3xTg-AD Mouse Model Research Articles

Differential effects of chronic immunosuppression on behavioral, epigenetic, and Alzheimer\u2019s disease-associated markers in 3xTg-AD mice

BackgroundCirculating autoantibodies and sex-dependent discrepancy in prevalence are unexplained phenomena of Alzheimer’s disease (AD). Using the 3xTg-AD mouse model, we reported that adult males show early manifestations of systemic autoimmunity, increased emotional reactivity, enhanced expression of the histone variant macroH2A1 in the cerebral cortex, and loss of plaque/tangle pathology. Conversely, adult females display less severe autoimmunity and retain their AD-like phenotype. This study examines the link between immunity and other traits of the current 3xTg-AD model.MethodsYoung 3xTg-AD and wild-type mice drank a sucrose-laced 0.4 mg/ml solution of the immunosuppressant cyclophosphamide on weekends for 5 months. After behavioral phenotyping at 2 and 6 months of age, we assessed organ mass, serologic markers of autoimmunity, molecular markers of early AD pathology, and expression of genes associated with neurodegeneration.ResultsChronic immunosuppression prevented hematocrit drop and reduced soluble Aβ in 3xTg-AD males while normalizing the expression of histone variant macroH2A1 in 3xTg-AD females. This treatment also reduced hepatosplenomegaly, lowered autoantibody levels, and increased the effector T cell population while decreasing the proportion of regulatory T cells in both sexes. Exposure to cyclophosphamide, however, neither prevented reduced brain mass and BDNF expression nor normalized increased tau and anxiety-related behaviors.ConclusionThe results suggest that systemic autoimmunity increases soluble Aβ production and affects transcriptional regulation of macroH2A1 in a sex-related manner. Despite the complexity of multisystem interactions, 3xTg-AD mice can be a useful in vivo model for exploring the regulatory role of autoimmunity in the etiology of AD-like neurodegenerative disorders.

Hydrogen sulfide is neuroprotective in Alzheimer's disease by sulfhydrating GSK3β and inhibiting Tau hyperphosphorylation.

Alzheimer's disease (AD), the most common cause of dementia and neurodegeneration in the elderly, is characterized by deterioration of memory and executive and motor functions. Neuropathologic hallmarks of AD include neurofibrillary tangles (NFTs), paired helical filaments, and amyloid plaques. Mutations in the microtubule-associated protein Tau, a major component of the NFTs, cause its hyperphosphorylation in AD. We have shown that signaling by the gaseous molecule hydrogen sulfide (H2S) is dysregulated during aging. H2S signals via a posttranslational modification termed sulfhydration/persulfidation, which participates in diverse cellular processes. Here we show that cystathionine γ-lyase (CSE), the biosynthetic enzyme for H2S, binds wild type Tau, which enhances its catalytic activity. By contrast, CSE fails to bind Tau P301L, a mutant that is present in the 3xTg-AD mouse model of AD. We further show that CSE is depleted in 3xTg-AD mice as well as in human AD brains, and that H2S prevents hyperphosphorylation of Tau by sulfhydrating its kinase, glycogen synthase kinase 3β (GSK3β). Finally, we demonstrate that sulfhydration is diminished in AD, while administering the H2S donor sodium GYY4137 (NaGYY) to 3xTg-AD mice ameliorates motor and cognitive deficits in AD.

Olfactory dysfunction in the 3xTg-AD model of Alzheimer's disease.

