Transgenic Alzheimer's Disease Model Research Articles

Activity Rhythms Are Largely Intact in APPNL-G-F Alzheimer's Disease Mice.

Circadian rhythm dysfunction is present in Alzheimer's disease. Animal models of Alzheimer's disease have been employed to investigate whether this dysfunction is a risk factor or symptom of the disease. The circadian phenotype in mouse models of Alzheimer's disease is very disparate in terms of the degree and timing of the dysfunction. This is likely a result of some models elevating amyloid-β protein precursor instead of just the amyloid-β fragment present in human Alzheimer's disease. We characterized activity rhythms in a novel knock-in mouse model (APPNL-G-F) of Alzheimer's disease that elevates amyloid-β without overexpressing amyloid-β protein precursor. Despite increased rhythm amplitude, total activity, and a shortening of free-running period at 15 months of age, all other aspects of the activity rhythm were similar to controls from three to fifteen months of age. At two months of age, these mice were also able to entrain to a light-dark cycle with a period right on the edge of entrainment, which further suggests a healthy functioning circadian system. These data open the possibility that circadian rhythm disruptions in transgenic models of Alzheimer's disease could be a result of these models having an artificial phenotype caused by overexpression of amyloid-β protein precursor.

Overview of Transgenic Mouse Models for Alzheimer's Disease.

This review describes several transgenic mouse models of Alzheimer's disease (AD), a devastating neurodegenerative disorder that causes progressive cognitive decline and is diagnosed postmortem by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal tau neurofibrillary tangles in the cerebral cortex. Currently there is no intervention that cures, prevents, or even slows disease progression. Its complex etiology and pathology pose significant challenges for animal model development, and there is no single model that faithfully recapitulates both the pathological aspects and behavioral phenotypes of AD. Nearly 200 transgenic rodent models of AD have been generated primarily based on mutations linked to Aβ protein misprocessing in the familial form of the disease. More recent models incorporate mutations in tau protein, as well as mutations associated with the sporadic form of the disease. The salient features, strengths, limitations, and key differentiators for the most commonly used and best characterized of these models are considered here. While the translational utility of many of these models to assess the potential of novel therapeutics is in dispute, knowledge of the different models available and a detailed understanding of their features can aid in the selection of the optimal model to explore disease mechanisms or evaluate candidate medications. We comment on the predictive utility of these models considering recent clinical trial failures and discuss trends and future directions in the development of models for AD based on the plethora of clinical data that have been generated over the last decade. © 2019 by John Wiley & Sons, Inc.

Targeted Lipidomics Investigation of N‐acylethanolamines in a Transgenic Mouse Model of AD: A Longitudinal Study

In the present work, mice overexpressing mutant amyloid precursor protein (Tg2576), a transgenic model of Alzheimer's disease (AD), are used to investigate a specific lipid profile over the course of disease progression. Using a targeted lipidomic approach, plasma levels of N‐acylethanolamines with different length and unsaturation at presymptomatic, mild‐symptomatic, and symptomatic disease stages are measured. Moreover, N‐acylethanolamines are also assessed in the brain areas most affected in AD. The ethanolamides of palmitic, oleic, arachidonic, eicosapentaenoic, and docosahexaenoic acids do not show any significant alteration in blood of Tg2576 mice at the different stages analyzed, as compared to wild‐type. Except for N‐docosahexaenoylethanolamine, a general tendency to decrease is instead detected for all measured N‐acylethanolamines in the cortex, hippocampus, striatum, and cerebellum of symptomatic Tg2576 mice. Together, the data can help to redefine the range of lipid‐associated signals in Alzheimer pathophysiology.Practical Application: The development of novel therapies for AD is strongly narrowed not only by the lack of a full comprehension of underlying pathophysiological mechanisms but also by the absence of affordable, reliable, and noninvasive biomarkers. Hence, there is the practical necessity to acquire accessible blood biomarkers to provide rapid, cost‐effective, and critical information to timely identify disease stage and implement preventive strategies aimed at slowing down cognitive decline. In this study, a targeted lipidomics investigation of N‐acylethanolamines at different stages of disease progression, clearly indicates that the discovery of innovative blood biomarkers should be refocused on different indices of deranged lipid metabolism for a realistic prediction of the risk of AD.It is investigated that potential alterations of N‐acylethanolamines content during disease development in a transgenic mouse model of Alzheimer's disease (AD). Circulating and central N‐acylethanolamine levels did not show any alteration in Tg2576 mice at different disease stages.

Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease

Drug repurposing is an efficient strategy for new drug discovery. Our latest study found that nitazoxanide (NTZ), an approved anti-parasite drug, was an autophagy activator and could alleviate the symptom of Alzheimer's disease (AD). In order to further improve the efficacy and discover new chemical entities, a series of NTZ-based derivatives were designed, synthesized, and evaluated as autophagy activator against AD. All compounds were screened by the inhibition of phosphorylation of p70S6K, which was the direct substrate of mammalian target of rapamycin (mTOR) and its phosphorylation level could reflect the mTOR-dependent autophagy level. Among these analogs, compound 22 exhibited excellent potency in promoting β-amyloid (Aβ) clearance, inhibiting tau phosphorylation, as well as stimulating autophagy both in vitro and in vivo. What's more, 22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice. These results demonstrated that 22 was a potential candidate for the treatment of AD.

Loss of Midbrain Dopamine Neurons and Altered Apomorphine EEG Effects in the 5xFAD Mouse Model of Alzheimer's Disease.

Cognitive malfunction, synaptic dysfunction, and disconnections in neural networks are core deficits in Alzheimer's disease (AD). 5xFAD mice, a transgenic model of AD, are characterized by an enhanced level of amyloid-β and abnormal neurotransmission. The dopaminergic (DA) system has been shown to be involved in amyloid-β transformations and neuronal plasticity; however, its role in functional network changes in familial AD still remains unclear. In 5xFAD and non-transgenic freely moving mice, electroencephalograms (EEGs) were simultaneously recorded from the secondary motor cortex (MC), superficial layers of the hippocampal CA1 area (HPC), substantia nigra (SN), and ventral tegmental area (VTA). EEGs and their frequency spectra were analyzed before and after systemic injection of a DA receptor agonist, apomorphine (APO). In the baseline EEG from MC and HPC of 5xFAD mice, delta and alpha oscillations were enhanced and beta activity was attenuated, compared to control mice. In VTA and SN of 5xFAD mice, delta-theta activity was decreased and beta oscillations dominated. In control mice, APO suppressed delta activity in VTA to a higher extent than in MC, whereas in 5xFAD mice, this difference was eliminated due to attenuation of the delta suppression in VTA. APO increased beta activity in MC of mice from both groups while significant beta suppression was observed in VTA of 5xFAD mice. These mice were characterized by significant decrease of tyrosine hydroxylase immunopositive cells in both VTA and SN and of DA transporter in MC and hippocampal dentate gyrus. We suggest that the EEG modifications observed in 5xFAD mice are associated with alterations in dopaminergic transmission, resulting in adaptive changes in the cerebral networks in the course of familial AD development.

Molecular mechanism of adiponectin in alleviating the anxiety- and depression-like behaviors in triple transgenic Alzheimer's disease model mice

Objective To observe the effects of adiponectin (APN) on anxiety- and depression-like behaviors occurred in APP/PS1/tau triple transgenic Alzheimer’s disease (3xTg-AD) model mice and investigate the possible mechanism. Methods The 9-month-old 3xTg-AD mice and wild type (WT) mice were randomly divided into four groups (n=8 for each group): WT+ Saline, WT+ APN, 3xTg-AD+ Saline and 3xTg-AD+ APN groups. The mouse was chronically intracerebroventricular injection of APN or saline under free moving condition.Elevated plus maze task was used to evaluate the anxiety-like behaviors.Sucrose preference test and tail suspension test were used to evaluate the depression-like behaviors. Western blot was used to detect the protein expression levels of p-AMPK, AMPK, p-GSK-3β (Ser9), GSK-3β and SIRT1 in the hippocampus of each mouse. Results In the elevated plus maze test, the time percentage spent in open arms of 3xTg-AD+ Saline mice was ((4.2±2.7)%), which significantly lower than that in WT+ Saline group ((10.1±4.1)%)(q=4.349, P<0.01) and in 3xTg-AD+ APN group ((9.7±3.3)%)(q=4.065, P<0.01). In the sucrose preference test, the sucrose preference percentage in 3xTg-AD+ Saline group((48.8±5.3)%) was lower than that in WT+ Saline group ((60.9±6.7)%)(q=4.522, P<0.01) and in 3xTg-AD+ APN group ((59.3±6.2)%)(q=3.911, P<0.05). As for tail suspension test, the immobility time percentage in 3xTg-AD+ Saline group((40.7±9.9)%) was higher than that in WT+ Saline group ((27.1±4.8)%)(q=5.257, P<0.001) and in 3xTg-AD+ APN group ((31.4±6.0)%)(q=3.624, P<0.05). The result of Western blot showed that there was no significant difference in expression level of AMPK and GSK-3β among four groups. However, compared with that in WT+ Saline group, the expression levels of p-AMPK (q=3.586, P<0.05), p-GSK-3β (Ser9) (q=3.125, P<0.05), and SIRT1 (q=3.044, P<0.05) in 3xTg-AD+ Saline group were significantly decreased. In addition, compared with that in 3xTg-AD+ Saline group, the expression levels of p-AMPK (q=3.374, P<0.05) and p-GSK-3β (Ser9) (q=3.063, P<0.05) in 3xTg-AD+ APN group were obviously up-regulated without affecting the SIRT1. Conclusion Adiponectin can effectively alleviate the anxiety- and depression-like behaviors of 9-month-old 3xTg-AD mice by up-regulating the protein expression of p-AMPK and p-GSK-3β (Ser9) in the hippocampus. Key words: Adiponectin; Alzheimer’s disease (AD); APP/PS1/Tau triple-transgenic AD (3xTg-AD) mice; Anxiety; Depression

