Number Of Amyloid Plaques Research Articles

Effects of Intravenously Administered Plasma from Exercise-Trained Donors on Microglia and Cytokines in a Transgenic Rat Model of Alzheimer's Disease.

Microglia and inflammation play a significant role in Alzheimer's disease (AD). Physical exercise and peripheral signals can influence microglial activity in the brain. Modulating the inflammatory response in the brain may provide therapeutic approaches for AD. To assess the effects of intravenously administered blood plasma from exercise-trained donor rats on cognitive function, microglia, and cytokine levels in an AD rat model at two different pathological stages; an early pre-plaque stage and a later stage closer to the emergence of extracellular plaques. Male transgenic McGill-R-Thy1-APP rats aged 2 and 5 months received 14 injections over 6 weeks: 1) plasma from exercise-trained rats (ExPlas), 2) plasma from sedentary rats (SedPlas), or 3) saline. Cognitive function was evaluated in a novel object recognition task. Microglia count and morphology were analyzed in cornu ammonis, dentate gyrus, entorhinal cortex, and subiculum. Amyloid plaque number and size were assessed in the rats with the later treatment start. A multiplex assay was used to measure 23 cytokines in cornu ammonis. In rats treated from 2 months of age, ExPlas and SedPlas increased number and length of microglial branches in cornu ammonis and dentate gyrus compared to saline. Only ExPlas-treated rats exhibited similar changes in subiculum, while entorhinal cortex showed no differences across treatments. Microglia count remained unaffected. In rats treated from 5 months of age, there were no significant differences in microglia count or morphology or the number or size of amyloid plaques in any brain region. Compared to both other treatments in early pre-plaque stage rats, SedPlas increased TNF-α levels. ExPlas upregulated GM-CSF, IL-18, and VEGF, while SedPlas increased IL-10 compared to saline. In later-stage rats, ExPlas upregulated IL-17, and SedPlas upregulated TNF-α compared to saline. There were no effects of treatments on recognition memory. Intravenous injections of blood plasma from exercise-trained and sedentary donors differentially modulated microglial morphology and cytokine levels in the AD rat model at an early pre-plaque stage of pathology. Exercised plasma may reduce proinflammatory TNF-α signaling and promote microglial responses to early Aβ accumulation but the lack of treatment effects in the later-stage rats emphasizes the potential importance of treatment timing.

Modulation of Cytosolic Phospholipase A2 as a Potential Therapeutic Strategy for Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder lacking any curative treatment up to now. Indeed, actual medication given to the patients alleviates only symptoms. The cytosolic phospholipase A2 (cPLA2-IVA) appears as a pivotal player situated at the center of pathological pathways leading to AD and its inhibition could be a promising therapeutic approach. A cPLA2-IVA inhibiting peptide was identified in the present work, aiming to develop an original therapeutic strategy. We targeted the cPLA2-IVA using the phage display technology. The hit peptide PLP25 was first validated in vitro (arachidonic acid dosage [AA], cPLA2-IVA cellular translocation) before being tested in vivo. We evaluated spatial memory using the Barnes maze, amyloid deposits by MRI and immunohistochemistry (IHC), and other important biomarkers such as the cPLA2-IVA itself, the NMDA receptor, AβPP and tau by IHC after i.v. injection in APP/PS1 mice. Showing a high affinity for the C2 domain of this enzyme, the peptide PLP25 exhibited an inhibitory effect on cPLA2-IVA activity by blocking its binding to its substrate, resulting in a decreased release of AA. Coupled to a vector peptide (LRPep2) in order to optimize brain access, we showed an improvement of cognitive abilities of APP/PS1 mice, which also exhibited a decreased number of amyloid plaques, a restored expression of cPLA2-IVA, and a favorable effect on NMDA receptor expression and tau protein phosphorylation. cPLA2-IVA inhibition through PLP25 peptide could be a promising therapeutic strategy for AD.