Alzheimer’s disease (AD) is an incurable neurodegenerative disease in which the risk of development increases with age. People with AD are plagued with deficits in their cognition, memory, and basic social skills. Many of these deficits are believed to be caused by the formation of amyloid-β plaques and neurofibrillary tangles in regions of the brain associated with memory, such as the hippocampus. However, one of the early, preclinical symptoms of AD is the loss of olfactory detection and discrimination. To determine if a mouse model of AD expresses the same olfactory dysfunction seen in human AD, 3xTg-AD mice were given a buried food test and, unlike previous studies, compared to their background and parental strains. Results showed that over 52 weeks, the 3xTg-AD mice took significantly longer to find the buried food than the control strains. The olfactory bulbs of the 3xTg-AD mice were removed, sliced, and stained using Congo red for histological analysis. Amyloid deposits were observed predominantly in the granule layer of the olfactory bulb beginning at 13 weeks of age in 3xTg-AD mice, but not in the control strains of mice. Further examination of the buried food test data revealed that 3xTg-AD females had a significantly longer latency to detect the buried food than males beginning at 26 weeks of age. Overall, this study provides further validation of the 3xTg-AD mouse model of AD and supports the idea that simple olfactory testing could be part of the diagnostic process for human AD.

Genetic Ablation of Neuronal Mitochondrial Calcium Uptake Halts Alzheimer's Disease Progression

Alzheimer’s disease (AD) is characterized by the extracellular deposition of amyloid beta, intracellular neurofibrillary tangles, synaptic dysfunction, and neuronal cell death. These phenotypes correlate with and are linked to elevated neuronal intracellular calcium (iCa2+) levels. Recently, our group reported that mitochondrial calcium (mCa2+) overload, due to loss of mCa2+ efflux capacity, contributes to AD development and progression. We also noted proteomic remodeling of the mitochondrial calcium uniporter channel (mtCU) in sporadic AD brain samples, suggestive of altered mCa2+ uptake in AD. Since the mtCU is the primary mechanism for Ca2+ uptake into the mitochondrial matrix, inhibition of the mtCU has the potential to reduce or prevent mCa2+ overload in AD. Here, we report that neuronal-specific loss of mtCU-dependent mCa2+ uptake in the 3xTg-AD mouse model of AD reduced Aβ and tau-pathology, synaptic dysfunction, and cognitive decline. Knockdown of Mcu in a cellular model of AD significantly decreased matrix Ca2+ content, oxidative stress and cell death. These results suggest that inhibition of neuronal mCa2+ uptake is a novel therapeutic target to impede AD progression.

Self-Protecting Biomimetic Nanozyme for Selective and Synergistic Clearance of Peripheral Amyloid-β in an Alzheimer's Disease Model.

Clearance of peripheral amyloid-β (Aβ) has been demonstrated to be promising for overcoming the blood-brain barrier (BBB) hurdle to eliminate brain-derived Aβ associated with Alzheimer's disease (AD). Even so, current developed therapeutic assays for clearance of peripheral Aβ are still facing challenges on how to avoid interference of certain biological molecules and prevent triggering the activation of immune responses and blood clotting. Here, a biomimetic nanozyme (CuxO@EM-K) with augmented protein adsorption resistance, minimized immunogenicity, and enhanced biocompatibility is designed and synthesized. The CuxO@EM-K is made of CuxO nanozyme wrapped with modified 3xTg-AD mouse erythrocyte membrane with Aβ-targeting pentapeptide KLVFF. KLVFF serves as Aβ-specific ligand that works together with erythrocyte membrane to selectively capture Aβ in the blood. Meanwhile, the erythrocyte membrane coating prevents protein coronas formation and thus retains Aβ-targeting ability of CuxO@EM-K in biological fluids. More importantly, the CuxO core with multiple antioxidant enzyme-like activities stabilizes the outer erythrocyte membrane and simultaneously mitigates Aβ-induced membrane oxidative damage, which enables the extended systemic circulation indispensable for adsorbing Aβ. In vivo studies demonstrate that CuxO@EM-K not only reduces Aβ burden in the blood and brain but also ameliorates memory deficits in the widely used 3xTg-AD mouse model. Moreover, CuxO@EM-K shows no apparent toxicity in 3xTg-AD mice. Overall, this work provides an example for developing biocompatible and synergistic clearance of peripheral Aβ associated with AD.

