Deficits In Transgenic Mouse Model Research Articles

Cellulose ether treatment inhibits amyloid beta aggregation, neuroinflammation and cognitive deficits in transgenic mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is an incurable, progressive and devastating neurodegenerative disease. Pathogenesis of AD is associated with the aggregation and accumulation of amyloid beta (Aβ), a major neurotoxic mediator that triggers neuroinflammation and memory impairment. Recently, we found that cellulose ether compounds (CEs) have beneficial effects against prion diseases by inhibiting protein misfolding and replication of prions, which share their replication mechanism with Aβ. CEs are FDA-approved safe additives in foods and pharmaceuticals. Herein, for the first time we determined the therapeutic effects of the representative CE (TC-5RW) in AD using in vitro and in vivo models. Our in vitro studies showed that TC-5RW inhibits Aβ aggregation, as well as neurotoxicity and immunoreactivity in Aβ-exposed human and murine neuroblastoma cells. In in vivo studies, for the first time we observed that single and weekly TC-5RW administration, respectively, improved memory functions of transgenic 5XFAD mouse model of AD. We further demonstrate that TC-5RW treatment of 5XFAD mice significantly inhibited Aβ oligomer and plaque burden and its associated neuroinflammation via regulating astrogliosis, microgliosis and proinflammatory mediator glial maturation factor beta (GMFβ). Additionally, we determined that TC-5RW reduced lipopolysaccharide-induced activated gliosis and GMFβ in vitro. In conclusion, our results demonstrate that CEs have therapeutic effects against Aβ pathologies and cognitive impairments, and direct, potent anti-inflammatory activity to rescue neuroinflammation. Therefore, these FDA-approved compounds are effective candidates for developing therapeutics for AD and related neurodegenerative diseases associated with protein misfolding.

Depletion of voltage‐gated potassium channel Kv1.1 contributes to behavioral deficits in transgenic mouse model of Alzheimer’s disease

AbstractBackgroundPatients with Alzheimer's disease (AD) are at risk for seizures and accelerated cognitive decline. Mechanisms of seizures and related synaptic dysfunction in AD are active areas of investigation. Alterations in ion channels have been identified in transgenic mouse models of AD, but levels of voltage‐gated potassium channels (VGKCs) have not been fully explored. In particular, little is known about Kv1.1 channels in AD. Mutations in Kv1.1 or autoantibodies against Kv1.1 cause neuronal overexcitation in several human diseases, including episodic ataxia type 1, epilepsy, myokymia, and limbic encephalitis, indicating that Kv1.1 is critical for regulating neuronal excitability.MethodTo explore VGKCs in AD, we used hAPP‐J20 mice ages 4‐6 months and determined mRNA and protein levels of four highly expressed VGKCs ‐ Kv1.1, Kv1.2, Kv1.4, and Kv4.2 ‐ in dentate gyrus, entorhinal cortex, motor cortex, and somatosensory cortex (SSC).ResultUsing RT‐qPCR, we identified reductions in Kv1.1 mRNA in the SSC of hAPP‐J20 mice. Western blotting revealed reductions in the Kv1.1 channel in the SSC of hAPP‐J20 mice and human parietal cortex in mild and moderate stages of AD. Immunolabeling revealed that the reductions in Kv1.1 channels in the SSC occurred in pyramidal cells and GABAergic interneurons. Kv1.1 levels in the SSC were lower in hAPP‐J20 mice, which overexpress mutant hAPP and have high Aβ(1‐42) levels, than in the wild‐type hAPP line I5, suggesting some dependence on Aβ(1‐42) levels. Levetiracetam treatment (75 mg/kg/day) administered for 28 days did not affect Kv1.1 levels in hAPP‐J20 mice. To assess Kv1.1 depletion in an AD model, we crossed Kv1.1 heterozygous mice (Kv1.1 +/‐) with hAPP‐J9 mice, which have lower expression of mutant hAPP than J20 mice. We performed behavioral tests on mice ages 4‐9 months. While Kv1.1 +/‐ mice and hAPP‐J9 mice had normal survival, the double mutant (Kv1.1 +/‐ hAPP‐J9) mice had premature mortality and impairments in elevated plus maze and light‐dark box tests (n=16‐25 mice/genotype) of anxiety.ConclusionThese data indicate that elevated Aβ(1‐42) levels may act synergistically with Kv1.1 depletion to exacerbate cognitive deterioration in AD. Ongoing investigation will further characterize the relationships between Kv1.1 loss and AD‐related hyperexcitability.

