Brains Of 5xFAD Mice Research Articles

5xFAD Mice Display Sex-Dependent Inflammatory Gene Induction During the Prodromal Stage of Alzheimer's Disease.

Alzheimer's disease (AD) pathology consists of extracellular deposits of amyloid-β peptides (Aβ) and intracellular neurofibrillary tangles. These pathological alterations are accompanied by a neuroinflammatory response consisting of increased expression of inflammatory mediators. An anti-inflammatory strategy designed to prevent or delay the development of AD would benefit from knowing when neuroinflammation appears in the transgenic models during prodromal disease stages relative to Aβ pathology. We investigated the expression patterns of inflammatory mediators in the brain of 5xFAD mice in comparison to development of Aβ deposition. Expression changes in inflammatory mediators and glial markers are more robust in female mice starting at three months of age, in contrast to males in which there is no clear trend through five months. Female and male 5xFAD mice also displayed an age-dependent increase in cortical Aβ deposition congruent with neuroinflammation. Thus, in the 5xFAD mouse model of AD, administration of an anti-inflammatory agent would be most efficacious when administered before three months of age.

HUMAN UMBILICAL CORD BLOOD DERIVED MESENCHYMAL STEM CELLS REDUCE PHOSPHORYLATION AND AGGREGATION OF TAU IN AN ALZHEIMER’S DISEASE MODEL

In Alzheimer's Disease (AD), administration of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) mitigate hyperphosphorylation and aggregation of tau as well as improve impairment of spatial learning and memory in AD model. hUCB-MSCs were isolated and expanded from umbilical cord blood. The 5xFAD model rapidly develops severe amyloid pathology and appears cognitive impairment at 4 to 6 months-of-age. All assays were qualified or quantified by thioflavin T assay, immunofluorescence, western blot analysis, enzyme-linked immunosorbent assays and T-maze test. hUCB-MSCs have inhibitory effect on tau aggregation through in vitro aggregation assays using K18 fragment of human tau. Remarkably, hUCB-MSCs specifically decreases autophosphorylation of tyrosine 216 on the GSK-3β residue, as a kinase to promote phosphorylation of tau. Moreover, hUCB-MSCs effectively decreased phosphorylated forms of Tau at Thr181, Thr231 and Ser404, whereas effects of total Tau proteins on its stability by hUCB-MSCs were not detected. Strikingly, these phenomena mentioned above lead to results that paired helical filaments (PHF) of tau in the brain of 5XFAD mice diminished by treatment of hUCB-MSCs. Additionally, in T-maze testing, administered mice support that hUCB-MSCs have behavioral improvement of memory tasks most likely to occur in AD model. hUCB-MSCs diminish the phosphorylation and aggregation of tau through regulation of hUCB-MSCs, thus elucidating a therapeutic mechanism for AD.

Impaired Peripheral Lymphatic Function and Cerebrospinal Fluid Outflow in a Mouse Model of Alzheimer's Disease.

Cerebrospinal fluid (CSF) outflow from the brain occurs through absorption into the arachnoid villi and, more predominantly, through meningeal and olfactory lymphatics that ultimately drain into the peripheral lymphatics. Impaired CSF outflow has been postulated as a contributing mechanism in Alzheimer's disease (AD). Herein we conducted near-infrared fluorescence imaging of CSF outflow into the peripheral lymph nodes (LNs) and of peripheral lymphatic function in a transgenic mouse model of AD (5XFAD) and wild-type (WT) littermates. CSF outflow was assessed from change in fluorescence intensity in the submandibular LNs as a function of time following bolus, an intrathecal injection of indocyanine green (ICG). Peripheral lymphatic function was measured by assessing lymphangion contractile function in lymphatics draining into the popliteal LN following intradermal ICG injection in the dorsal aspect of the hind paw. The results show 1) significantly impaired CSF outflow into the submandibular LNs of 5XFAD mice and 2) reduced contractile frequency in the peripheral lymphatics as compared to WT mice. Impaired CSF clearance was also evidenced by reduction of fluorescence on ventral surfaces of extracted brains of 5XFAD mice at euthanasia. These results support the hypothesis that lymphatic congestion caused by reduced peripheral lymphatic function could limit CSF outflow and may contribute to the cause and/or progression of AD.

CYP46A1 Activation by Efavirenz Leads to Behavioral Improvement without Significant Changes in Amyloid Plaque Load in the Brain of 5XFAD Mice.