Changes in the brain transcriptome after DNA Aβ42 trimer immunization in a 3xTg-AD mouse model

Alzheimer's disease (AD) has been associated with accumulation of amyloid beta (Aβ) peptides in brain, and immunotherapy targeting Aβ provides potential for AD prevention. We have used a DNA Aβ42 trimer construct for immunization of 3xTg-AD mice and found previously significant reduction of amyloid and tau pathology due to the immunotherapy. We show here that DNA Aβ42 immunized 3xTg-AD mice showed better performance in nest building activities and had a higher 24 months survival rate compared to the non-treated AD controls. The analysis of differently expressed genes in brains from 24 months old mice showed significant increases transcript levels between non-immunized AD mice and wild-type controls for genes involved in microglia and astrocyte function, cytokine and inflammatory signaling, apoptosis, the innate and adaptive immune response and are consistent with an inflammatory phenotype in AD. Most of these upregulated genes were downregulated in the DNA Aβ42 immunized 3xTg-AD mice due to the vaccine. Transcript numbers for the immediate early genes, Arc, Bdnf, Homer1, Egr1 and cfos, involved in neuronal and neurotransmission pathways which were much lower in the non-immunized 3xTg-AD mice, were restored to wild-type mouse brain levels in DNA Aβ42 immunized 3xTg-AD mice indicating positive effects of DNA Aβ42 immunotherapy on synapse stability and plasticity. The immune response after immunization is complex, but the multitude of changes after DNA Aβ42 immunization shows that this response moves beyond the amyloid hypothesis and into direction of disease prevention.

Bacteria isolated from the stools of Alzheimer’s disease patients exacerbate cognitive impairment in 3xTg AD mouse model

AbstractBackgroundHuman microbiota‐associated (HMA) murine models are developed by gavaging mice with human bacteria or stools and are increasingly used to study the relation between the human microbiota and disease. The aim of this study is to evaluate the effect of gut bacteria isolated from donors with or without Alzheimer’s dementia on behavior in AD transgenic (Tg) mice.MethodSixty female, one‐year 3xTg mice (APPSWE, PS1M146V and TauP301L) received (1) antibiotic treatment (for 14 days before the first gavage), (2) stomach acid suppressant administration, (3) laxative administration (immediately before the first gavage) and, (4) microbiota transplantation (or saline, once every 2 weeks for 2 months). The transplanted microbiota consisted of bacteria isolated from stools of donors pertaining to four different profiles: i) amyloid positive AD patient, amyloid negative cognitively healthy subjects ii) with or iii) without protective APOE genotype and, iv) young healthy donor. As additional control, we included a group of mice that received bacteria isolated from stools of untreated 3xTg mice. Stools collection and behavioral assessment (open‐field test, Y‐maze test, radial maze test, elevated plus maze test) was performed before antibiotic treatment and at day 3, 30, 60 after the first gavage. All mice were sacrificed at day 60 for ex‐vivo assessments.ResultAfter 60 days from the first gavage, the bacteria from the AD patient induced AD‐like behavior in 3xTg mice, including impaired general activity in the open‐field test and exacerbated anxiety in the elevated plus maze test, compared with mice that received saline or bacteria from untreated 3xTg mice. The bacteria from the other human donors did not influence mouse behavior.ConclusionThe microbiota of AD patients induced an AD‐like phenotype in 3xTg mice. Brain and gut ex‐vivo assessments, 16S rRNA gene sequencing as well as behavioral longitudinal analysis are on‐going to evaluate the human microbiota transplantation efficiency and its effect on AD pathology and inflammation.

Age-Dependent Decline in Synaptic Mitochondrial Function Is Exacerbated in Vulnerable Brain Regions of Female 3xTg-AD Mice.