Fluorinated gamma‐carboline derivatives delay motor deficits in transgenic mouse model of neuronal proteinopathy

AbstractBackgroundAggregation of specific proteins is a key molecular event in pathogenesis of neurodegenerative diseases known as proteinopathies. Various products of this pathological aggregation cause neuronal dysfunction and death by different mechanisms. Prevention of protein aggregation at initial stages of this multistep process is seen as an important mechanism of therapeutic intervention into pathogenesis of proteinopathies.MethodWe used FUS(1‐359) mouse model of proteinopathy that is characterized by the formation of neuronal inclusions similar in ALS patients to determine effects of oral administration of gamma‐carboline fluorinated derivatives. Chronic treatments started at the age of two month prior to first visible symptoms and continued for 60 days or until the first symptoms were registered.ResultA statistically significant increase in the mean lifespan was observed in experimental groups treated with tested compounds compared to the non‐treated control transgenic animals. Administration of fluorinated gamma‐carboline derivatives also statistically significantly delayed the debut of clinical symptoms manifestation of the neurodegenerative process in transgenic animals. Moreover, chronic treatments prevented overall weight loss which was a characteristic feature of the undertreated controls. The most effective fluorinated gamma‐carbolines improved the disease duration leading to significant increase in animal lifespan. We used Noldus Catwalk gate analysis system to study effect of compounds on the very first signs of motor dysfunction. We performed multi‐dimension scaling analysis analyzing data from transgenic mice to identify a set of parameters distinguishing between transgenic and wild type mice prior to neurological pathology symptoms become visible. More detailed characterization of the effect of fluorinated gamma‐carboline derivates on animal nervous system at presymptomatic stage is required for better understanding of the mechanism of the drug action.ConclusionOverall, our study suggests that chronic administration gamma‐carbolines significantly prolongs the presymptomatic stage of FUS‐proteinopathy delaying the symptoms and enhancing the lifespan of treated animals. This study was supported by RSF 19‐13‐00378 (synthesis of compounds) and by the Program of Russian Academy of Sciences #18 (biological studies). Animals were provided by the Bioresource Collection of the Centre for Collective Use IPAC RAS (No. 0090‐2017‐0016).

Avenanthramide-C Restores Impaired Plasticity and Cognition in Alzheimer's Disease Model Mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and dementia with no effective treatment. Here, we investigated a novel compound from oats named avenanthramide-C (Avn-C), on AD-related memory impairment and behavioral deficits in transgenic mouse models. Acute hippocampal slices of wild-type or AD transgenic mice were treated with Avn-C in the presence or absence of oligomeric Aβ42. LTP analyses and immunoblotting were performed to assess the effect of Avn-C on Aβ-induced memory impairment. To further investigate the effect of Avn-C on impaired memory and Aβ pathology, two different AD transgenic mice (Tg2576 and 5XFAD) models were orally treated with either Avn-C or vehicle for 2weeks. They were then assessed for the effect of the treatment on neuropathologies and behavioral impairments. Avn-C reversed impaired LTP in both ex vivo- and in vivo-treated AD mice hippocampus. Oral administration (6mg/kg per day) for 2weeks in AD mice leads to improved recognition and spatial memory, reduced caspase-3 cleavage, reversed neuroinflammation, and to accelerated glycogen synthase kinase-3β (pS9GSK-3β) and interleukin (IL-10) levels. Avn-C exerts its beneficial effects by binding to α1A adrenergic receptors to stimulate adenosine monophosphate-activated kinase (AMPK). All of the beneficial effects of Avn-C on LTP retrieval could be blocked by prazosin hydrochloride, a specific inhibitor of α1A adrenergic receptors. Our findings provide evidence, for the first time, that oats' Avn-C reverses the AD-related memory and behavioral impairments, and establish it as a potential candidate for Alzheimer's disease drug development.