M1 Muscarinic Receptor Activation Rescues β-Amyloid-Induced Cognitive Impairment through AMPA Receptor GluA1 Subunit

M1 muscarinic receptors have long been identified as a potential therapeutic target for the treatment of cognitive impairment in Alzheimer's disease (AD). Our previous study has shown that M1 receptors promote membrane insertion and synaptic delivery of AMPA receptor GluA1 subunit. In this study, we sought to determine whether activation of M1 receptor would rescue the cognitive impairment in AD model mice through modulation of GluA1 subunit. For the mice injected with aggregated β-amyloid (Aβ) fragments to impair learning and memory, activation of M1 receptors could rescue it by reducing the latency to find the platform and spending more time in the target quadrant in the probe test in the Morris water maze. However, such an effect was ablated in mice with Ser845 residue of GluA1 mutated to alanine. Furthermore, the activation of M1 receptors enhanced the expression of GluA1 and its phosphorylation at Ser845 and drove GluA1 to incorporate with PSD95, a postsynaptic marker, in the hippocampi from Aβ-injected wild type mice but not from the mutant mice. Moreover, for 9-month-old APP/PS1 transgenic AD model mice, which may resemble the late AD, M1 receptor activation could not improve the cognitive impairment significantly. In addition, the enhancement of GluA1 expression and its phosphorylation at Ser845 were not observed in their hippocampi. Taken together, the study indicated that M1 receptor activation rescued the cognitive deficit through modulating the trafficking of GluA1-containing AMPA receptors and the therapeutics targeting M1 receptors should aim at mild AD or even pre-AD.

Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer\u2019s disease: study protocol for a randomised controlled trial (ELAD study)

BackgroundLiraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer’s disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer’s disease compared to those who are receiving placebo.Methods/designELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer’s dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer’s Disease Assessment Scale—Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer’s Disease Cooperative Study—Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group.DiscussionAlzheimer’s disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer’s treatment.Trial registrationClinicalTrials.gov, NCT01843075. Registration 30 April 2013.

Glia Maturation Factor‐Antibody Injection Reduces Behavioral Impairment, Neuro Inflammation and Amyloid Pathology in 5XFAD Mice Brains

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of beta‐amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain. Emerging evidence suggested that in neurodegenerative disease, aggregation of these proteins can promotes neuroinflammation and neurodegeneration. Glia maturation factor (GMF), a neuroinflammatory protein isolated and cloned in our laboratory play an important role in the pathogenesis of AD. To study the relationship between overexpression of GMF, glial activation and neuroinflammation, we used 9‐month‐old 5XFAD mice, a transgenic model of AD. We intravenously (iv) injected single dose of GMF antibody and found that antibody injection leads to: improvements in behavioral deficits, decreased activation of glial cells and reduced expression of pro‐inflammatory cytokines and amyloid pathology. We report that aberrant expression of GMF, GFAP, IBA1, and co‐localization of GMF with GFAP, IBA1 and Aβ significantly more in 5XFAD mice as compared with wild type mice. However, following GMF antibody injection, we found significant reduced expression of GMF, GFAP, IBA1 and Aβ in the cortex region of 5XFAD mice. We conclude that GMF‐antibody may be used to reduce neuroinflammation in neurodegenerative diseases including Alzheimer's disease.Support or Funding InformationNational Institutes of Health Grants NS073670, AG048205 and Veterans Affairs Merit Award I01BX002477 to AZ.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Impaired Glucose Tolerance and Reduced Plasma Insulin Precede Decreased AKT Phosphorylation and GLUT3 Translocation in the Hippocampus of Old 3xTg-AD Mice.

