Triple Transgenic Alzheimer's Disease Mice Research Articles

Depletion of NK Cells Improves Cognitive Function in the Alzheimer Disease Mouse Model

Despite mounting evidence suggesting the involvement of the immune system in regulating brain function, the specific role of immune and inflammatory cells in neurodegenerative diseases remain poorly understood. In this study, we report that depletion of NK cells, a type of innate lymphocytes, alleviates neuroinflammation, stimulates neurogenesis, and improves cognitive function in a triple-transgenic Alzheimer disease (AD) mouse model. NK cells in the brains of triple-transgenic AD mouse model (3xTg-AD) mice exhibited an enhanced proinflammatory profile. Depletion of NK cells by anti-NK1.1 Abs drastically improved cognitive function of 3xTg-AD mice. NK cell depletion did not affect amyloid β concentrations but enhanced neurogenesis and reduced neuroinflammation. Notably, in 3xTg-AD mice depleted of NK cells, microglia demonstrated a homeostatic-like morphology, decreased proliferative response and reduced expression of neurodestructive proinflammatory cytokines. Together, our results suggest a proinflammatory role for NK cells in 3xTg-AD mice and indicate that targeting NK cells might unlock novel strategies to combat AD.

Selenium Restores Synaptic Deficits by Modulating NMDA Receptors and Selenoprotein K in an Alzheimer's Disease Model.

Aims: Strong evidence has implicated synaptic failure as a direct contributor to cognitive decline in Alzheimer's disease (AD), and selenium (Se) supplementation has demonstrated potential for AD treatment. However, the exact roles of Se and related selenoproteins in mitigating synaptic deficits remain unclear. Results: Our data show that selenomethionine (Se-Met), as the major organic form of Se in vivo, structurally restored synapses, dendrites, and spines, leading to improved synaptic plasticity and cognitive function in triple transgenic AD (3 × Tg-AD) mice. Furthermore, we found that Se-Met ameliorated synaptic deficits by inhibiting extrasynaptic N-methyl-d-aspartate acid receptors (NMDARs) and stimulating synaptic NMDARs, thereby modulating calcium ion (Ca2+) influx. We observed that a decrease in selenoprotein K (SELENOK) levels was closely related to AD, and a similar disequilibrium was found between synaptic and extrasynaptic NMDARs in SELENOK knockout mice and AD mice. Se-Met treatment upregulated SELENOK levels and restored the balance between synaptic and extrasynaptic NMDAR expression in AD mice. Innovation: These findings establish a key signaling pathway linking SELENOK and NMDARs with synaptic plasticity regulated by Se-Met, and thereby provide insight into mechanisms by which Se compounds mediate synaptic deficits in AD. Conclusion: Our study demonstrates that Se-Met restores synaptic deficits through modulating Ca2+ influx mediated by synaptic and extrasynaptic NMDARs in 3 × Tg-AD mice, and suggests a potentially functional interaction between SELENOK and NMDARs. Antioxid. Redox Signal. 35, 863-884.

Chronic hyperglycemia impairs hippocampal neurogenesis and memory in an Alzheimer’s disease mouse model

During aging, lifestyle-related factors shape the brain's response to insults and modulate the progression of neurodegenerative pathologies such as Alzheimer's disease (AD). This is the case for chronic hyperglycemia associated with type 2 diabetes, which reduces the brain's ability to handle the neurodegenerative burden associated with AD. However, the mechanisms behind the effects of chronic hyperglycemia in the context of AD are not fully understood. Here, we show that newly generated neurons in the hippocampal dentate gyrus of triple transgenic AD (3xTg-AD) mice present increased dendritic arborization and a number of synaptic puncta, which may constitute a compensatory mechanism allowing the animals to cope with a lower neurogenesis rate. Contrariwise, chronic hyperglycemia decreases the complexity and differentiation of 3xTg-AD newborn neurons and reduces the levels of β-catenin, a key intrinsic modulator of neuronal maturation. Moreover, synaptic facilitation is depressed in hyperglycemic 3xTg-AD mice, accompanying the defective hippocampal-dependent memory. Our data suggest that hyperglycemia evokes cellular and functional alterations that accelerate the onset of AD-related symptoms, namely memory impairment.