Tolfenamic Acid Attenuates 3-Nitropropionic Acid-Induced Biochemical Alteration in Mice

Tolfenamic acid (TA), a nonsteroidal anti-inflammatory drug, shows neuroprotective effects and alleviates cognitive deficits in transgenic mouse models of Alzheimer's disease. However, whether TA can prevent the biochemical alterations induced by intraperitoneal injection of 3-nitropropionic acid (3-NP) in mice is still unknown. In this study, the striatal lesion area was measured by 2,3,5-triphenyltetrazolium chloride staining. Glutamate, SDH and ATP levels were tested using colorimetric assay kits. The neuroinflammatory cytokine levels were tested by ELISA kits. The expression of synaptic proteins and the subtypes of the NMDA receptor were tested by western blotting. TA was orally administered 10days before 3-NP injection (pretreatment) or on the same day as 3-NP injection (co-treatment). TA pretreatment showed the strongest neuroprotective effects: pretreatment significantly attenuated the 3-NP-induced muscular weakness in the forelimb and alterations in glutamate level, mitochondrial function, and pro-inflammatory cytokine release in the brains of mice. These results suggest that TA has preventive and protective effects on 3-NP-induced neurotoxicity.

Lack of BACE1 S-palmitoylation reduces amyloid burden and mitigates memory deficits in transgenic mouse models of Alzheimer’s disease

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by pathological brain lesions and a decline in cognitive function. β-Amyloid peptides (Aβ), derived from proteolytic processing of amyloid precursor protein (APP), play a central role in AD pathogenesis. β-Site APP cleaving enzyme 1 (BACE1), the transmembrane aspartyl protease which initiates Aβ production, is axonally transported in neurons and accumulates in dystrophic neurites near cerebral amyloid deposits in AD. BACE1 is modified by S-palmitoylation at four juxtamembrane cysteine residues. S-palmitoylation is a dynamic posttranslational modification that is important for trafficking and function of several synaptic proteins. Here, we investigated the in vivo significance of BACE1 S-palmitoylation through the analysis of knock-in mice with cysteine-to-alanine substitution at the palmitoylated residues (4CA mice). BACE1 expression, as well as processing of APP and other neuronal substrates, was unaltered in 4CA mice despite the lack of BACE1 S-palmitoylation and reduced lipid raft association. Whereas steady-state Aβ levels were similar, synaptic activity-induced endogenous Aβ production was not observed in 4CA mice. Furthermore, we report a significant reduction of cerebral amyloid burden and BACE1 accumulation in dystrophic neurites in the absence of BACE1 S-palmitoylation in mouse models of AD amyloidosis. Studies in cultured neurons suggest that S-palmitoylation is required for dendritic spine localization and axonal targeting of BACE1. Finally, the lack of BACE1 S-palmitoylation mitigates cognitive deficits in 5XFAD mice. Using transgenic mouse models, these results demonstrate that intrinsic posttranslational S-palmitoylation of BACE1 has a significant impact on amyloid pathogenesis and the consequent cognitive decline.

Intensive ‘Brain Training’ Intervention Fails to Reduce Amyloid Pathologies or Cognitive Deficits in Transgenic Mouse Models of Alzheimer’s Disease

Alzheimer's disease (AD) is aprogressive neurodegenerative disorder that is the leading cause of dementia in the elderly. Amyloid-β protein (Aβ) depositions in both the brain parenchyma and the cerebral vasculature are recognized as important pathological components that contribute to the cognitive impairments found in individuals with AD. Because pharmacological options have been minimally effective in treating cognitive impairment to date, interest in the development of preventative lifestyle intervention strategies has increased in the field. One controversial strategy, cognitive-specific stimulation, has been studied previously in human participants and has been widely commercialized in the form of 'brain-training games.' In the present study, we developed ahighly controlled, isolated cognitive training intervention program for mice. Two transgenic mouse lines, one that develops Aβ deposition largely in brain parenchyma, and another in the cerebral microvasculature, progressed through aseries of domain-specific tasks for an average of 4months. Despite the high intensity and duration of the intervention, we found little evidence of positive benefits for AD amyloid pathologies and post-training cognitive testing in these two models. Taken together, these results support the current evidence in human studies that cognitive-specific stimulation does not lead to ameasurable reduction in AD pathology or an improvement in general brain health.