Efavirenz, the FDA-approved anti-retroviral medication, is evaluated in the clinical trial in patients with mild cognitive impairment or early dementia due to Alzheimer's disease. Efavirenz is assessed for activation of cytochrome P450 46A1 (CYP46A1), a CNS-specific enzyme that converts cholesterol to 24-hydroxycholesterol. Cholesterol 24-hydroxylation is the major pathway for brain cholesterol removal, and a mechanism that controls brain cholesterol turnover. The present study tested efavirenz on 5XFAD mice (an Alzheimer's model) at a very low daily dose of 0.1mg/kg body weight. Efavirenz treatment started from three months of age, after amyloid plague appearance, and continued for 6months. This treatment led to CYP46A1 activation in the brain, enhancement of brain cholesterol turnover, behavioral improvements, reduction in microglia activation but increased astrocyte reactivity. The levels of the soluble and insoluble amyloid 40 and 42 peptides were unchanged while the number and area of the dense core amyloid plaques were slightly decreased. The measurements of the brain levels of several pre- and post-synaptic proteins (Munc13-1, PSD-95, gephyrin, synaptophysin, synapsin-1, and calbindin-D28k) suggested efavirenz effect at the synaptic level. Efavirenz treatment in the present work seems to represent a model of behavioral and other improvements independent of the levels of the amyloid peptides and provides insight into potential outcomes of the future clinical trial.

Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.

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.

Plasma Rich in Growth Factors (PRGF) Disrupt the Blood-Brain Barrier Integrity and Elevate Amyloid Pathology in the Brains of 5XFAD Mice.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder affecting 5.4 million people in the United States. Currently approved pharmacologic interventions for AD are limited to symptomatic improvement, not affecting the underlying pathology. Therefore, the search for novel therapeutic strategies is ongoing. A hallmark of AD is the compromised blood-brain barrier (BBB); thus, developing drugs that target the BBB to enhance its integrity and function could be a novel approach to prevent and/or treat AD. Previous evidence has shown the beneficial effects of growth factors in the treatment of AD pathology. Based on reported positive results obtained with the product Endoret®, the objective of this study was to investigate the effect of plasma rich in growth factors (PRGF) on the BBB integrity and function, initially in a cell-based BBB model and in 5x Familial Alzheimer’s Disease (5xFAD) mice. Our results showed that while PRGF demonstrated a positive effect in the cell-based BBB model with the enhanced integrity and function of the model, the in-vivo findings showed that PRGF exacerbated amyloid pathology in 5xFAD brains. At 10 and 100% doses, PRGF increased amyloid deposition associated with increased apoptosis and neuroinflammation. In conclusion, our results suggest PRGF may not provide beneficial effects against AD and the consideration to utilize growth factors should further be investigated.

Repurposing the KCa3.1 inhibitor senicapoc for Alzheimer's disease.

ObjectiveMicroglia play a pivotal role in the initiation and progression of Alzheimer's disease (AD). We here tested the therapeutic hypothesis that the Ca2+‐activated potassium channel KCa3.1 constitutes a potential target for treating AD by reducing neuroinflammation.MethodsTo determine if KCa3.1 is relevant to AD, we tested if treating cultured microglia or hippocampal slices with Aβ oligomer (AβO) activated KCa3.1 in microglia, and if microglial KCa3.1 was upregulated in 5xFAD mice and in human AD brains. The expression/activity of KCa3.1 was examined by qPCR, Western blotting, immunohistochemistry, and whole‐cell patch‐clamp. To investigate the role of KCa3.1 in AD pathology, we resynthesized senicapoc, a clinically tested KCa3.1 blocker, and determined its pharmacokinetic properties and its effect on microglial activation, Aβ deposition and hippocampal long‐term potentiation (hLTP) in 5xFAD mice.ResultsWe found markedly enhanced microglial KCa3.1 expression/activity in brains of both 5xFAD mice and AD patients. In hippocampal slices, microglial KCa3.1 expression/activity was increased by AβO treatment, and its inhibition diminished the proinflammatory and hLTP‐impairing activities of AβO. Senicapoc exhibited excellent brain penetrance and oral availability, and in 5xFAD mice, reduced neuroinflammation, decreased cerebral amyloid load, and enhanced hippocampal neuronal plasticity.InterpretationOur results prompt us to propose repurposing senicapoc for AD clinical trials, as senicapoc has excellent pharmacological properties and was safe and well‐tolerated in a prior phase‐3 clinical trial for sickle cell anemia. Such repurposing has the potential to expedite the urgently needed new drug discovery for AD.