Ultrasound with microbubbles improves memory, ameliorates pathology and modulates hippocampal proteomic changes in a triple transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease manifested by cognitive impairment. As a unique approach to open the blood-brain barrier (BBB) noninvasively and temporarily, a growing number of studies showed that low-intensity focused ultrasound in combination with microbubbles (FUS/MB), in the absence of therapeutic agents, is capable of ameliorating amyloid or tau pathology, concurrent with improving memory deficits of AD animal models. However, the effects of FUS/MB on both the two pathologies simultaneously, as well as the memory behaviors, have not been reported so far.Methods: In this study, female triple transgenic AD (3×Tg-AD) mice at eight months of age with both amyloid-β (Aβ) deposits and tau phosphorylation were treated by repeated FUS/MB in the unilateral hippocampus twice per week for six weeks. The memory behaviors were investigated by the Y maze, the Morris water maze and the step-down passive avoidance test following repeated FUS/MB treatments. Afterwards, the involvement of Aβ and tau pathology were assessed by immunohistochemical analysis. Neuronal health and phagocytosis of Aβ deposits by microglia in the hippocampus were examined by confocal microscopy. Further, hippocampal proteomic alterations were analyzed by employing two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with mass spectrometry.Results: The three independent memory tasks were indicative of evident learning and memory impairments in eight-month-old 3×Tg-AD mice, which developed intraneuronal Aβ, extracellular diffuse Aβ deposits and phosphorylated tau in the hippocampus and amygdala. Following repeated FUS/MB treatments, significant improvement in learning and memory ability of the 3×Tg-AD mice was achieved. Amelioration in both Aβ deposits and phosphorylated tau in the sonicated hemisphere was induced in FUS/MB-treated 3×Tg-AD mice. Albeit without increase in neuron density, enhancement in axonal neurofilaments emerged from the FUS/MB treatment. Confocal microscopy revealed activated microglia engulfing Aβ deposits in the FUS/MB-treated hippocampus. Further, proteomic analysis revealed 20 differentially expressed proteins, associated with glycolysis, neuron projection, mitochondrial pathways, metabolic process and ubiquitin binding etc., in the hippocampus between FUS/MB-treated and sham-treated 3×Tg-AD mice.Conclusions: Our findings reinforce the positive therapeutic effects on AD models with both Aβ and tau pathology induced by FUS/MB-mediated BBB opening, further supporting the potential of this treatment regime for clinical applications.

Ca2+-permeable TRPV1 pain receptor knockout rescues memory deficits and reduces amyloid-β and tau in a mouse model of Alzheimer's disease.

The transient receptor potential vanilloid 1 (TRPV1) protein is a pain receptor that elicits a hot sensation when an organism eats the capsaicin of red chili peppers. This calcium (Ca2+)-permeable cation channel is mostly expressed in the peripheral nervous system sensory neurons but also in the central nervous system (e.g. hippocampus and cortex). Preclinical studies found that TRPV1 mediates behaviors associated with anxiety and depression. Loss of TRPV1 functionality increases expression of genes related to synaptic plasticity and neurogenesis. Thus, we hypothesized that TRPV1 deficiency may modulate Alzheimer's disease (AD). We generated a triple-transgenic AD mouse model (3xTg-AD+/+) with wild-type (TRPV1+/+), hetero (TRPV1+/-) and knockout (TRPV1-/-) TRPV1 to investigate the role of TRPV1 in AD pathogenesis. We analyzed the animals' memory function, hippocampal Ca2+ levels and amyloid-β (Aβ) and tau pathologies when they were 12months old. We found that compared with 3xTg-AD-/-/TRPV1+/+ mice, 3xTg-AD+/+/TRPV1+/+ mice had memory impairment and increased levels of hippocampal Ca2+, Aβ and total and phosphorylated tau. However, 3xTg-AD+/+/TRPV1-/- mice had better memory function and lower levels of hippocampal Ca2+, Aβ, tau and p-tau, compared with 3xTg-AD+/+/TRPV1+/+ mice. Examination of 3xTg-AD-derived primary neuronal cultures revealed that the intracellular Ca2+ chelator BAPTA/AM and the TRPV1 antagonist capsazepine decreased the production of Aβ, tau and p-tau. Taken together, these results suggested that TRPV1 deficiency had anti-AD effects and promoted resilience to memory loss. These findings suggest that drugs or food components that modulate TRPV1 could be exploited as therapeutics to prevent or treat AD.