Synaptic aging has been associated with neuronal circuit dysfunction and cognitive decline. Reduced mitochondrial function may be an early event that compromises synaptic integrity and neurotransmission in vulnerable brain regions during physiological and pathological aging. Thus, we aimed to measure mitochondrial function in synapses from three brain regions at two different ages in the 3xTg-AD mouse model and in wild mice. We found that aging is the main factor associated with the decline in synaptic mitochondrial function, particularly in synapses isolated from the cerebellum. Accumulation of toxic compounds, such as tau and Aβ, that occurred in the 3xTg-AD mouse model seemed to participate in the worsening of this decline in the hippocampus. The changes in synaptic bioenergetics were also associated with increased activation of the mitochondrial fission protein Drp1. These results suggest the presence of altered mechanisms of synaptic mitochondrial dynamics and their quality control during aging and in the 3xTg-AD mouse model; they also point to bioenergetic restoration as a useful therapeutic strategy to preserve synaptic function during aging and at the early stages of Alzheimer’s disease (AD).

Yuan-Hu Zhi Tong Prescription Mitigates Tau Pathology and Alleviates Memory Deficiency in the Preclinical Models of Alzheimer's Disease.

Alzheimer’s disease (AD) is characterized by memory dysfunction, Aβ plaques together with phosphorylated tau-associated neurofibrillary tangles. Unfortunately, the present existing drugs for AD only offer mild symptomatic cure and have more side effects. As such, developments of effective, nontoxic drugs are immediately required for AD therapy. Present study demonstrates a novel role of Chinese medicine prescription Yuan-Hu Zhi Tong (YZT) in treating AD, and it has substantiated the in vivo effectiveness of YZT in two different transgenic mice models of AD, namely P301S tau and 3XTg-AD mice. Oral treatment of YZT significantly ameliorates motor dysfunction as well as promotes the clearance of aggregated tau in P301S tau mice. YZT improves the cognitive function and reduces the insoluble tau aggregates in 3XTg-AD mice model. Furthermore, YZT decreases the insoluble AT8 positive neuron load in both P301S tau and 3XTg-AD mice. Using microarray and the “Connectivity Map” analysis, we determined the YZT-induced changes in expression of signaling molecules and revealed the potential mechanism of action of YZT. YZT might regulate ubiquitin proteasomal system for the degradation of tau aggregates. The research results show that YZT is a potential drug candidate for the therapy of tau pathogenesis and memory decline in AD.

9R, the cholinesterase and amyloid beta aggregation dual inhibitor, as a multifunctional agent to improve cognitive deficit and neuropathology in the triple-transgenic Alzheimer's disease mouse model

Alzheimer's disease (AD) is the most common kind of dementia in the aging population leading to great social and financial burdens in many countries around the world. For decades, disease-modifying drug developed using the “one target, one drug” strategy failed to conquer this disease. Recently, we have designed and synthesized 9R, which exhibited dual inhibition of cholinesterase and amyloid beta (Aβ) aggregation in vitro. Herein, we evaluated the in vivo efficacy of 9R in a triple transgenic AD (3xTg-AD) mouse model. 3xTg-AD mice (10-month-old) were dosed intraperitoneally with 9R (daily 3, 10 or 30 mg/kg) for a month. Known cholinesterase inhibitor donepezil (0.3 mg/kg) and Aβ aggregation inhibitor tramiprosate (30 mg/kg) were used as positive controls. Cognitive performance of the mice was then evaluated by using Morris Water Maze (MWM), Y-maze tasks and Open Field test. The acetylcholine level, degree of Aβ deposition, amyloid precursor protein (APP) processing, neuroinflammation, tau deposition and tau hyperphosphorylation in the brains of the 3xTg-AD mice were examined. We have observed that one-month treatment with 9R significantly improved cognitive deficits in 3xTg-AD mice. Moreover, 9R treatment enhanced the brain acetylcholine level and mitigated the amyloid burden, tau hyperphosphorylation and neuroinflammation in the mouse brains. The effects of 9R on APP processing, neuroinflammation, tau hyperphosphorylation and Cdk-p25 action demonstrated its multifunctional role in 3xTg-AD mouse model. Our results suggested that the use of multi-target compound could be a potential approach to treat AD.