Uncaria rhynchophylla ameliorates amyloid beta deposition and amyloid beta-mediated pathology in 5XFAD mice

One of the pathological hallmarks of Alzheimer's disease (AD) is the abnormal aggregation of amyloid beta (Aβ) peptides. Uncaria rhynchophylla (UR), one of the Uncaria species, has long been used to treat neurodegenerative disease. In particular, it has been reported that UR inhibits aggregation of Aβ in vitro. However, little is known about the histological effects of UR treatment on Aβ pathology in AD animal models. In the present study, we investigated the effect of UR on Aβ aggregation, Aβ-mediated pathologies and adult hippocampal neurogenesis in the brain of 5XFAD mice. First, using the thioflavin T assay and amyloid staining, we demonstrated that UR treatment effectively inhibited Aβ aggregation and accumulation in the cortex and subiculum. Second, immunofluorescence staining showed that administration of UR attenuated gliosis and neurodegeneration in the subiculum and cortex. Third, UR treatment ameliorated impaired adult hippocampal neurogenesis. The present results indicate that UR significantly alleviates Aβ deposition and Aβ-mediated neuropathology in the brain in 5XFAD mice, suggesting the potency of UR as a preventive and therapeutic agent for AD.

Short-Term Fish Oil Treatment Changes the Composition of Phospholipids While Not Affecting the Expression of Mfsd2a Omega-3 Transporter in the Brain and Liver of the 5xFAD Mouse Model of Alzheimer's Disease.

Long-term fish oil (FO) supplementation is able to improve Alzheimer’s disease (AD) pathology. We aimed to determine the impact of short-term fish oil (FO) intake on phospholipids composition and plaque pathology in 5xFAD mice, a widely used animal model of AD. A 3-week-long FO supplementation administered at 3 months of age decreased the number of dense core plaques in the 5xFAD cortex and changed phospholipids in the livers and brains of wild-type (Wt) and 5xFAD mice. Livers of both genotypes responded by increase of n-3 and reciprocal decrease of n-6 fatty acids. In Wt brains, FO supplementation induced elevation of n-3 fatty acids and subsequent enhancement of n-6/n-3 ratio. However, in 5xFAD brains the improved n-6/n-3 ratio was mainly due to FO-induced decrease in arachidonic and adrenic n-6 fatty acids. Also, brain and liver abundance of n-3 fatty acids were strongly correlated in Wts, oppositely to 5xFADs where significant brain-liver correlation exists only for n-6 fatty acids. Expression of omega-3 transporter Mfs2a remained unchanged after FO supplementation. We have demonstrated that even a short-term FO intake improves the phospholipid composition and has a significant effect on plaque burden in 5xFAD brains when applied in early stages of AD pathology.

Visualization of Altered Hippocampal Connectivity in an Animal Model of Alzheimer\u2019s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline and neurodegeneration in the hippocampus. Despite the pathological importance of the hippocampal degeneration in AD, little topographical evidence exists of impaired hippocampal connectivity in patients with AD. To investigate the anatomical connections of the hippocampus, we injected the neurotracer 1,1′-dioctadecyl-3,3,3′3,3′-tetramethyl-indocarbocyanine perchlorate (DiI) into the hippocampi of 5XFAD mice, which were used as an animal model of AD. In wild-type controls, DiI-containing cells were found in the entorhinal cortex, medial septum, locus coeruleus, dorsal raphe, substantia nigra pars compacta, and olfactory bulb. Hippocampal inputs were decreased in multiple brain regions in the 5XFAD mice compared to wild-type littermate mice. These results are the first to reveal alterations at the cellular level in hippocampal connectivity in the brains of 5XFAD mice. These results suggest that anatomical mapping of hippocampal connectivity will elucidate new pathogenic mechanisms and therapeutic targets for AD treatment.