Early treatment with an M1 and sigma-1 receptor agonist prevents cognitive decline in a transgenic rat model displaying Alzheimer-like amyloid pathology

The application of the selective allosteric M1 muscarinic and sigma-1 receptor agonist, AF710B (aka ANAVEX3-71), has shown to attenuate Alzheimer’s disease-like hallmarks in McGill-R-Thy1-APP transgenic rats when administered at advanced pathological stages. It remains unknown whether preventive treatment strategies applying this compound may be equally effective. We tested whether daily oral administration of AF710B (10 µg/kg) in 7-month-old, preplaque, McGill-R-Thy1-APP rats for 7 months, followed by a 4-week washout period, could prevent Alzheimer’s disease-like pathological hallmarks. Long-term AF710B treatment prevented the cognitive impairment of McGill-R-Thy1-APP rats. The effect was accompanied by a reduction in the number of amyloid plaques in the hippocampus and the levels of Aβ42 and Aβ40 peptides in the cerebral cortex. AF710B treatment also reduced microglia and astrocyte recruitment toward CA1 hippocampal Aβ-burdened neurons compared to vehicle-treated McGill-R-Thy1-APP rats, also altering the inflammatory cytokines profile. Lastly, AF710B treatment rescued the conversion of brain-derived neurotrophic factor precursor to its mature and biologically active form. Overall, these results suggest preventive and disease-modifying properties of the compound.

The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aβ clearance in 5XFAD mice.

Previously, we showed that the sphingosine-1-phosphate (S1P) transporter spinster 2 (Spns2) mediates activation of microglia in response to amyloid β peptide (Aβ). Here, we investigated if Ponesimod, a functional S1P receptor 1 (S1PR1) antagonist, prevents Aβ-induced activation of glial cells and Alzheimer's disease (AD) pathology. We used primary cultures of glial cells and the 5XFAD mouse model to determine the effect of Aβ and Ponesimod on glial activation, Aβ phagocytosis, cytokine levels and pro-inflammatory signaling pathways, AD pathology, and cognitive performance. Aβ42 increased the levels of TLR4 and S1PR1, leading to their complex formation. Ponesimod prevented the increase in TLR4 and S1PR1 levels, as well as the formation of their complex. It also reduced the activation of the pro-inflammatory Stat1 and p38 MAPK signaling pathways, while activating the anti-inflammatory Stat6 pathway. This was consistent with increased phagocytosis of Aβ42 in primary cultured microglia. In 5XFAD mice, Ponesimod decreased the levels of TNF-α and CXCL10, which activate TLR4 and Stat1. It also increased the level of IL-33, an anti-inflammatory cytokine that promotes Aβ42 phagocytosis by microglia. As a result of these changes, Ponesimod decreased the number of Iba-1+ microglia and GFAP+astrocytes, and the size and number of amyloid plaques, while improving spatial memory as measured in a Y-maze test. Ponesimod targeting S1PR1 is a promising therapeutic approach to reprogram microglia, reduce neuroinflammation, and increase Aβ clearance in AD. NIHR01AG064234, RF1AG078338, R21AG078601, VAI01BX003643.

Ethanol exposure alters Alzheimer's-related pathology, behavior, and metabolism in APP/PS1 mice

Epidemiological studies identified alcohol use disorder (AUD) as a risk factor for Alzheimer's disease (AD), yet there is conflicting evidence on how alcohol use promotes AD pathology. In this study, a 10-week moderate two-bottle choice drinking paradigm was used to identify how chronic ethanol exposure alters amyloid-β (Aβ)-related pathology, metabolism, and behavior. Ethanol-exposed APPswe/PSEN1dE9 (APP/PS1) mice showed increased brain atrophy and an increased number of amyloid plaques. Further analysis revealed that ethanol exposure led to a shift in the distribution of plaque size in the cortex and hippocampus. Ethanol-exposed mice developed a greater number of smaller plaques, potentially setting the stage for increased plaque proliferation in later life. Ethanol drinking APP/PS1 mice also exhibited deficits in nest building, a metric of self-care, as well as increased locomotor activity and central zone exploration in an open field test. Ethanol exposure also led to a diurnal shift in feeding behavior which was associated with changes in glucose homeostasis and glucose intolerance. Complementary in vivo microdialysis experiments were used to measure how acute ethanol directly modulates Aβ in the hippocampal interstitial fluid (ISF). Acute ethanol transiently increased hippocampal ISF glucose levels, suggesting that ethanol directly affects cerebral metabolism. Acute ethanol also selectively increased ISF Aβ40, but not ISF Aβ42, levels during withdrawal. Lastly, chronic ethanol drinking increased N-methyl-d-aspartate receptor (NMDAR) and decreased γ-aminobutyric acid type-A receptor (GABAAR) mRNA levels, indicating a potential hyperexcitable shift in the brain's excitatory/inhibitory (E/I) balance. Collectively, these experiments suggest that ethanol may increase Aβ deposition by disrupting metabolism and the brain's E/I balance. Furthermore, this study provides evidence that a moderate drinking paradigm culminates in an interaction between alcohol use and AD-related phenotypes with a potentiation of AD-related pathology, behavioral dysfunction, and metabolic impairment.