Neuroprotective Effects of Chronic Resveratrol Treatment and Exercise Training in the 3xTg-AD Mouse Model of Alzheimer's Disease.

To date, there is no cure or effective treatment for Alzheimer’s disease (AD), a chronic neurodegenerative condition that affects memory, language, and behavior. AD is characterized by neuroinflammation, accumulation of brain amyloid-beta (Aβ) oligomers and neurofibrillary tangles, increased neuronal apoptosis, and loss of synaptic function. Promoting regular exercise and a diet containing polyphenols are effective non-pharmacological approaches that prevent the progression of neurodegenerative diseases. In this study, we measured various conformational toxic species of Aβ and markers of inflammation, apoptosis, endolysosomal degradation, and neuroprotection after 5 months of exercise training (ET), resveratrol (Resv) treatment, or combination treatment in the 3xTg-AD mouse model of AD. Our main results indicate that Resv decreased neuroinflammation and accumulation of Aβ oligomers, increased levels of neurotrophins, synaptic markers, silent information regulator, and decreased markers of apoptosis, autophagy, endolysosomal degradation and ubiquitination in the brains of 3xTg-AD mice. ET improved some markers related to neuroprotection, but when combined with Resv treatment, the benefits achieved were as effective as Resv treatment alone. Our results show that the neuroprotective effects of Resv, ET or Resv and ET are associated with reduced toxicity of Aβ oligomers, suppression of neuronal autophagy, decreased apoptosis, and upregulation of key growth-related proteins.

Cognitive Impairment in the 3xTg-AD Mouse Model of Alzheimer's Disease is Affected by Aβ-ImmunoTherapy and Cognitive Stimulation.

Clinical symptoms of Alzheimer’s Disease (AD) include behavioral alterations and cognitive impairment. These functional phenotypes early occur in triple-transgenic (3xTg-AD) mice. Specifically, behavioral alterations are first detected when mice are at around 2.5 months old and cognitive impairment in between 3- and 5-month-old mice. In this work, the effect of chronic Aβ-immunotherapy on behavioral and cognitive abilities was tested by monthly administering the antibody fragment scFv-h3D6 to 3xTg-AD female mice from 5 to 9 months of age. An untreated group was used as a reference, as well as to attain some information on the effect of training during the longitudinal study. Behavioral and psychological symptoms of dementia (BPSD)-like symptoms were already evident in 5-month-old mice, in the form of neophobia and anxious-like behavior. The exploratory activity decreased over the longitudinal study, not only for 3xTgAD mice but also for the corresponding non-transgenic mice (NTg). Learning abilities of 3xTg-AD mice were not seriously compromised but an impairment in long-term spatial memory was evident at 5 months of age. Interestingly, scFv-h3D6-treatment affected the cognitive impairment displayed by 5-month-old 3xTg-AD mice. It is worth noting that training also reduced cognitive impairment of 3xTg-AD mice over the longitudinal study, suggesting that to properly quantify the isolated therapeutic potential of any drug on cognition using this model it is convenient to perform a prompt, age-matched study rather than a longitudinal study. In addition, a combination of both training and Aβ-immunotherapy could constitute a possible approach to treat Alzheimer’s disease.

417 - Olfactory signatures in models of aging and Alzheimer’s disease and the effect of social isolation: A translational neuroscience approach in times of coronavirus pandemic (COVID-19)