Allopregnanolone Reverses Bioenergetic Deficits in Female Triple Transgenic Alzheimer's Mouse Model.

Previously, we reported that the neurosteroid allopregnanolone (Allo) promoted neural stem cell regeneration, restored cognitive function, and reduced Alzheimer's Disease (AD) pathology in the triple transgenic Alzheimer's mouse model (3xTgAD). To investigate the underlying systems biology of Allo action in AD models in vivo, we assessed the regulation of Allo on the bioenergetic system of the brain. Outcomes of these analysis indicated that Allo significantly reversed deficits in mitochondrial respiration and biogenesis and key mitochondrial enzyme activity and reduced lipid peroxidation in the 3xTgAD mice in vivo. To explore the mechanisms by which Allo regulates the brain metabolism, we conducted targeted transcriptome analysis. These data further confirmed that Allo upregulated genes involved in glucose metabolism, mitochondrial bioenergetics, and signaling pathways while simultaneously downregulating genes involved in Alzheimer's pathology, fatty acid metabolism, and mitochondrial uncoupling and dynamics. Upstream regulatory pathway analysis predicted that Allo induced peroxisome proliferator-activated receptor gamma (PPARG) and coactivator 1-alpha (PPARGC1A) pathways while simultaneously inhibiting the presenilin 1 (PSEN 1), phosphatase and tensin homolog (PTEN), and tumor necrosis factor (TNF) pathways to reduce AD pathology. Collectively, these data indicate that Allo functions as a systems biology regulator of bioenergetics, cholesterol homeostasis, and β-amyloid reduction in the brain. These systems are critical to neurological health, thus providing a plausible mechanistic rationale for Allo as a therapeutic to promote neural cell function and reduce the burden of AD pathology.

Isoflurane mediated neuropathological and cognitive impairments in the triple transgenic Alzheimer's mouse model are associated with hippocampal synaptic deficits in an age-dependent manner.

Many in vivo studies suggest that inhalational anesthetics can accelerate or prevent the progression of neuropathology and cognitive impairments in Alzheimer Disease (AD), but the synaptic mechanisms mediating these ambiguous effects are unclear. Here, we show that repeated exposures of neonatal and old triple transgenic AD (3xTg) and non-transgenic (NonTg) mice to isoflurane (Iso) distinctly increased neurodegeneration as measured by S100β levels, intracellular Aβ, Tau oligomerization, and apoptotic markers. Spatial cognition measured by reference and working memory testing in the Morris Water Maze (MWM) were altered in young NonTg and 3xTg. Field recordings in the cornu ammonis 1 (CA1) hippocampus showed that neonatal control 3xTg mice exhibited hypo-excitable synaptic transmission, reduced paired-pulse facilitation (PPF), and normal long-term potentiation (LTP) compared to NonTg controls. By contrast, the old control 3xTg mice exhibited hyper-excitable synaptic transmission, enhanced PPF, and unstable LTP compared to NonTg controls. Repeated Iso exposures reduced synaptic transmission and PPF in neonatal NonTg and old 3xTg mice. LTP was normalized in old 3xTg mice, but reduced in neonates. By contrast, LTP was reduced in old but not neonatal NonTg mice. Our results indicate that Iso-mediated neuropathologic and cognitive defects in AD mice are associated with synaptic pathologies in an age-dependent manner. Based on these findings, the extent of this association with age and, possibly, treatment paradigms warrant further study.