Novel Luteolin-Loaded Chitosan Decorated Nanoparticles for Brain-Targeting Delivery in a Sporadic Alzheimer's Disease Mouse Model: Focus on Antioxidant, Anti-Inflammatory, and Amyloidogenic Pathways.

Preparation and evaluation of a non-invasive intranasal luteolin delivery for the management of cognitive dysfunction in Alzheimer’s disease (AD) using novel chitosan decorated nanoparticles. Development of luteolin-loaded chitosomes was followed by full in vitro characterization. In vivo efficacy was evaluated using a sporadic Alzheimer’s disease (SAD) animal model via intracerebroventricular injection of 3 mg/kg streptozotocin (ICV-STZ). Treatment groups of luteolin suspension and chitosomes (50 mg/kg) were then intranasally administered after 5 h of ICV-STZ followed by everyday administration for 21 consecutive days. Behavioral, histological, immunohistochemical, and biochemical studies were conducted. Chitosomes yielded promising quality attributes in terms of particle size (PS) (412.8 ± 3.28 nm), polydispersity index (PDI) (0.378 ± 0.07), Zeta potential (ZP) (37.4 ± 2.13 mv), and percentage entrapment efficiency (EE%) (86.6 ± 2.05%). Behavioral findings showed obvious improvement in the acquisition of short-term and long-term spatial memory. Furthermore, histological evaluation revealed an increased neuronal survival rate with a reduction in the number of amyloid plaques. Biochemical results showed improved antioxidant effects and reduced pro-inflammatory mediators’ levels. In addition, a suppression by half was observed in the levels of both Aβ aggregation and hyperphosphorylated-tau protein in comparison to the model control group which in turn confirmed the capability of luteolin-loaded chitosomes (LUT-CHS) in attenuating the pathological changes of AD. The prepared nanoparticles are considered a promising safe, effective, and non-invasive nanodelivery system that improves cognitive function in SAD albino mice as opposed to luteolin suspension.

Focused ultrasound as a non-invasive method with therapeutic potential in patients with Alzheimer's disease

Alzheimer's disease (AD) is a common, progressive neurodegenerative disease characterized by abnormal deposition of β-amyloid (Aβ) and hyperphosphorylated tau protein. Despite the fact that biomarkers and methods of treating AD are currently being actively studied, there is still no therapy that can significantly reduce the progression of this disease. Therefore, the search for therapeutic disease-modifying strategies is becoming increasingly popular. One such strategy is the use of focused ultrasound (FUS) under MRI guidance using a contrast agent (microbubbles). Under the influence of low-intensity FUS, the blood-brain barrier (BBB) is temporarily opened, which is the main obstacle to the effective delivery of therapeutic compounds to the brain, imposing dimensional and biochemical restrictions on the passage of molecules. One of the processes associated with AD is BBB dysfunction, and therefore the study of the effects of FUS in patients with AD is of interest. The literature data show the effectiveness of FUS in animal models of AD. The researchers attribute the effectiveness of the method to the fact that exposure to FUS induces the opening of BBB and reduces the number of amyloid plaques. It has also been demonstrated that FUS can facilitate the delivery of therapeutic drugs to the brain. This allows considering FUS as a new non-invasive method of treatment. Further research is needed to assess the effectiveness of this method in patients with AD.

IKK2/NF-κB Activation in Astrocytes Reduces amyloid β Deposition: A Process Associated with Specific Microglia Polarization.