Long-term RF exposure on behavior and cerebral glucose metabolism in 5xFAD mice

Given the increased public concern about the deleterious biological consequences of radiofrequency electromagnetic fields (RF-EMFs), the involvement of RF-EMFs in neurodegenerative diseases, especially Alzheimer’s disease (AD), has received increased consideration. To investigate the effect of long-term RF-EMF exposure on AD progression, we exposed 5xFAD mice to 1950 MHz RF-EMF at a specific absorption rate of 5.0 W/kg for 2 h/day and 5 days/week for 8 months. Behavioral changes were assessed by an open field test and an object recognition memory task after RF exposure was terminated. In addition, cerebral glucose metabolism was analyzed in the brains of the 5xFAD mice using 18F-deoxyglucose positron emission tomography. The hyperactivity-like and anxiolytic behaviors of the 5xFAD mice in open field tests were rescued by RF exposure. Furthermore, long-term RF-EMF exposure improved the cognitive deficits of 5xFAD mice that were observed in the object recognition memory test. Consistent with the behavioral changes, glucose metabolism in the hippocampus and amygdala regions of the brains of 5xFAD mice following RF exposure was significantly increased compared to glucose metabolism in the brains of sham-exposed mice. These data suggest that long-term exposure to RF-EMF might exert beneficial effects on AD in 5xFAD mice.

Role of microglial amylin receptors in mediating beta amyloid (A\u03b2)-induced inflammation

BackgroundNeuroinflammation in the brain consequent to activation of microglia is viewed as an important component of Alzheimer’s disease (AD) pathology. Amyloid beta (Aβ) protein is known to activate microglia and unleash an inflammatory cascade that eventually results in neuronal dysfunction and death. In this study, we sought to identify the presence of amylin receptors on human fetal and murine microglia and determine whether Aβ activation of the inflammasome complex and subsequent release of cytokines is mediated through these receptors.MethodsThe presence of dimeric components of the amylin receptor (calcitonin receptor and receptor activity modifying protein 3) were first immunohistochemically identified on microglia. Purified human fetal microglial (HFM) cultures were incubated with an in vivo microglial marker, DyLight 594-conjugated tomato lectin, and loaded with the membrane-permeant green fluorescent dye, Fluo-8L-AM for measurements of intracellular calcium [Ca2+]i. HFM and BV-2 cells were primed with lipopolysaccharide and then exposed to either human amylin or soluble oligomeric Aβ1–42 prior to treatment with and without the amylin receptor antagonist, AC253. Changes in the inflammasome complex, NLRP3 and caspase-1, were examined in treated cell cultures with Western blot and fluorometric assays. RT-PCR measurements were performed to assess cytokine release. Finally, in vivo studies were performed in transgenic mouse model of AD (5xFAD) to examine the effects of systemic administration of AC253 on markers of neuroinflammation in the brain.ResultsAcute applications of human amylin or Aβ1–42 resulted in an increase in [Ca2+]i that could be blocked by the amylin receptor antagonist, AC253. Activation of the NLRP3 and caspase-1 and subsequent release of cytokines, TNFα and IL-1β, was diminished by AC253 pretreatment of HFMs and BV2 cells. In vivo, intraperitoneal administration of AC253 resulted in a reduction in microglial markers (Iba-1 and CD68), caspase-1, TNFα, and IL-1β. These reductions in inflammatory markers were accompanied by reduction in amyloid plaque and size in the brains of 5xFAD mice compared to controls.ConclusionMicroglial amylin receptors mediate Aβ-evoked inflammation, and amylin receptor antagonists therefore offer an attractive therapeutic target for intervention in AD.

Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer's disease

Cytochrome P450 46A1 (CYP46A1 or cholesterol 24-hydroxylase) controls cholesterol elimination from the brain and plays a role in higher order brain functions. Genetically enhanced CYP46A1 expression in mouse models of Alzheimer's disease mitigates the manifestations of this disease. We enhanced CYP46A1 activity pharmacologically by treating 5XFAD mice, a model of rapid amyloidogenesis, with a low dose of the anti-HIV medication efavirenz. Efavirenz was administered from 1 to 9 months of age, and mice were evaluated at specific time points. At one month of age, cholesterol homeostasis was already disturbed in the brain of 5XFAD mice. Nevertheless, efavirenz activated CYP46A1 and mouse cerebral cholesterol turnover during the first four months of administration. This treatment time also reduced amyloid burden and microglia activation in the cortex and subiculum of 5XFAD mice as well as protein levels of amyloid precursor protein and the expression of several genes involved in inflammatory response. However, mouse short-term memory and long-term spatial memory were impaired, whereas learning in the context-dependent fear test was improved. Additional four months of drug administration (a total of eight months of treatment) improved long-term spatial memory in the treated as compared to the untreated mice, further decreased amyloid-β content in 5XFAD brain, and also decreased the mortality rate among male mice. We propose a mechanistic model unifying the observed efavirenz effects. We suggest that CYP46A1 activation by efavirenz could be a new anti-Alzheimer's disease treatment and a tool to study and identify normal and pathological brain processes affected by cholesterol maintenance.