Several studies have demonstrated that mouse models of Alzheimer's disease (AD) can exhibit impaired peripheral glucose tolerance. Further, in the APP/PS1 mouse model, this is observed prior to the appearance of AD-related neuropathology (e.g., amyloid-β plaques; Aβ) or cognitive impairment. In the current study, we examined whether impaired glucose tolerance also preceded AD-like changes in the triple transgenic model of AD (3xTg-AD). Glucose tolerance testing (GTT), insulin ELISAs, and insulin tolerance testing (ITT) were performed at ages prior to (1-3 months and 6-8 months old) and post-pathology (16-18 months old). Additionally, we examined for altered insulin signaling in the hippocampus. Western blots were used to evaluate the two-primary insulin signaling pathways: PI3K/AKT and MAPK/ERK. Since the PI3K/AKT pathway affects several downstream targets associated with metabolism (e.g., GSK3, glucose transporters), western blots were used to examine possible alterations in the expression, translocation, or activation of these targets. We found that 3xTg-AD mice display impaired glucose tolerance as early as 1 month of age, concomitant with a decrease in plasma insulin levels well prior to the detection of plaques (∼14 months old), aggregates of hyperphosphorylated tau (∼18 months old), and cognitive decline (≥18 months old). These alterations in peripheral metabolism were seen at all time points examined. In comparison, PI3K/AKT, but not MAPK/ERK, signaling was altered in the hippocampus only in 18-20-month-old 3xTg-AD mice, a time point at which there was a reduction in GLUT3 translocation to the plasma membrane. Taken together, our results provide further evidence that disruptions in energy metabolism may represent a foundational step in the development of AD.

Dysfunctional microglia:neuron interactions with significant female bias in a developmental gene x environment rodent model of Alzheimer's disease

Signaling between microglia and neurons is poorly characterized in the pathophysiology of Alzheimer's disease (AD), particularly with regards to gene and environmental (GxE) interactions early in life. This study investigated the maladaptation of microglia:neuron signaling and subsequent susceptibility to neurodegeneration using a developmental origin of adult disease (DOAD) model of AD, characterized previously. Here, we report that postnatal exposure to lead (Pb) in a transgenic (Tg) rodent model of AD resulted in significant female bias consequent to GxE interactions. Atypical, non-neuroprotective microglial phenotypes were observed months after cessation of Pb exposure, as well as evidence for neuronal compensation, that was not observed in WT mice. Specifically, microglia from Pb-exposed Tg (GxE) females exhibited atypical polarization profiles for activation earlier and more severely than males and WT mice, that persisted over time to become contextually maladaptive. By postnatal day (PND) 240, microglia from GxE females also sequestered less neurotoxic iron in the hippocampus. In the same GxE female population, measures of neuronal parameters, such as hippocampal TrkB expression, revealed evidence of disharmonious and compensatory interactions with microglia within the pathological progression. Likewise, GxE interactions resulted in female-biased, late-life changes to key synaptic proteins crucial to synapse dynamics and microglial signaling. These incongruent microglia:neuronal dynamics were observed in GxE males at later ages compared to females, and not observed in either gene- or environment-only populations. Altogether, our results support a gene x environment model of female-biased microglial susceptibility to later-life development of AD, and highlight markers for maladaptive microglia:neuron signaling and compensation.