Alzheimer’s disease (AD) is a common neurodegenerative disease that is accompanied by pronounced neuroinflammatory responses mainly characterized by marked microgliosis and astrogliosis. However, it remains open as to how different aspects of astrocytic and microglial activation affect disease progression. Previously, we found that microglia expansion in the spinal cord, initiated by IKK2/NF-κB activation in astrocytes, exhibits stage-dependent beneficial effects on the progression of amyotrophic lateral sclerosis. Here, we investigated the impact of NF-κB-initiated neuroinflammation on AD pathogenesis using the APP23 mouse model of AD in combination with conditional activation of IKK2/NF-κB signaling in astrocytes. We show that NF-κB activation in astrocytes triggers a distinct neuroinflammatory response characterized by striking astrogliosis as well as prominent microglial reactivity. Immunohistochemistry and Congo red staining revealed an overall reduction in the size and number of amyloid plaques in the cerebral cortex and hippocampus. Interestingly, isolated primary astrocytes and microglia cells exhibit specific marker gene profiles which, in the case of microglia, point to an enhanced plaque clearance capacity. In contrast, direct IKK2/NF-κB activation in microglia results in a pro-inflammatory polarization program. Our findings suggest that IKK2/NF-κB signaling in astrocytes may activate paracrine mechanisms acting on microglia function but also on APP processing in neurons.

Long-Term Treatment of Cuban Policosanol Attenuates Abnormal Oxidative Stress and Inflammatory Response via Amyloid Plaques Reduction in 5xFAD Mice.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder resulting in cognitive decline or dementia, the number of patients with AD is continuously increasing. Although a lot of great progress has been made in research and development of AD therapeutics, there is no fundamental cure for this disease yet. This study demonstrated the memory-improving effects of Cuban policosanol (PCO) in 5xFAD mice, which is an animal model of AD. Following 4-months of treatment with PCO in 5xFAD mice, we found that the number of amyloid plaques decreased in the brain compared to the vehicle-treated 5xFAD mice. Long-term PCO treatment in 5xFAD mice resulted in the reduction of gliosis and abnormal inflammatory cytokines level (interleukin [IL]-1β, IL-6, and tumor necrosis factor [TNF]-α) in the cortex and hippocampus. Levels of lipid peroxide (4-hydroxynonenal [4-HNE]) and superoxide dismutase (SOD1 and SOD2) levels were also recoverd in the brains of PCO-treated 5xFAD mice. Notably, PCO administration reduced memory deficits in the passive avoidance test, as well as synaptic loss (PSD-95, synaptophysin) in 5xFAD mice. Collectively, we identified the potential effects of PCO as a useful supplement to delay or prevent AD progression by inhibiting the formation of Aβ plaques in the brain.

Aducanumab: The first targeted Alzheimer's therapy.

Alzheimer's disease (AD) is an irreversible brain disorder associated with severe progressive dementia and is characterized by deposits of amyloid plaques in the brain. Over the past 20 years, the mortality of strokes and heart disease has decreased, but deaths from AD have increased. The four drugs used clinically to treat AD can only relieve symptoms but cannot slow the progression of the disease. Aducanumab, a human monoclonal antibody that preferentially binds to aggregated amyloid-β to reduce the number of amyloid plaques and slow disease progression, was approved to treat AD by the US Food and Drug Administration on June 7, 2021. It is the first disease-modifying therapy for AD, but there is considerable controversy regarding the drug's approval. Aducanumab offers hope for millions of patients.

In vivo Evaluation of a Newly Synthesized Acetylcholinesterase Inhibitor in a Transgenic Drosophila Model of Alzheimer's Disease.

Alzheimer’s disease is a neurodegenerative disease characterized by disrupted memory, learning functions, reduced life expectancy, and locomotor dysfunction, as a result of the accumulation and aggregation of amyloid peptides that cause neuronal damage in neuronal circuits. In the current study, we exploited a transgenic Drosophila melanogaster line, expressing amyloid-β peptides to investigate the efficacy of a newly synthesized acetylcholinesterase inhibitor, named XJP-1, as a potential AD therapy. Behavioral assays and confocal microscopy were used to characterize the drug effect on AD symptomatology and amyloid peptide deposition. The symptomatology induced in this particular transgenic model recapitulates the scenario observed in human AD patients, showing a shortened lifespan and reduced locomotor functions, along with a significant accumulation of amyloid plaques in the brain. XJP-1 treatment resulted in a significant improvement of AD symptoms and a reduction of amyloid plaques by diminishing the amyloid aggregation rate. In comparison with clinically effective AD drugs, our results demonstrated that XJP-1 has similar effects on AD symptomatology, but at 10 times lower drug concentration than donepezil. It also showed an earlier beneficial effect on the reduction of amyloid plaques at 10 days after drug treatment, as observed for donepezil at 20 days, while the other drugs tested have no such effect. As a novel and potent AChE inhibitor, our study demonstrates that inhibition of the enzyme AChE by XJP-1 treatment improves the amyloid-induced symptomatology in Drosophila, by reducing the number of amyloid plaques within the fruit fly CNS. Thus, compound XJP-1 has the therapeutic potential to be further investigated for the treatment of AD.