Crocus sativus Extract Tightens the Blood-Brain Barrier, Reduces Amyloid β Load and Related Toxicity in 5XFAD Mice.

Crocus sativus, commonly known as saffron or Kesar, is used in Ayurveda and other folk medicines for various purposes as an aphrodisiac, antispasmodic, and expectorant. Previous evidence suggested that Crocus sativus is linked to improving cognitive function in Alzheimer's disease (AD) patients. The aim of this study was to in vitro and in vivo investigate the mechanism(s) by which Crocus sativus exerts its positive effect against AD. The effect of Crocus sativus extract on Aβ load and related toxicity was evaluated. In vitro results showed that Crocus sativus extract increases the tightness of a cell-based blood-brain barrier (BBB) model and enhances transport of Aβ. Further in vivo studies confirmed the effect of Crocus sativus extract (50 mg/kg/day, added to mice diet) on the BBB tightness and function that was associated with reduced Aβ load and related pathological changes in 5XFAD mice used as an AD model. Reduced Aβ load could be explained, at least in part, by Crocus sativus extract effect to enhance Aβ clearance pathways including BBB clearance, enzymatic degradation and ApoE clearance pathway. Furthermore, Crocus sativus extract upregulated synaptic proteins and reduced neuroinflammation associated with Aβ pathology in the brains of 5XFAD mice. Crocin, a major active constituent of Crocus sativus and known for its antioxidant and anti-inflammatory effect, was also tested separately in vivo in 5XFAD mice. Crocin (10 mg/kg/day) was able to reduce Aβ load but to a lesser extent when compared to Crocus sativus extract. Collectively, findings from this study support the positive effect of Crocus sativus against AD by reducing Aβ pathological manifestations.

Microglia contributes to plaque growth by cell death due to uptake of amyloid β in the brain of Alzheimer's disease mouse model

Pathological hallmarks of Alzheimer's disease (AD) include extracellularly accumulated amyloid β (Aβ) plaques and intracellular neurofibrillary tangles in the brain. Activated microglia, brain-resident macrophages, are also found surrounding Aβ plaques. The study of the brain of AD mouse models revealed that Aβ plaque formation is completed by the consolidation of newly generated plaque clusters in vicinity of existed plaques. However, the dynamics of Aβ plaque formation, growth and the mechanisms by which microglia contribute to Aβ plaque formation are unknown. In the present study, we confirmed how microglia are involved in Aβ plaque formation and their growth in the brain of 5XFAD mice, the Aβ-overexpressing AD transgenic mouse model, and performed serial intravital two-photon microscopy (TPM) imaging of the brains of 5XFAD mice crossed with macrophage/microglia-specific GFP-expressing CX3CR1GFP/GFP mice. We found that activated microglia surrounding Aβ plaques take up Aβ, which are clusters developed inside activated microglia in vivo and this was followed by microglial cell death. These dying microglia release the accumulated Aβ into the extracellular space, which contributes to Aβ plaque growth. This process was confirmed by live TPM in vivo imaging and flow cytometry. These results suggest that activated microglia can contribute to formation and growth of Aβ plaques by causing microglial cell death in the brain. GLIA 2016;64:2274-2290.

Mesenchymal Stem Cells as Treatment for Behavioral Deficits and Neuropathology in the 5xFAD Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by a progressive loss of memory and other cognitive disturbances. The neuropathology of AD includes the major hallmarks of toxic amyloid-β oligomer accumulation and neurofibrillary tangles, as well as increased oxidative stress, cholinergic dysfunction, synapse loss, changes in endogenous neurotrophic factors, and overall degeneration of the brain. Adult mesenchymal stem cells (MSCs) offer the potential for a readily available treatment that would be long lasting, have low likelihood of rejection, and could target a variety of pathological deficits. MSCs have been shown to be effective in alleviating symptoms in some transgenic models of AD, but the optimal location for transplanting MSCs has yet to be determined. In the present study, the behavioral effects of transplantation of MSCs into the lateral ventricles, the hippocampus, or both of these regions were compared in the 5xFAD mouse model of AD. The results indicate that MSC transplants effectively reduce learning deficits in the 5xFAD mouse model and demonstrate a clear impact of MSCs on the levels of Aβ42 in the brains of 5xFAD mice. Overall, these findings support the hypothesis that MSCs may be a viable treatment for AD, especially when injected into the lateral ventricles.