A phase Ib multiple ascending dose study of the safety, tolerability, and central nervous system availability of AZD0530 (saracatinib) in Alzheimer's disease.

IntroductionDespite significant progress, a disease-modifying therapy for Alzheimer’s disease (AD) has not yet been developed. Recent findings implicate soluble oligomeric amyloid beta as the most relevant protein conformation in AD pathogenesis. We recently described a signaling cascade whereby oligomeric amyloid beta binds to cellular prion protein on the neuronal cell surface, activating intracellular Fyn kinase to mediate synaptotoxicity. Fyn kinase has been implicated in AD pathophysiology both in in vitro models and in human subjects, and is a promising new therapeutic target for AD. Herein, we present a Phase Ib trial of the repurposed investigational drug AZD0530, a Src family kinase inhibitor specific for Fyn and Src kinase, for the treatment of patients with mild-to-moderate AD.MethodsThe study was a 4-week Phase Ib multiple ascending dose, randomized, double-blind, placebo-controlled trial of AZD0530 in AD patients with Mini-Mental State Examination (MMSE) scores ranging from 16 to 26. A total of 24 subjects were recruited in three sequential groups, with each randomized to receive oral AZD0530 at doses of 50 mg, 100 mg, 125 mg, or placebo daily for 4 weeks. The drug:placebo ratio was 3:1. Primary endpoints were safety, tolerability, and cerebrospinal fluid (CSF) penetration of AZD0530. Secondary endpoints included changes in clinical efficacy measures (Alzheimer’s Disease Assessment Scale – cognitive subscale, MMSE, Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory, Neuropsychiatric Inventory, and Clinical Dementia Rating Scale – Sum of Boxes) and regional cerebral glucose metabolism measured by fluorodeoxyglucose positron emission tomography.ResultsAZD0530 was generally safe and well tolerated across doses. One subject receiving 125 mg of AZD0530 was discontinued from the study due to the development of congestive heart failure and atypical pneumonia, which were considered possibly related to the study drug. Plasma/CSF ratio of AZD0530 was 0.4. The 100 mg and 125 mg doses achieved CSF drug levels corresponding to brain levels that rescued memory deficits in transgenic mouse models. One-month treatment with AZD0530 had no significant effect on clinical efficacy measures or regional cerebral glucose metabolism.ConclusionsAZD0530 is reasonably safe and well tolerated in patients with mild-to-moderate AD, achieving substantial central nervous system penetration with oral dosing at 100–125 mg. Targeting Fyn kinase may be a promising therapeutic approach in AD, and a larger Phase IIa clinical trial of AZD0530 for the treatment of patients with AD has recently launched.Trial registrationClinicalTrials.gov: NCT01864655. Registered 12 June 2014.

THE EFFECT OF RESVERATROL SUPPLEMENTATION ON THE EFFECTS OF A HIGH-FAT DIET IN A 3XTGAD FEMALE MOUSE MODEL OF ALZHEIMER'S DISEASE