Bexarotene therapy ameliorates behavioral deficits and induces functional and molecular changes in very-old Triple Transgenic Mice model of Alzheimer´s disease.

IntroductionBexarotene, a retinoid X receptor agonist, improves cognition in murine models of Alzheimer’s disease (AD). This study evaluated the effects of bexarotene on pathological and electrophysiological changes in very old triple transgenic AD mice (3xTg-AD mice).Methods24-month-old 3xTg-AD mice were treated with bexarotene (100 mg/kg/day for 30 days). The Morris water maze was used to evaluate spatial memory; immunofluorescence and confocal microscopy were used to evaluate pathological changes; and in vivo electrophysiological recordings were used to evaluate basal transmission and plasticity in the commissural CA3-CA1 pathway.ResultsIn addition to cognitive improvement, bexarotene-treated 3xTg-AD mice were found to have 1) reductions of astrogliosis and reactive microglia both in cortex and hippocampus; 2) increased ApoE expression restricted to CA1; 3) increased number of cells co-labeled with ApoE and NeuN; 4) recovery of NeuN expression, suggesting neuronal protection; and, 5) recovery of basal synaptic transmission and synaptic plasticity.DiscussionThese results indicate that bexarotene-induced improvement in cognition is due to multiple changes that contribute to recovery of synaptic plasticity.

Transcranial direct current stimulation does not improve memory deficits or alter pathological hallmarks in a rodent model of Alzheimer's disease

Alzheimer's disease (AD) is a progressive and debilitating degenerative disorder for which there are currently no effective therapeutic options. Non-invasive neuromodulation, including transcranial direct current stimulation (tDCS), has been investigated for the treatment of cognitive symptoms in AD. Results from clinical and preclinical studies, however, have been somewhat controversial. We investigate whether tDCS delivered to triple transgenic (3xTg) AD mice improves memory deficits and mitigates the development of AD-type neuropathology.3xTg AD mice and controls were implanted with paddle electrodes over the skull. The cathode was anterior to bregma and the anode anterior to lamda. tDCS was delivered for 20 min/day, 5 days/week over three weeks at 50 μA. Though this amplitude was lower than the one used in the preclinical literature, it generated a high current density compared to the clinical scenario. Memory testing was conducted during treatment weeks 2 and 3. Post-mortem pathological AD markers were studied. Our results show that performance of 3xTg mice in the novel object recognition and Morris water maze tests was significantly impaired compared to that of controls. In addition, AD transgenics had an increased expression of tau, phosphorylated-tau and amyloid precursor protein in the hippocampus. tDCS did not improve behavioural deficits or mitigated the development of AD neuropathology in 3xTg animals. In summary, we found that tDCS at the settings selected in our study was largely ineffective in improving memory performance or altering the expression of AD pathological hallmarks in a validated mouse model.

Beneficial effects of resveratrol and exercise training on cardiac and aortic function and structure in the 3xTg mouse model of Alzheimer's disease.

Background: Studies have indicated an association between Alzheimer’s disease (AD) and increased risk of developing cardiovascular complications. Lifestyle modifiable factors, such as exercise and diet, are known to prevent cardio-cerebral disease. Recent studies demonstrate that hearts from early onset triple-transgenic AD mice exhibit pathologies, but it is not clear whether cardiovascular function is altered in this model. Methods: In this study, we measured in vivo cardiovascular function in 7-month-old male 3xTg mice and age-matched wild-type (WT) mice using high-frequency high-resolution ultrasound imaging. Results: Our findings indicated that aortic root measurements and interventricular septal dimensions were similar in 3xTg and wild-type mice. Systolic function, expressed as ejection fraction and fractional shortening, were decreased in 3xTg mice. Late (A) ventricular filling velocities, the early/atrial (E/A) ratio, and mitral valve deceleration time, all indices of diastolic function, were increased in 3xTg mice compared to WT mice. Treadmill exercise training and resveratrol supplementation in the diet for 5 months improved ejection fraction, fractional shortening, and restored diastolic deceleration times. Pulse wave velocity was ~33% higher in 3xTg, and accompanied by a significant increase in elastin fiber fragmentation within the aortic wall, which was associated with decrease in elastin content and fiber length. Aortic wall and adventitia thickness were increased in 3xTg mice compared to the WT group. Exercise training and resveratrol supplementation, or both, improved overall aortic morphology with no change in pulse wave velocity. Conclusion: Taken together, the results indicate that the aberrations in cardiac function and aortic elastin morphology observed in the 3xTg mouse model of AD can be prevented with exercise training and treatment with resveratrol. The benefits of regular exercise training and resveratrol supplementation of heart and aortic structure in the 3xTg mouse support the value of healthy lifestyle factors on cardiovascular health.