Magnetic resonance imaging of noradrenergic neurons

Noradrenaline is a neurotransmitter involved in general arousal, selective attention, memory, inflammation, and neurodegeneration. The purpose of this work was to delineate noradrenergic neurons in vivo by T1-weighted MRI with magnetization transfer (MT). In the brainstem of human and mice, MRI identified the locus coeruleus, dorsal motor vagus nucleus, and nucleus tractus solitarius. Given (1) the long T1 and low magnetization transfer ratio for the noradrenergic cell groups compared to other gray matter, (2) significant correlation between MT MRI signal intensity and proton density, and (3) no correlation between magnetization transfer ratio (or R1) and iron, copper, or manganese in human brain, the high MRI signal of the noradrenergic neurons must be attributed to abundant water protons interacting with any T1-shortening paramagnetic ions in active cells rather than to specific T1-shortening molecules. The absence of a high MRI signal from the locus coeruleus of Ear2(−/−) mice lacking noradrenergic neurons confirms that cell bodies of noradrenergic neurons are the source of the bright MRI appearance. The observation of this high signal in DBH(−/−) mice, in 3-week-old mice, and in mice under hyperoxia/hypercapnia/hypoxia together with the general absence of neuromelanin (NM) in noradrenergic neurons of young rodents further excludes that it is due to NM, dopamine β-hydroxylase, their binding to paramagnetic ions, blood inflow, or hemoglobin. Instead, these findings indicate a high density of water protons whose T1 is shortened by paramagnetic ions as the relevant source of the high MRI signal. In the brain of APP/PS1/Ear2(−/−) mice, a transgenic model of Alzheimer’s disease, MRI detected noradrenergic neuron loss in the locus coeruleus. Proton magnetic resonance spectroscopy revealed that a 60–75% reduction of noradrenaline is responsible for a reduction of N-acetylaspartate and glutamate in the hippocampus as well as for a shortening of the water proton T2 in the frontal cortex. These results suggest that a concurrent shortage of noradrenaline in Alzheimer’s disease accelerates pathologic processes such as inflammation and neuron loss.

Systems biology identifies preserved integrity but impaired metabolism of mitochondria due to a glycolytic defect in Alzheimer's disease neurons.

Mitochondrial dysfunction is implicated in most neurodegenerative diseases, including Alzheimer's disease (AD). We here combined experimental and computational approaches to investigate mitochondrial health and bioenergetic function in neurons from a double transgenic animal model of AD (PS2APP/B6.152H). Experiments in primary cortical neurons demonstrated that AD neurons had reduced mitochondrial respiratory capacity. Interestingly, the computational model predicted that this mitochondrial bioenergetic phenotype could not be explained by any defect in the mitochondrial respiratory chain (RC), but could be closely resembled by a simulated impairment in the mitochondrial NADH flux. Further computational analysis predicted that such an impairment would reduce levels of mitochondrial NADH, both in the resting state and following pharmacological manipulation of the RC. To validate these predictions, we utilized fluorescence lifetime imaging microscopy (FLIM) and autofluorescence imaging and confirmed that transgenic AD neurons had reduced mitochondrial NAD(P)H levels at rest, and impaired power of mitochondrial NAD(P)H production. Of note, FLIM measurements also highlighted reduced cytosolic NAD(P)H in these cells, and extracellular acidification experiments showed an impaired glycolytic flux. The impaired glycolytic flux was identified to be responsible for the observed mitochondrial hypometabolism, since bypassing glycolysis with pyruvate restored mitochondrial health. This study highlights the benefits of a systems biology approach when investigating complex, nonintuitive molecular processes such as mitochondrial bioenergetics, and indicates that primary cortical neurons from a transgenic AD model have reduced glycolytic flux, leading to reduced cytosolic and mitochondrial NAD(P)H and reduced mitochondrial respiratory capacity.

Trans ε viniferin decreases amyloid deposits and inflammation in a mouse transgenic Alzheimer model.

As Alzheimer’s disease (AD) induces several cellular and molecular damages, it could be interesting to use multi-target molecules for therapeutics. We previously published that trans ε-viniferin induced the disaggregation of Aβ42 peptide and inhibited the inflammatory response in primary cellular model of AD. Here, effects of this stilbenoid were evaluated in transgenic APPswePS1dE9 mice. We report that trans ε-viniferin could go through the blood brain barrier, reduces size and density of amyloid deposits and decreases reactivity of astrocytes and microglia, after a weekly intraperitoneal injection at 10 mg/kg from 3 to 6 months of age.

Naringenin promotes microglial M2 polarization and Aβ degradation enzyme expression.