Background:Mid-life obesity can increase the risk for developing dementia later in life, particularly Alzheimer’s disease (AD), and experimental diet-induced obesity increases AD-like pathology and/or behavioural deficits in transgenic mouse models of AD. However, most of these experimental studies assess the effect of high fat diet (HFD) in male mice only, and effects in female mice are less clear. Moreover, our previous work has shown that HFD also affects memory in healthy controls and that this effect is gender dependent.Resveratrol (RSV) has recently showed to improve health and life span of mice on a HFD and to improve learning and memory in both aged and AD mice, effects that are thought to be due to its anti-oxidant and/or anti-inflammatory properties. However until now no studies have been done taking into account both AD and co-morbidities (obesity). Therefore, the aim of this study was to test the effect of RSV in female 3xTgADmice fed with a HFD.Methods:Groups of female 3xTgAD and control (Non-Tg) mice w ere maintained on a control (12% fat) or a HFD (60% fat) for 12 months with or without RSV supplementation in the drinking water (5 mg/Kg/day). Body weight (BW) was monitored weekly. Behaviour was assessed at 12 months of treatment using the open-field and Y-maze spontaneous alternation tests. Epididymal fat, brown adipose tissue (BAT) and liver weight were measured after culling.Results: RSV did not affect BW in female 3xTgADmice fed a HFD but a decrease in weight gain was observed in Non-Tg HFD animals. HFD increased epididymal fat and BAT weight in both Non-Tg and 3xTgAD mice, and RSV reversed this effect only in Non-Tg mice. HFD also elevated liver weight in Non-Tg mice, which was reversed by RSV. RSV had no effect on behaviour or memory in both groups. Conclusions: These results suggest that RSV is able to reverse metabolic changes induced by the HFD in female Non-Tg mice but not in 3xTgAD animals, with no effect on behaviour in either. In conclusion, the effect of a HFD on memory is not affected by RSV and therefore is unlikely to be due to changes in oxidative stress and/or inflammation.

THE PROTECTIVE EFFECTS OF GEPT ON HIPPOCAMPAL NEURONS AND SYNAPSES OF APP/PS1 TRANSGENIC MICE

Background:Mid-life obesity can increase the risk for developing dementia later in life, particularly Alzheimer’s disease (AD), and experimental diet-induced obesity increases AD-like pathology and/or behavioural deficits in transgenic mouse models of AD. However, most of these experimental studies assess the effect of high fat diet (HFD) in male mice only, and effects in female mice are less clear. Moreover, our previous work has shown that HFD also affects memory in healthy controls and that this effect is gender dependent.Resveratrol (RSV) has recently showed to improve health and life span of mice on a HFD and to improve learning and memory in both aged and AD mice, effects that are thought to be due to its anti-oxidant and/or anti-inflammatory properties. However until now no studies have been done taking into account both AD and co-morbidities (obesity). Therefore, the aim of this study was to test the effect of RSV in female 3xTgADmice fed with a HFD.Methods:Groups of female 3xTgAD and control (Non-Tg) mice w ere maintained on a control (12% fat) or a HFD (60% fat) for 12 months with or without RSV supplementation in the drinking water (5 mg/Kg/day). Body weight (BW) was monitored weekly. Behaviour was assessed at 12 months of treatment using the open-field and Y-maze spontaneous alternation tests. Epididymal fat, brown adipose tissue (BAT) and liver weight were measured after culling.Results: RSV did not affect BW in female 3xTgADmice fed a HFD but a decrease in weight gain was observed in Non-Tg HFD animals. HFD increased epididymal fat and BAT weight in both Non-Tg and 3xTgAD mice, and RSV reversed this effect only in Non-Tg mice. HFD also elevated liver weight in Non-Tg mice, which was reversed by RSV. RSV had no effect on behaviour or memory in both groups. Conclusions: These results suggest that RSV is able to reverse metabolic changes induced by the HFD in female Non-Tg mice but not in 3xTgAD animals, with no effect on behaviour in either. In conclusion, the effect of a HFD on memory is not affected by RSV and therefore is unlikely to be due to changes in oxidative stress and/or inflammation.

Towards a computational model of learning and social interactions of mice in IntelliCage

