocampus were estimated using stereological techniques, and newborn neurons were observed using double-labelling immunofluorescence. Marked neuronal loss in both the CA1 field and dentate gyrus (DG) and deficits in both the neurogenesis and survival of new neurons in the DG of middle-aged APP/PS1 mice were observed. Running exercise could improve the spatial learning and memory abilities, reduce amyloid plaques in the hippocampi, delay neuronal loss, induce neurogenesis, and promote the survival of newborn neurons in the DG of middle-aged APP/PS1 mice. Exercise-induced protection of neurons and adult neurogenesis within the DG might be part of the important structural basis of the improved spatial learning and memory abilities observed in AD mice.

The Role of Insulin/IGF-1/PI3K/Akt/GSK3β Signaling in Parkinson's Disease Dementia.

Dementia, a condition that frequently afflicts patients in advanced stages of Parkinson's disease (PD), results in decreased quality of life and survival time. Nevertheless, the pathological mechanisms underlying Parkinson's disease dementia (PDD) are not completely understood. The symptoms characteristic of PDD may be the result of functional and structural deficiencies. The present study implicates the accumulation of Lewy bodies in the cortex and limbic system as a potent trigger in the development of PDD. In addition, significant Alzheimer-type pathologies, including amyloid-β (Aβ) plaques and NFTs, are observed in almost half of PDD patients. Interestingly, links between PDD pathogenesis and the mechanisms underlying the development of insulin resistance have begun to emerge. Furthermore, previous studies have demonstrated that insulin treatment reduces amyloid plaques in Alzheimer's disease (AD), and normalizes the production and functionality of dopamine and ameliorates motor impairments in 6-OHDA-induced rat PD models. GSK3β, a downstream substrate of PI3K/Akt signaling following induction by insulin and IGF-1, exerts an influence on AD and PD physiopathology. The genetic overexpression of GSK3β in cortex and hippocampus results in signs of neurodegeneration and spatial learning deficits in in vivo models (Lucas et al., 2001), whereas its inhibition results in improvements in cognitive impairment in these rodents, including AD and PD. Accordingly, insulin- or IGF-1-activated PI3K/Akt/GSK3β signaling may be involved in PDD pathogenesis, at least in the pathology of PD-type + AD-type.

Phos-tau peptide immunization of amyloid-tg-mice reduced non-mutant phos-tau pathology, improved cognition and reduced amyloid plaques

Tau-immumotherapy has shown promising results in tangle/tauopathy-tg animal models. Here we immunized amyloid-mice (APPSwe/PSEN1dE9-tg, presenting amyloid-plaques, not neurofibrillary-tangles) with phos-tau peptides, previously shown by us to have high efficacy in mutant-tau tauopathy-mice. These amyloid-mice allowed us to test the effect of the vaccine in a model of familial AD patients with mutant amyloid plaque pathology, where tau pathology - once develops - is of non-mutant tau. Fourteen-month-old amyloid-mice were immunized with phos-tau peptides or vehicle. Eight weeks later, amelioration of cognitive impairment was noticed. Histological analysis revealed that the phos (non-mutant)-tau pathology (detected by us in these aged amyloid-mice while not in non-tg-mice), was lower in the phos-tau immunized amyloid-mice than in the non-immunized mice. Interestingly, we detected a decrease in amyloid plaque pathology, probably associated with the increased microglial burden, which surrounded both tau and amyloid pathology. These results point to the added value of immunizing AD-mice with the phos-tau-vaccine, targeting both tau and amyloid pathology, which may have clinical relevance. It also points to the multifaceted interplay between tau/amyloid pathologies.

Long-Term SSRI Use May Slow Progression to Alzheimer’s Dementia

Long-Term SSRI Use May Slow Progression to Alzheimer’s Dementia

Efficacy and Safety of the Immunization with DNA for Alzheimer's Disease in Animal Models: A Systematic Review from Literature.