Sensory systems ensure the ability to perceive and recognize the world. Therefore, the temporal course and the severity of their involution through the aging process can be critical. In the elderly, sensory impairments significantly increase their risk of biological, psychological and social impoverishment. Olfactory loss, known to happen in bacterial and viral infections and considered an early biomarker in Alzheimer’s and Parkinson’s diseases neurodegenerative processes, has been reported also as an early indicator of current infection by SARS-CoV-2. At the translational level, in the present work, we have studied olfactory ethograms in normal and advanced AD-related pathological aging using wildtype and the 3xTg-AD mice, a genetic model of Alzheimer’s disease that presents AD-cognitive dysfunction but also a conspicuous BPSD-like phenotype. An olfactory paradigm, involving the equivalent to one day food deprivation, was used to investigate in middle-aged males and females with normal and AD-pathological aging the ethological patterns shown in the olfactory inspection of a new cage with beddings and the posterior detection, finding and consumption of food pellets hidden in this new anxiogenic environment. Males with normal and pathological aging were equally delayed in their first contact with food pellets, while in female sex this latency was dependent on the genotype (longer in 3xTg-AD mice, shorter in those with normal aging). Once the animals had inspected the arena, the latencies to smell, find and eat the food pellets were found progressively increased in males with normal aging, but consecutively developed in 3xTg-AD mice. In contrast, both groups of females exhibited longer delays as compared to males, and the temporal pattern of their ethogram to smell-find-eat the food was faster. In 3xTg-AD males, social isolation (naturally occurring due to death of counterparts) emphasized these olfactory patterns, which were independent of the punctual loss of weight of this paradigm. The results show that this paradigm provides distinct contextual, sex and genotype olfactory ethogram signatures useful to investigate olfactory function in normal and AD-pathological aging. Also, that isolation has an impact enhancing the changes in the olfactory signature here described, for the first time, in the 3xTg-AD mice model of Alzheimer’s disease.

Role of sex and high-fat diet in metabolic and hypothalamic disturbances in the 3xTg-AD mouse model of Alzheimer\u2019s disease

BackgroundHypothalamic dysfunction occurs early in the clinical course of Alzheimer’s disease (AD), likely contributing to disturbances in feeding behavior and metabolic function that are often observed years prior to the onset of cognitive symptoms. Late-life weight loss and low BMI are associated with increased risk of dementia and faster progression of disease. However, high-fat diet and metabolic disease (e.g., obesity, type 2 diabetes), particularly in mid-life, are associated with increased risk of AD, as well as exacerbated AD pathology and behavioral deficits in animal models. In the current study, we explored possible relationships between hypothalamic function, diet/metabolic status, and AD. Considering the sex bias in AD, with women representing two-thirds of AD patients, we sought to determine whether these relationships vary by sex.MethodsWT and 3xTg-AD male and female mice were fed a control (10% fat) or high-fat (HF 60% fat) diet from ~ 3–7 months of age, then tested for metabolic and hypothalamic disturbances.ResultsOn control diet, male 3xTg-AD mice displayed decreased body weight, reduced fat mass, hypoleptinemia, and mild systemic inflammation, as well as increased expression of gliosis- and inflammation-related genes in the hypothalamus (Iba1, GFAP, TNF-α, IL-1β). In contrast, female 3xTg-AD mice on control diet displayed metabolic disturbances opposite that of 3xTg-AD males (increased body and fat mass, impaired glucose tolerance). HF diet resulted in expected metabolic alterations across groups (increased body and fat mass; glucose intolerance; increased plasma insulin and leptin, decreased ghrelin; nonalcoholic fatty liver disease-related pathology). HF diet resulted in the greatest weight gain, adiposity, and glucose intolerance in 3xTg-AD females, which were associated with markedly increased hypothalamic expression of GFAP and IL-1β, as well as GFAP labeling in several hypothalamic nuclei that regulate energy balance. In contrast, HF diet increased diabetes markers and systemic inflammation preferentially in AD males but did not exacerbate hypothalamic inflammation in this group.ConclusionsThese findings provide further evidence for the roles of hypothalamic and metabolic dysfunction in AD, which in the 3xTg-AD mouse model appears to be dependent on both sex and diet.

A Biocompatible Second Near-Infrared Nanozyme for Spatiotemporal and Non-Invasive Attenuation of Amyloid Deposition through Scalp and Skull.