In [1] we have studied cognitive deficits in transgenic mouse model of Alzheimer's Disease. In particular, we used automated mice cages (IntelliCage) to investigate how healthy and transgenic mice learn the location of a reward (sweetened water provided in only one of the four corners of the cage) in different social situations. We showed that co-housing transgenic mice with healthy companions can alleviate learning deficits. We also showed that the ability to find the reward is modulated by the circadian rhythm. A natural continuation of that study is to find specific mechanisms of learning and social interactions responsible for the observed patterns of behavior. To that end we now employ a collection of computational models of learning and decision making [2]. In the models we use the Rescorla-Wagner rule for the learned values of the actions supplemented by a model-specific decision-making rule. In the simplest case we assume the decisions are based purely on the learned rewards, with the probabilities of actions given by the softmax distribution. Such a simple model, in which animals are ignorant of each other, fits the trend of the learning curve well both for healthy (Figure ​(Figure1A)1A) and transgenic (not shown) mice. However, it does not capture the circadian oscillations. Figure 1 Experimental and model learning curves of healthy mice. Left: model without interactions between animals. Right: model with minimal social interactions. Thin lines mark the standard deviation of model curves over 100 repetitions. Next we study a model in which the interactions between animals are included in a minimal form. Specifically, the probability of visiting given corner is reduced if the corner is already occupied by another mouse at the time the choice of the action takes place. In this case we observe that the model learning-curve starts to exhibit oscillations around the trend (Figure ​(Figure1B).1B). Still, the amplitude of these oscillations is significantly smaller than in experimental data, which suggests that other effects come also into play.

P3‐045: Effects of a high‐fat diet on the cerebrovasculature and neuroinflammation in an experimental model of Alzheimer's disease

Background:Western diets and mid-life obesity are considered risk factors for developing dementia. Experimentally, such diets increase ADlike pathology and/or behavioural deficits in transgenic mouse models of AD. We have shown that a high-fat diet increases memory deficits in male triple-transgenic (3xTgAD) mice, though the mechanisms underlying this effect are unknown. Several structural and functional cerebrovascular abnormalities are associated with AD, including impaired integrity of the blood brain barrier (BBB) and neurovascular inflammation. A common underlying feature of both obesity and AD is chronic inflammation. The aim of this project is to determine the molecular mechanisms underlying detrimental effects of a high-fat diet on AD, and to test the hypothesis that inflammatory driven changes in cerebrovascular function are crucial. Methods: Groups of male 3xTgAD and control (non-Tg) mice were maintained on a control diet or a high-fat diet for periods from 3to 16 months of age. Overt changes in BBB integrity (IgG), cerebrovascular endothelial activation (intracellular adhesion molecule; ICAM) and neuroinflammation (microglial activation, Iba1) were assessed by immunohistochemistry on brain sections. Brain homogenates from control fed 9-month-old female 3xTgAD and non-Tg mice were used to assess cerebrovascular activation/inflammation (ICAM and vascular adhesion molecule; VCAM) by ELISA. Results: No significant differences were observed in IgG staining in the brains of non-Tg and 3xTgAD male mice on either a control or high-fat diet at all ages tested. Increases in ICAM/VCAM protein expression were identified in the hippocampus of 9-month-old 3xTgAD female mice. However, no differences in the number of ICAM positive vessels between male Non-Tg and 3xTgAD mice on either a control or high-fat diet were identified by immunohistochemistry. Age-related increases in the number of activated microglia were observed in the hippocampus of 3xTgAD when compared to non-Tg control mice. High-fat feeding increased the number of activated microglia in the hippocampus of non-Tg mice but had no effect in 3xTgAD mice.Conclusions: These data suggest that a high-fat diet can induce neuroinflammation in the absence of AD-related pathology and that the mechanisms underlying the detrimental effects of a high-fat diet on behaviour in 3xTgAD mice remain to be resolved.

Spontaneous Ocular and Neurologic Deficits in Transgenic Mouse Models of Multiple Sclerosis and Noninvasive Investigative Modalities: A Review