Vitamin D interacts with Esr1 and Igf1 to regulate molecular pathways relevant to Alzheimer's disease.

BackgroundIncreasing evidence suggests a potential therapeutic benefit of vitamin D supplementation against Alzheimer’s disease (AD). Although studies have shown improvements in cognitive performance and decreases in markers of the pathology after chronic treatment, the mechanisms by which vitamin D acts on brain cells are multiple and remain to be thoroughly studied. We analyzed the molecular changes observed after 5 months of vitamin D3 supplementation in the brains of transgenic 5xFAD (Tg) mice, a recognized mouse model of AD, and their wild type (Wt) littermates. We first performed a kinematic behavioural examination at 4, 6 and 8 months of age (M4, M6 and M8) followed by a histologic assessment of AD markers. We then performed a comparative transcriptomic analysis of mRNA regulation in the neocortex and hippocampus of 9 months old (M9) female mice.ResultsTranscriptomic analysis of the hippocampus and neocortex of both Wt and Tg mice at M9, following 5 months of vitamin D3 treatment, reveals a large panel of dysregulated pathways related to i) immune and inflammatory response, ii) neurotransmitter activity, iii) endothelial and vascular processes and iv) hormonal alterations. The differentially expressed genes are not all direct targets of the vitamin D-VDR pathway and it appears that vitamin D action engages in the crosstalk with estrogen and insulin signaling. The misexpression of the large number of genes observed in this study translates into improved learning and memory performance and a decrease in amyloid plaques and astrogliosis in Tg animals.ConclusionsThis study underlies the multiplicity of action of this potent neurosteroid in an aging and AD-like brain. The classical and non-classical actions of vitamin D3 can act in an additive and possibly synergistic manner to induce neuroprotective activities in a context-specific way.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0087-2) contains supplementary material, which is available to authorized users.

PHF-tau propagation in the presence of Amyloid ß pathology

PHF-tau propagation in the presence of Amyloid ß pathology

Recent nanomedicine articles of outstanding interest: functional nanomaterials for Brain Research through Advancing Innovative Neurotechnologies initiative.

2016 Alzheimer’s disease diagnostics & therapy Aβ oligomer-targeted magnetic nanoparticles for early-stage Alzheimer’s disease diagnosis Evaluation of: Viola KL, Sbarboro J, Sureka R et al. Towards non-invasive diagnostic imaging of early-stage Alzheimer’s disease. Nat. Nanotechnol. 10(1), 91–98 (2015). Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease, affecting one in nine people over the age of 65 years [1]. Despite huge personal and economic costs, development of efficacious treatments for AD is being held back by the lack of powerful diagnostic methods. Neurotoxic amyloid β oligomers (AβOs) are considered appropriate biomarkers for AD because AβOs appear early in the brain of patients with AD as main initiators of synapse failure [2]. Therefore, an AβO-directed imaging diagnostic would provide molecule-targeted contrast for localization of early AβO accumulation in AD. Recently, Viola et al. reported a biocompatible, strong T2 contrast nanoprobe for MRI of AD-related AβOs [3]. They selected an Fe 3 O 4 magnetic nanostructure (MNS) and a monoclonal NU4 antibody as a T2 contrast platform and a recognizer of AβOs, respectively. Twelve to sixteen nanometer MNSs were synthesized by thermal decomposition of an iron-oleate complex and stabilized by nitro-dopamine as the surface anchor group and polyethylene glycol as a spacer. The NU4-conjugated MNS retained the high affinity and specificity of the parent antibody allowing for quick reaching toxic AβOs oligomers in vivo. AβO-targeted MNSs were delivered by intranasal administration and crossed the blood–brain barrier (BBB) to reach AβOs in the brain of 5XFAD mice. The MRI probe detected AD-causing AβOs in the mouse model within 4 h after administration and showed significant clearance from the brain within 96 h after administration. The development of nanomaterials targeting AβOs has diagnostic potential for early-stage AD.