Efficacy of Adipose-Derived Stem Cells as a Potential Cellular Therapy of Alzheimer’s Disease: A Comprehensive Systematic Review

Context: Elderlies are more prone to neurodegenerative diseases. One of the most common neurodegenerative diseases with limited effective treatments available is Alzheimer’s disease (AD). Adipose-derived stem cells (ADSCs) with neuroregenerative and neuroprotective capabilities have shown great potential to serve as a potential cellular therapy for AD. Adipose-derived stem cells’ efficacy in the treatment of AD is evaluated in this systematic review. Data Sources: Literature search was performed via PubMed, Cochrane Library, ScienceDirect, Wiley Online Library, and EBSCOhost databases, selecting studies which evaluated the effect of ADSCs on AD from inception to 6 August 2020. The SYRCLE Risk of Bias tool was used to assess pre-clinical studies in animal models, and MINORS Risk of Bias tool was used to assess non-randomized phase 1 clinical trials. Conclusions: Overall, seven studies, including two in-vitro studies, four in-vivo mice model studies, and one non-randomized phase 1 clinical trial, were included in this systematic review. Adipose-derived stem cells showed significant potential, proven by their neuroregenerative (i.e., increased neurogenesis, synaptogenesis, synaptic and dendritic stability, and cognitive and spatial skills) and neuroprotective capabilities (i..e., decreased Aβ concentration, APP-CT concentration, P-tau concentration, number of amyloid plaques, oxidative stress, and neuron apoptosis when exposed to Aβ). Adipose-derived stem cells demonstrated promising efficacy in treating AD patients.

Low‐dose radiation therapy: A new potential treatment targeting amyloid load and neuroinflammation in an AD rat model

AbstractBackgroundLow‐dose radiation therapy (LD‐RT) has shown to be effective to decrease systemic amyloid load and has an anti‐inflammatory effect in chronic inflammatory pathologies. Consequently, we propose to use LD‐RT to decrease two central hallmarks of AD: amyloid load and neuroinflammation. Our collaborators demonstrated recently that a fractionated protocol (2 Gray in 5 fractions delivered daily) significantly reduced amyloid plaques and improved cognition in an AD mouse model (Marples et al., 2016). The aim of our study is to 1) evaluate the impact of LD‐RT on amyloid load and neuroinflammation in another animal model of AD and 2) compare the efficacy of treatment accounting for the neuropathological stage.MethodWe used TgF344‐AD (TgAD) rats developing amyloid pathology and presenting the advantage to develop endogenous tauopathy. Brains were unilaterally exposed to LD‐RT with the same fractionated radiation schedule than our collaborators (2 Gray in 5 fractions daily) at two different pathology stages: at an early (9‐month‐old) or an advanced stage (19‐month‐old). TgAD and WT littermate sham‐treated animals were used as control. At an early stage, the 18kDa translocator protein (TSPO) density in different brain regions (frontal cortex, hippocampus, striatum, cerebellum, brain residues) was measured using ex vivo [I123]‐Clinde binding. Animals underwent behavioral evaluation (general locomotion, working memory) 4 months after LD‐RT performed at an advanced AD stage. The number of amyloid plaques was quantified in the hippocampus on immunostained slices.ResultFor the first time, we observed a normalization of TSPO levels in the entire brain (‐52%, p<0.001), revealing a strong reduction of neuroinflammation. Interestingly, at an advanced stage, LD‐RT reduces hyperlocomotion (‐44%, p<0.05) and significantly improves working memory (+72%, p<0.05), without modifying the amyloid load.ConclusionWe were able to replicate, in a different animal model, the beneficial effect of LD‐RT on cognition of old animals. This could be mediated by an anti‐inflammatory effect as shown by the TSPO‐signal reduction. The LD‐RT impact on amyloid plaques previously reported could not be confirmed when the pathology has strongly progressed. Longitudinal imaging studies will allow a more in‐depth analysis of the effect of LD‐RT on amyloid and neuroinflammation over the disease course.