Multiple sclerosis (MS) is an autoimmune, inflammatory, neurodegenerative, demyelinating disease of the central nervous system, predominantly involving myelinated neurons of the brain, spinal cord, and optic nerve. Optic neuritis is frequently associated with MS and often precedes other neurologic deficits associated with MS. A large number of patients experience visual defects and have abnormalities concomitant with neurologic abnormalities. Transgenic mice manifesting spontaneous neurologic and ocular disease are unique models that have revolutionized the study of MS. Spontaneous experimental autoimmune encephalomyelitis (sEAE) presents with spontaneous onset of demyelination, without the need of an injectable immunogen. This review highlights the various models of sEAE, their disease characteristics, and applicability for future research. The study of optic neuropathy and neurologic manifestations of demyelination in sEAE will expand our understanding of the pathophysiological mechanisms underlying MS. Early and precise diagnosis of MS with different noninvasive methods has opened new avenues in managing symptoms, reducing morbidity, and limiting disease burden. This review discusses the spectrum of available noninvasive techniques, such as electrophysiological and behavioral assessment, optical coherence tomography, scanning laser polarimetry, confocal scanning laser ophthalmoscopy, pupillometry, magnetic resonance imaging, positron emission tomography, gait, and cardiovascular monitoring, and their clinical relevance.

Valproate reduces tau phosphorylation via cyclin-dependent kinase 5 and glycogen synthase kinase 3 signaling pathways

Valproate (VPA) is a widely used anticonvulsant and mood-stabilizing drug. Recent studies have shown that VPA could reduce amyloid-β generation, and improve memory deficits in transgenic mouse models of Alzheimer's disease (AD). However, whether VPA affects tau phosphorylation and the underlying mechanism has not been established. Here, we showed that systemic treatment of APP and presenilin 1 double transgenic mice with VPA (50 mg/kg, once a day for 12 weeks), significantly reduced the levels of tau phosphorylation at the sites of Thr205, Ser396 and Thr231. Meanwhile, VPA treatment markedly reduced the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β), two protein kinases involved in abnormal hyperphosphorylation of tau. In an okadaic acid-induced tau hyperphosphorylation SH-SY5Y cell model, the anti-tau-phosphorylation effect of VPA was further confirmed, accompanied by a marked decrease in the activities of CDK5 and GSK3β. Our present data suggest that the inhibitory effects of VPA on tau hyperphosphorylation might be mediated through both CDK5 and GSK3β signaling pathways.

Overexpression of Glutaminyl Cyclase, the Enzyme Responsible for Pyroglutamate Aβ Formation, Induces Behavioral Deficits, and Glutaminyl Cyclase Knock-out Rescues the Behavioral Phenotype in 5XFAD Mice

Pyroglutamate-modified Aβ (AβpE3-42) peptides are gaining considerable attention as potential key players in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Overexpressing AβpE3-42 induced a severe neuron loss and neurological phenotype in TBA2 mice. In vitro and in vivo experiments have recently proven that the enzyme glutaminyl cyclase (QC) catalyzes the formation of AβpE3-42. The aim of the present work was to analyze the role of QC in an AD mouse model with abundant AβpE3-42 formation. 5XFAD mice were crossed with transgenic mice expressing human QC (hQC) under the control of the Thy1 promoter. 5XFAD/hQC bigenic mice showed significant elevation in TBS, SDS, and formic acid-soluble AβpE3-42 peptides and aggregation in plaques. In 6-month-old 5XFAD/hQC mice, a significant motor and working memory impairment developed compared with 5XFAD. The contribution of endogenous QC was studied by generating 5XFAD/QC-KO mice (mouse QC knock-out). 5XFAD/QC-KO mice showed a significant rescue of the wild-type mice behavioral phenotype, demonstrating the important contribution of endogenous mouse QC and transgenic overexpressed QC. These data clearly demonstrate that QC is crucial for modulating AβpE3-42 levels in vivo and prove on a genetic base the concept that reduction of QC activity is a promising new therapeutic approach for AD.