Phototherapy, such as photodynamic therapy and photothermal therapy, holds great potential for modulation of Alzheimer's β-amyloid (Aβ) self-assembly. Unfortunately, current works for phototherapy of Alzheimer's disease (AD) are just employing either visible or first near-infrared (NIR-I) light with limited tissue penetration, which can not avoid damaging nearby normal tissues of AD patients through the dense skull and scalp. To overcome the shortcomings of AD phototherapy, herein we report an amyloid targeting, N-doped three-dimensional mesoporous carbon nanosphere (KD8@N-MCNs) as a second near-infrared (NIR-II) PTT agent. This makes it possible for photothermal dissociation of Aβ aggregates through the scalp and skull in a NIR-II window without hurting nearby normal tissues. Besides, KD8@N-MCNs have both superoxide dismutase and catalase activities, which can scavenge intracellular superfluous reactive oxygen species and alleviate neuroinflammation in vivo. Furthermore, KD8@N-MCNs efficiently cross the blood-brain barrier owing to the covalently grafted target peptides of KLVFFAED on the nanosphere surface. In vivo studies demonstrate that KD8@N-MCNs decrease Aβ deposits, ameliorate memory deficits, and alleviate neuroinflammation in the 3xTg-AD mouse model. Our work provides a biocompatible and non-invasive way to attenuate AD-associated pathology.

IL-6 Trans-Signaling in the Brain Influences the Metabolic Phenotype of the 3xTg-AD Mouse Model of Alzheimer's Disease.

Alzheimer’s disease (AD) is a neurodegenerative disorder that causes the most prevalent dementia in the elderly people. Obesity and insulin resistance, which may cause major health problems per se, are risk factors for AD, and cytokines such as interleukin-6 (IL-6) have a role in these conditions. IL-6 can signal either through a membrane receptor or by trans-signaling, which can be inhibited by the soluble form of the co-receptor gp130 (sgp130). We have addressed the possibility that blocking IL-6 trans-signaling in the brain could have an effect in the triple transgenic 3xTg-AD mouse model of AD and/or in obesity progression, by crossing 3xTg-AD mice with GFAP-sgp130Fc mice. To serve as control groups, GFAP-sgp130Fc mice were also crossed with C57BL/6JOlaHsd mice. Seventeen-month-old mice were fed a control diet (18% kcal from fat) and a high-fat diet (HFD; 58.4% kcal from fat). In our experimental conditions, the 3xTg-AD model showed a mild amyloid phenotype, which nevertheless altered the control of body weight and related endocrine and metabolic factors, suggestive of a hypermetabolic state. The inhibition of IL-6 trans-signaling modulated some of these traits in both 3xTg-AD and control mice, particularly during HFD, and in a sex-dependent manner. These experiments provide evidence of IL-6 trans-signaling playing a role in the CNS of a mouse model of AD.

Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer's disease

There is increasing evidence that myelin disruption is related to cognitive decline in Alzheimer's disease (AD). In the CNS, myelin is produced by oligodendrocytes, which are generated throughout life by adult oligodendrocyte progenitor cells (OPCs), also known as NG2-glia. To address whether alterations in myelination are related to age-dependent changes in OPCs, we analyzed NG2 and myelin basic protein (MBP) immunolabelling in the hippocampus of 3×Tg-AD mice at 6 and 24 months of age, compared with non-Tg age-matched controls. There was an age-related decrease in MBP immunostaining and OPC density, together with a decline in the number of OPC sister cells, a measure of OPC replication. Notably, the loss of myelin and OPC sister cells occurred earlier at 6 months in 3xTg-AD, suggesting accelerated aging, although there was not a concomitant decline in OPC numbers at this age, suggesting the observed changes in myelin were not a consequence of replicative exhaustion, but possibly of OPC disruption or senescence. In line with this, a key finding is that compared to age-match controls, OPC displayed marked morphological atrophy at 6 months in 3xTg-AD followed by morphological hypertrophy at 24 months, as deduced from significant changes in total cell surface area, total cell volume, somata volume and branching of main processes. Moreover, we show that hypertrophic OPCs surround and infiltrate amyloid-β (Aβ) plaques, a key pathological hallmark of AD. The results indicate that OPCs undergo complex age-related remodeling in the hippocampus of the 3xTg-AD mouse model. We conclude that OPC disruption is an early pathological sign in AD and is a potential factor in accelerated myelin loss and cognitive decline.