A pulse of hope in the fight against Alzheimer’s

Flashes of strobe lights and the beat of stereo speakers filled the otherwise pitch-black, shoebox-sized cages. The mice inside may not have danced, but their brains caught the rhythm. Pulses of light and sound delivered to mouse brains at a frequency of 40 hertz appeared to reduce the number of amyloid plaques and tau protein tangles, hallmarks of the Alzheimer’s brain—seen here in a coronal slice from a patient with Alzheimer’s disease ( Left ), compared with normal brain ( Right ). Image credit: Science Source/Alfred Pasieka. The pulses of light and sound, delivered at a frequency of 40 per second, or 40 hertz, jumpstarted the mice’s neurons to fire electrical signals in time with the pulses—and subsequently reduced the number of amyloid plaques and tau protein tangles in their brains, two hallmarks of Alzheimer’s disease. Hour-long sessions on seven days in the nightclub-esque boxes also improved the animals’ working memory, sensory processing, and spatial navigation (1). “Every result seems to be too good to be true,” says Li-Huei Tsai, director of The Picower Institute for Learning and Memory at the Massachusetts Institute of Technology in Cambridge, who led the experiment. The synchronous rhythmic firing of neurons is critical for a healthy, functioning brain (2)—one that can accurately recall old memories and efficiently process new information. Large groups of neurons oscillating on and off together generate brain waves. Although it’s not yet clear why, this synchrony seems to strengthen coordination across brain regions and between different types of brain cells. “Brain rhythms are known to participate in all forms of cognition. And changes of brain rhythms appear to be implicated in all forms of neurological disease,” says Nancy Kopell, a math professor and director of the Cognitive Rhythms Collaborative at Boston University in MA. Growing evidence indicates that neurons in many animals, including humans, …

Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer's Disease.

The inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with 3 compounds in clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer's disease (AD). Evaluation of cognitive impairment and pathological hallmarks were used in 2 models of age-related cognitive decline and AD using 3 structurally different and potent sEH inhibitors as chemical probes. sEH is upregulated in brains from AD patients. Our findings supported the beneficial effects of central sEH inhibition, regarding reducing cognitive impairment, neuroinflammation, tau hyperphosphorylation pathology, and the number of amyloid plaques. This study suggests that inhibition of inflammation in the brain by targeting sEH is a relevant therapeutic strategy for AD.

Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer's disease.

A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid‐beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV‐ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary Aβ1‐42 (fAβ1‐42) than at CT12. BMAL1 directly drives transcription of REV‐ERB proteins, which are implicated in microglial activation. Interestingly, pharmacological inhibition of REV‐ERBs with the small molecule antagonist SR8278 or genetic knockdown of REV‐ERBs‐accelerated microglial uptake of fAβ1‐42 and increased transcription of BMAL1. SR8278 also promoted microglia polarization toward a phagocytic M2‐like phenotype with increased P2Y12 receptor expression. Finally, constitutive deletion of Rev‐erbα in the 5XFAD model of AD decreased amyloid plaque number and size and prevented plaque‐associated increases in disease‐associated microglia markers including TREM2, CD45, and Clec7a. Altogether, our work suggests a novel strategy for controlling Aβ clearance and neuroinflammation by targeting REV‐ERBs and provides new insights into the role of REV‐ERBs in AD.

New evidence for dual binding site inhibitors of acetylcholinesterase as improved drugs for treatment of Alzheimer's disease

Profound synaptic dysfunction contributes to early loss of short-term memory in Alzheimer's disease. This study was set up to analyze possible neuroprotective effects of two dual binding site inhibitors of acetylcholinesterase (AChE), a new 6-methyluracil derivative, C-35, and the clinically used inhibitor donepezil. Crystal structure of the complex between human AChE and C-35 revealed tight contacts of ligand along the enzyme active site gorge. Molecular dynamics simulations indicated that the external flexible part of the ligand establishes multiple transient interactions with the enzyme peripheral anionic site. Thus, C-35 is a dual binding site inhibitor of AChE.In transgenic mice, expressing a chimeric mouse/human amyloid precursor protein and a human presenilin-1 mutant, C-35 (5 mg/kg, i.p) and donepezil (0.75 mg/kg, i.p) partially reversed synapse loss, decreased the number of amyloid plaques, and restored learning and memory. To separate temporal symptomatic therapeutic effects, associated with the increased lifetime of acetylcholine in the brain, from possible disease-modifying effect, an experimental protocol based on drug withdrawal from therapy was performed. When administration of C-35 and donepezil was terminated three weeks after the trial started, animals that were receiving C-35 showed a much better ability to learn than those who received vehicle or donepezil. Our results provide additional evidence that dual binding site inhibitors of AChE have Alzheimer's disease-modifying action.