Epilepsy and Cognitive Impairments in Alzheimer Disease

Alzheimer disease (AD) is associated with cognitive decline and increased incidence of seizures. Seizure activity in AD has been widely interpreted as a secondary process resulting from advanced stages of neurodegeneration, perhaps in combination with other age-related factors. However, recent findings in animal models of AD have challenged this notion, raising the possibility that aberrant excitatory neuronal activity represents a primary upstream mechanism that may contribute to cognitive deficits in these models. The following observations suggest that such activity may play a similar role in humans with AD: (1) patients with sporadic AD have an increased incidence of seizures that appears to be independent of disease stage and highest in cases with early onset; (2) seizures are part of the natural history of many pedigrees with autosomal dominant early-onset AD, including those with mutations in presenilin-1, presenilin-2, or the amyloid precursor protein, or with duplications of wild-type amyloid precursor protein; (3) inheritance of the major known genetic risk factor for AD, apolipoprotein E4, is associated with subclinical epileptiform activity in carriers without dementia; and (4) some cases of episodic amnestic wandering and disorientation in AD are associated with epileptiform activity and can be prevented with antiepileptic drugs. Here we review recent experimental data demonstrating that high levels of beta-amyloid in the brain can cause epileptiform activity and cognitive deficits in transgenic mouse models of AD. We conclude that beta-amyloid peptides may contribute to cognitive decline in AD by eliciting similar aberrant neuronal activity in humans and discuss potential clinical and therapeutic implications of this hypothesis.

Three weeks of running wheel exposure improves cognitive performance in the aged Tg2576 mouse

If begun early in life, exercise effectively reduces the development of cognitive deficits in transgenic mouse models of Alzheimer's disease (AD). However, the effectiveness of exercise, once the cognitive impairments are established, is not as clear. In terms of translating research in animal models to treatments involving exercise in Alzheimer's disease patients, it is critical to evaluate exercise intervention at time points that address not only prevention, but also treatment of cognitive decline. We provided exercise wheels to Tg2576 (TG) ( n = 12) and C57BL6 (WT) ( n = 17) mice at 16–18 months of age for three weeks. At this age animals have significant cognitive impairment and neuropathology consistent with AD. Age matched sedentary TG ( n = 13) and WT ( n = 12) mice were also included, as well as groups provided access to an immobile wheel (TG n = 9, WT n = 12). After three weeks, animals were evaluated in a radial arm water maze. Significant impairments were observed in the sedentary TG mice compared to WT in reference/long-term and working/short-term memory, as well as in probe trials. Exercised TG mice demonstrated improvements in memory, which made them indistinguishable from WT mice on all tasks. In addition, animals provided with an immobile wheel exhibited improvement in some, but not all cognitive measures. Our findings demonstrate that exercise can improve cognitive performance in a mouse model of AD even if applied after the development of pathology.

Papillomavirus-Like Particles Are an Effective Platform for Amyloid-β Immunization in Rabbits and Transgenic Mice

Immunization with amyloid-beta (Abeta) prevents the deposition of Abeta in the brain and memory deficits in transgenic mouse models of Alzheimer's disease (AD), opening the possibility for immunotherapy of AD in humans. Unfortunately, the first human trial of Abeta vaccination was complicated, in a small number of vaccinees, by cell-mediated meningoencephalitis. To develop an Abeta vaccine that lacks the potential to induce autoimmune encephalitis, we have generated papillomavirus-like particles (VLP) that display 1-9 aa of Abeta protein repetitively on the viral capsid surface (Abeta-VLP). This Abeta peptide was chosen because it contains a functional B cell epitope, but lacks known T cell epitopes. Rabbit and mouse vaccinations with Abeta-VLP were well tolerated and induced high-titer autoAb against Abeta, that inhibited effectively assembly of Abeta(1-42) peptides into neurotoxic fibrils in vitro. Following Abeta-VLP immunizations of APP/presenilin 1 transgenic mice, a model for human AD, we observed trends for reduced Abeta deposits in the brain and increased numbers of activated microglia. Furthermore, Abeta-VLP vaccinated mice also showed increased levels of Abeta in plasma, suggesting efflux from the brain into the vascular compartment. These results indicate that the Abeta-VLP vaccine induces an effective humoral immune response to Abeta and may thus form a basis to develop a safe and efficient immunotherapy for human AD.

Food for ThoughtEssential Fatty Acid Protects against Neuronal Deficits in Transgenic Mouse Model of AD

Interactions between environmental and genetic factors may contribute to neurodegenerative disease. In this issue of Neuron, Calon et al. report that a diet low in an essential omega-3 polyunsaturated fatty acid (docosahexaenoic acid) depletes postsynaptic proteins and exacerbates behavioral alterations in a transgenic mouse model of Alzheimer's disease.