Two kinds of microglia are known, classical M1 and alternative M2 phenotypes. Amyloid β (Aβ), a critical cause of Alzheimer's disease (AD), promotes M1 microglial polarization, leading to neuroinflammation and neuronal death. M2 microglia play important roles in anti-inflammatory effects, Aβ clearance, and memory recovery in AD. Therefore, increasing of M2 microglia is expected to recover from AD. We previously found that naringenin, a blood-brain barrier penetrating compound, decreased Aβ deposits and recovers memory function in transgenic AD model mice. Naringenin reportedly showed anti-inflammatory properties. Here, we aim to investigate potential effects of naringenin on microglial polarization and to reveal the underlying mechanisms of Aβ reduction. Primary cultured cortical microglia were treated with Aβ1-42 , following administration of naringenin. Naringenin remarkably promoted M2 microglia polarization and inhibited Aβ1-42 -induced M1 microglia activation. Because microglia reportedly played a critical role in cerebral Aβ clearance through Aβ degradation enzymes after phagocytosis, we investigated the expression of Aβ degradation enzymes, such as neprilysin and insulin degradation enzyme. After naringenin treatment, these Aβ degradation enzymes were downregulated in M1 microglia and upregulated in M2 microglia. Taken together, our results showed that naringenin increased Aβ degradation enzymes in M2 microglia, probably leading to Aβ plaque reduction.

Imbalance of Microglial TLR4/TREM2 in LPS-Treated APP/PS1 Transgenic Mice: A Potential Link Between Alzheimer's Disease and Systemic Inflammation.

Clinically, superimposed systemic inflammation generally has significant deleterious effects on the Alzheimer's disease (AD) progression. However, the related molecular mechanisms remain poorly understood. Microglial toll-like receptor 4 (TLR4) and triggering receptor expressed on myeloid cells 2 (TREM2) are two key regulators of inflammation that may play an essential role in this complex pathophysiological process. In this study, intraperitoneal injection of lipopolysaccharide (LPS) into APP/PS1 transgenic AD model was used to mimic systemic inflammation in the development of AD. Initial results from the cortex showed that compared with wild-type mice, APP/PS1 mice exhibited elevated gene and protein expression levels of both TLR4 and TREM2 with different degree. Interestingly, after LPS treatment, TLR4 expression was persistently up-regulated, while TREM2 expression was significantly down-regulated in APP/PS1 mice, suggesting that the negative regulatory effect of TREM2 on inflammation might be suppressed by LPS-induced hyperactive TLR4. This imbalance of TLR4/TREM2 contributed to microglial over-activation, followed by increased neuronal apoptosis in the cortex of APP/PS1 mice; these changes did not alter the expression level of Aβ1-42. Similar alterations were observed in our in vitro experiment with β-amyloid1-42 (Aβ1-42)-treated N9 microglia. Further, Morris water maze (MWM) testing data indicated that LPS administration acutely aggravated cognitive impairment in APP/PS1 mice, suggesting that the addition of systemic inflammation can potentially accelerate the progression of AD. Collectively, we conclude that an imbalance of TLR4/TREM2 may be a potential link between AD and systemic inflammation. TREM2 can serve as a potential therapeutic target for treating systemic inflammation in AD progression.

Metal–Organic Frameworks Harness Cu Chelating and Photooxidation Against Amyloid β Aggregation in Vivo

Recently, photooxygenation of amyloid β (Aβ) has emerged as an effective way to inhibit Aβ aggregation in Alzheimer's disease (AD) treatment. However, their further application has been highly obstructed by self-aggregation, no metal chelating ability, and poor protein-enrichment capacity. Herein, porphyrinic metal-organic frameworks (PMOFs) are utilized as a superior CuII chelating and photooxidation agent for inhibiting Aβ aggregation. We selected only four classical kinds of POMFs (Zr-MOF, Al-MOF, Ni-MOF, Hf-MOF) for further investigation in our study, which are stable in physiological conditions and exhibit excellent biocompatibility. Among them, Hf-MOF was the most efficient Aβ photooxidant. A possible explanation about the difference in capacity of 1 O2 generation of these four PMOFs has been provided according to the experimental results and DFT calculations. Furthermore, Hf-MOFs are modified with Aβ-targeting peptide, LPFFD. This can not only enhance Hf-MOFs targeting cellular Aβ to decrease Aβ-induced cytotoxicity, but also improve Aβ photooxidation in the complicated living environment. More intriguingly, in vivo studies indicate that the well-designed LPFFD modified Hf-MOFs can decrease Aβ-induced neurotoxicity and extend the longevity of the commonly used transgenic AD model Caenorhabditis elegans CL2006. Our work may open a new avenue for using MOFs as neurotoxic-metal-chelating and photo-therapeutic agents for AD treatment.