Background:Alzheimer’s disease (AD) is a neurodegenerative disease that does not have a proven cure; however, one of the most promising strategies for its treatment has been DNA vaccines.Objective:The present review is aimed to report the new developments of the efficacy and safety of DNA vaccines for AD in animal models.Method:The method PRISMA was used for this review. The article search was made in the electronic databases PubMed, LILACS, and Scopus using the descriptors ‘’Alzheimer disease” and ‘’Vaccine, DNA”. Articles published between January 2001 and September 2017 in English, Portuguese, and Spanish were included.Results:Upon the consensus, the researchers identified 28 original articles. The studies showed satisfying results as for the decrease of amyloid plaques in mouse, rabbits, and monkeys brains using mostly the DNA Aβ42 vaccine, AV-1955, and AdPEDI-(Aβ1-6)11, mainly with a gene gun. In addition to a reduction in tau by the first DNA vaccine (AV-1980D) targeting this protein. The use of adjuvants and boosters also had positive results as they increased the destruction of the amyloid plaques and induced an anti-inflammatory response profile without side effects.Conclusion:The results of DNA vaccines targeting the amyloid-β and the tau protein with or without adjuvants and boosters were promising in reducing amyloid plaques and tau protein without side effects in animals. Although there are many vaccines being tested in animals, few reach clinical trials. Thus, as a future perspective, we suggest that clinical studies should be conducted with vaccines that have been promising in animal models (e.g., DNA Aβ42 vaccine, AV-1955, and AdPEDI-(Aβ1-6)11).

Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer's disease

Type 2 diabetes mellitus (T2DM) has been identified as a high risk factor for Alzheimer's disease (AD). The impairment of insulin signaling has been found in AD brain. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, normalises insulin signaling and acts as a neuroprotective growth factor. We have previously shown that the long-lasting GLP-1 receptor (GLP-1R) agonist lixisenatide plays an important role in memory formation, synaptic plasticity and cell proliferation of rats. In the follow-up study, we analysed the neuroprotective effect and mechanism of lixisenatide, injected for 60 days at 10 nmol/kg i.p. once daily in APP/PS1/tau female mice and C57BL/6J female mice (as control) aged 12 month. The results showed that lixisenatide could reduce amyloid plaques, neurofibrillary tangles and neuroinflammation in the hippocampi of 12-month-old APP/PS1/tau female mice; activation of PKA-CREB signaling pathway and inhibition of p38-MAPK might be the important mechanisms in the neuroprotective function of lixisenatide. The study demonstrated that GLP-1R agonists such as lixisenatide might have the potential to be developed as a novel therapy for AD.

Peripheral Blood Mononuclear Cells of Alzheimer's Disease Patients Control CCL4 and CXCL10 Levels in a Human Blood Brain Barrier Model.

Alzheimer's disease (AD) is accompanied by a neuroinflammation triggering chemoattractant signals towards peripheral blood mononuclear cells (PBMCs), which in turn could reduce amyloid plaques after transmigration through the blood brain barrier (BBB). But the chemotactic environment remains unclear. To analyze five chemokines known to be involved in AD in three different cellular models to better understand the cellular and molecular interactions in the BBB. Chemokines (CCL-2, 4 and 5, CXCL10 and CX3CL1) were measured in isolated cells, a BBB model without PBMCs (H4 and hCMEC/D3 cells, a neuroglioma and human endothelial cells, respectively) and in a complete BBB model with PBMCs from AD patients at a moderate stage. In one set of experiments, H4 cells were treated with Aβ42. CCL2 and CCL5 significantly increased in hCMEC/D3 and H4 cells in the complete BBB model. In turn, the rate of CCL2 increased in PBMCs whereas for CCL5, it decreased. CXCL10 increased in all cellular actors in the complete BBB model, compared to isolated cells. For CCL4, PBMCs induced a robust increase in H4 and hCMEC/D3. In turn, the level of CCL4 decreased in PBMCs. Furthermore, PBMCs triggered a significant increase in CX3CL1 in hCMEC/D3. Surprisingly, no effect of Aβ42 was observed in the complete BBB model. These findings highlight the interest of a BBB model in order to explore chemokine production. For the first time, results showed that PBMCs from patients with AD can control the production of CCL4 and CXCL10 in a human BBB model.