Effects of Eugenol on Alzheimer’s Disease-like Manifestations in Insulin- and Aβ-Induced Rat Models

Eugenol is a phenylpropene having antidepressant properties. We investigated the effect of eugenol on amyloid plaques as a hallmark of Alzheimer’s disease (AD) in two AD rat models. In the latter, betaamyloid (Aβ) and insulin amyloid fibrils were injected into the rat hippocampus. After a one week lapse, the rats were treated with 0.01 and 0.02 mg/kg eugenol for two weeks. Passive avoidance learning and memory performance was assessed by measuring the step-through latency (STL). Amyloid plaques in the hippocampus were quantitatively evaluated and statistically analyzed using image processing software and ANOVA. Aβ amyloid was a more potent inducer of the signs related to Alzheimer’s disease than insulin. Eugenol at a 0.01 mg/kg dose improved memory and reduced the number of amyloid plaques significantly (P < 0.001). Possible mechanisms are proposed for the inhibitory effects of eugenol on hippocampus plaques.

Ginkgo biloba Extract Decreases Scopolamine-Induced Congophilic Amyloid Plaques Accumulation in Male Rat's Brain

Background: Scopolamine can induce amyloid β accumulation, oxidative stress, synaptic loss, and learning/memory deficit as seen in Alzheimer’s disease. Ginkgo biloba extract increases neurogenesis and suppresses the happening of pathological processes and cognitive decline. Objectives: Herein, we explored the effect of Ginkgo biloba extract on scopolamine-induced congophilic amyloid plaque accumulation and neurons density in the rats’ brain. Methods: Ginkgo biloba extract (40 and 80 mg/kg/day) was injected daily intraperitoneally for seven days before and after the scopolamine injection (3 mg/kg) in protective and treatment group rats. At the end of the experiments, the rats’ brains were removed and fixed in 4% paraformaldehyde. After histological processing, Congo red staining was used to assess amyloid plaques while cresyl violet staining was employed to determine the neuron density. Results: The administration of scopolamine led to increased congophilic amyloid plaque density in the hippocampus and cingulate cortex of the rats. Pretreatment with Ginkgo biloba extract significantly decreased congophilic amyloid plaque numbers in the hippocampus and cingulate cortex. In addition, scopolamine could reduce the hippocampal and cingulate cortex neuron numbers compared to the control group rats. However, Ginkgo biloba extract increased the hippocampal and cingulate cortex neuron numbers before and after the injection of scopolamine. Conclusions: Our results showed that Ginkgo biloba extract could play protective roles against some scopolamine-induced Alzheimer’s disease-like pathologic dysfunctions, including amyloid β accumulation and neuronal loss, suggesting that treatment with Ginkgo biloba extract might be a promising prophylactic target for Alzheimer’s disease.

Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition.

The triggers of late-onset sporadic Alzheimer’s disease (AD) are still poorly understood. Impairment of protein phosphorylation with age is well-known; however, the role of the phosphorylation in β-amyloid peptide (Aβ) is not studied sufficiently. Zinc-induced oligomerization of Aβ represents a potential seeding mechanism for the formation of neurotoxic Aβ oligomers and aggregates. Phosphorylation of Aβ by Ser8 (pS8-Aβ), localized inside the zinc-binding domain of the peptide, may significantly alter its zinc-induced oligomerization. Indeed, using dynamic light scattering, we have shown that phosphorylation by Ser8 dramatically reduces zinc-induced aggregation of Aβ, and moreover pS8-Aβ suppresses zinc-driven aggregation of non-modified Aβ in an equimolar mixture. We have further analyzed the effect of pS8-Aβ on the progression of cerebral amyloidosis with serial retro-orbital injections of the peptide in APPSwe/PSEN1dE9 murine model of AD, followed by histological analysis of amyloid burden in hippocampus. Unlike the non-modified Aβ that has no influence on the amyloidosis progression in murine models of AD, pS8-Aβ injections reduced the number of amyloid plaques in the hippocampus of mice by one-third. Recently shown inhibition of Na+,K+-ATPase activity by Aβ, which is thought to be a major contributor to neuronal dysfunction in AD, is completely reversed by phosphorylation of the peptide. Thus, several AD-associated pathogenic properties of Aβ are neutralized by its phosphorylation.