The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse Alzheimer’s Disease Models.

Brains that are affected by Alzheimer’s disease (AD) are characterized by the overload of extracellular amyloid β (Aβ) peptides, but recent data from cellular and animal models propose that Aβ deposition is preceded by intraneuronal accumulation of the direct precursor of Aβ, C99. These studies indicate that C99 accumulation firstly occurs within endosomal and lysosomal compartments and that it contributes to early-stage AD-related endosomal-lysosomal-autophagic defects. Our previous work also suggests that C99 accumulation itself could be a consequence of defective lysosomal-autophagic degradation. Thus, in the present study, we analyzed the influence of the overexpression of the transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, on C99 accumulation occurring in both AD cellular models and in the triple-transgenic mouse model (3xTgAD). In the in vivo experiments, TFEB overexpression was induced via adeno-associated viruses (AAVs), which were injected either into the cerebral ventricles of newborn mice or administrated at later stages (3 months of age) by stereotaxic injection into the subiculum. In both cells and the 3xTgAD mouse model, exogenous TFEB strongly reduced C99 load and concomitantly increased the levels of many lysosomal and autophagic proteins, including cathepsins, key proteases involved in C99 degradation. Our data indicate that TFEB activation is a relevant strategy to prevent the accumulation of this early neurotoxic catabolite.

Clathrin Nanoparticles Efficiently Deliver Brain-Derived Neurotrophic Factor (BDNF) to the Hippocampus, Reverse Oxidative Stress and Enhance Synaptogenesis and Memory in Alzheimer’s Mouse Model

BDNF promotes neuroregeneration and restores brain functions but cannot easily cross a blood-brain-barrier (BBB). Our goal was to develop BDNF-clathrin-nanoparticles (CNPs) that can efficiently target TrkB receptors and reverse deficits in 3xTg-AD mouse model of Alzheimer’s disease.

Scattering Angle Resolved Optical Coherence Tomography Detects Early Changes in 3xTg Alzheimer's Disease Mouse Model.

PurposeClinical intensity-based optical coherence tomographic retinal imaging is unable to resolve some of the earliest changes to Alzheimer's disease (AD) neurons. The aim of this pilot study was to demonstrate that scattering-angle-resolved optical coherence tomography (SAR-OCT), which is sensitive to changes in light scattering angle, is a candidate retinal imaging modality for early AD detection. SAR-OCT signal data may be sensitive to changes in intracellular constituent morphology that are not detectable with conventional OCT.MethodsIn this cross-sectional study, retinas of a triple transgenic mouse model of AD (3xTg-AD) were imaged alongside age-matched control mice (C57BL/6J) using SAR-OCT. A total of 32 mice (12 control, 20 3xTg-Ad) at four ages (10, 20, 30, and 45 weeks) were included in this cross-sectional study, and three retinal feature sets (scattering, thickness, and angiography) were examined between the disease and control groups.ResultsAD mice had significantly increased scattering diversity (lower SAR-OCT C parameter) at the earliest imaging time (10 weeks). Differences in the C parameter between AD and control mice were diminished at later times when both groups showed increased scattering diversity. AD mice have reduced retinal thickness compared to controls, particularly in central regions and superficial layers. No differences in vascular density or fractional blood volume between groups were detected.ConclusionsSAR-OCT is sensitive to scattering angle changes in a 3xTg-AD mouse model and could provide early-stage biomarkers for neurodegenerative diseases such as AD.Translational RelevanceClinical OCT systems may be modified to record SAR-OCT images for non-invasive retinal diagnostic imaging of patients with neurodegenerative diseases such as AD.