Amelioration of Alzheimer's disease pathology and cognitive deficits by immunomodulatory agents in animal models of Alzheimer's disease.

The most common age-related neurodegenerative disease is Alzheimer’s disease (AD) characterized by aggregated amyloid-β (Aβ) peptides in extracellular plaques and aggregated hyperphosphorylated tau protein in intraneuronal neurofibrillary tangles, together with loss of cholinergic neurons, synaptic alterations, and chronic inflammation within the brain. These lead to progressive impairment of cognitive function. There is evidence of innate immune activation in AD with microgliosis. Classically-activated microglia (M1 state) secrete inflammatory and neurotoxic mediators, and peripheral immune cells are recruited to inflammation sites in the brain. The few drugs approved by the US FDA for the treatment of AD improve symptoms but do not change the course of disease progression and may cause some undesirable effects. Translation of active and passive immunotherapy targeting Aβ in AD animal model trials had limited success in clinical trials. Treatment with immunomodulatory/anti-inflammatory agents early in the disease process, while not preventive, is able to inhibit the inflammatory consequences of both Aβ and tau aggregation. The studies described in this review have identified several agents with immunomodulatory properties that alleviated AD pathology and cognitive impairment in animal models of AD. The majority of the animal studies reviewed had used transgenic models of early-onset AD. More effort needs to be given to creat models of late-onset AD. The effects of a combinational therapy involving two or more of the tested pharmaceutical agents, or one of these agents given in conjunction with one of the cell-based therapies, in an aged animal model of AD would warrant investigation.

Aberrant accrual of BIN1 near Alzheimer's disease amyloid deposits in transgenic models.

Bridging integrator 1 (BIN1) is the most significant late-onset Alzheimer's disease (AD) susceptibility locus identified via genome-wide association studies. BIN1 is an adaptor protein that regulates membrane dynamics in the context of endocytosis and membrane remodeling. An increase in BIN1 expression and changes in the relative levels of alternatively spliced BIN1 isoforms have been reported in the brains of patients with AD. BIN1 can bind to Tau, and an increase in BIN1 expression correlates with Tau pathology. In contrast, the loss of BIN1 expression in cultured cells elevates Aβ production and Tau propagation by insfluencing endocytosis and recycling. Here, we show that BIN1 accumulates adjacent to amyloid deposits in vivo. We found an increase in insoluble BIN1 and a striking accrual of BIN1 within and near amyloid deposits in the brains of multiple transgenic models of AD. The peri-deposit aberrant BIN1 localization was conspicuously different from the accumulation of APP and BACE1 within dystrophic neurites. Although BIN1 is highly expressed in mature oligodendrocytes, BIN1 association with amyloid deposits occurred in the absence of the accretion of other oligodendrocyte or myelin proteins. Finally, super-resolution microscopy and immunogold electron microscopy analyses highlight the presence of BIN1 in proximity to amyloid fibrils at the edges of amyloid deposits. These results reveal the aberrant accumulation of BIN1 is a feature associated with AD amyloid pathology. Our findings suggest a potential role for BIN1 in extracellular Aβ deposition in vivo that is distinct from its well-characterized function as an adaptor protein in endocytosis and membrane remodeling.

Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer's disease model mice.

Nicotinamide adenine dinucleotide (NAD) supplementation to repair the disabled mitochondria is a promising strategy for the treatment of Alzheimer's disease (AD) and other dementia. Nicotinamide ribose (NR) is a safe NAD precursor with high oral bioavailability, and has beneficial effects on aging. Here, we applied NR supplied food (2.5g/kg food) to APP/PS1 transgenic AD model mice and aged mice for 3months. Cognitive function, locomotor activity and anxiety level were assessed by standard behavioral tests. The change of body weight, the activation of microglia and astrocytes, the accumulation of Aβ and the level of serum nicotinamide phosphoribosyltransferase (NAMPT) were determined for the evaluation of pathological processes. We found that NR supplementation improved the short-term spatial memory of aged mice, and the contextual fear memory of AD mice. Moreover, NR supplementation inhibited the activation of astrocytes and the elevation of serum NAMPT of aged mice. For AD model mice, NR supplementation inhibited the accumulation of Aβ and the migration of astrocyte to Aβ. In addition, NR supplementation inhibit the body weight gain of aged and APP/PS1 mice. Thus, NR has selective benefits for both AD and aged mice, and the oral uptake of NR can be used to prevent the progression of dementia.