Early growth response-1 regulates acetylcholinesterase and its relation with the course of Alzheimer's disease.

Our previous studies showed that the transcription factor early growth response-1 (EGR1) may play a role in keeping the brain cholinergic function intact in the preclinical stages of Alzheimer's disease (AD). In order to elucidate the mechanisms involved, we first performed data mining on our previous microarray study on postmortem human prefrontal cortex (PFC) for the changes in the expression of EGR1 and acetylcholinesterase (AChE) and the relationship between them during the course of AD. The study contained 49 patients, ranging from non-demented controls (Braak stage 0) to late AD patients (Braak stage VI). We found EGR1-mRNA was high in early AD and decreased in late AD stages, while AChE-mRNA was stable in preclinical AD and slightly decreased in late AD stages. A significant positive correlation was found between the mRNA levels of these two molecules. In addition, we studied the relationship between EGR1 and AChE mRNA levels in the frontal cortex of 3-12-months old triple-transgenic AD (3xTg-AD) mice. EGR1- and AChE-mRNA were lower in 3xTg-AD mice compared with wild-type (WT) mice. A significant positive correlation between these two molecules was present in the entire group and in each age group of either WT or 3xTg-AD mice. Subsequently, AChE expression was determined following up- or down-regulating EGR1 in cell lines and the EGR1 levels were found to regulate AChE at both the mRNA and protein levels. Dual-luciferase assay and electrophoretic mobility shift assay in the EGR1-overexpressing cells were performed to determine the functionally effective binding sites of the EGR1 on the AChE gene promoter. We conclude that the EGR1 can upregulate AChE expression by a direct effect on its gene promoter, which may contribute significantly to the changes in cholinergic function in the course of AD. The 3xTg-AD mouse model only reflects later stage AD.

A Diet Enriched in Palmitate and Deficient in Linoleate Exacerbates Oxidative Stress and Amyloid-β Burden in the Hippocampus of 3xTg-AD Mouse Model of Alzheimer's Disease.

Epidemiological studies have suggested a positive correlation between saturated fat intake and the risk for developing Alzheimer's disease (AD). While diets-enriched in the saturated free fatty acid (sFFA) palmitate has been shown to induce cognitive dysfunction and AD-like pathology, polyunsaturated fatty acids (PUFA) such as linoleate have been suggested to protect against AD in mouse models. However, the underlying cellular and molecular mechanisms that mediate the deleterious effects of palmitate or the protective effects of linoleate remain to be characterized. We fed 9-month-old cohorts of triple transgenic AD mice (3xTg-AD) and their-matched controls with a palmitate-enriched/linoleate-deficient diet for three months and determined the impact of the diet on oxidative stress, Bace1 promoter transactivation status, and amyloid-β (Aβ) burden. The palmitate-enriched/linoleate-deficient diet causes a profound increase in oxidative stress burden characterized by significant oxidative damage to lipids, proteins, and nucleic acids concomitant with deficits in the endogenous antioxidant defense capacity in the hippocampi of 3xTg-AD mice. These effects were also associated with increased NF-κB transcriptional activity resulting in NF-κB-mediated transactivation of the Bace1 promoter that culminated in higher BACE1 expression and activity, and Aβ production. Our study unveils a novel mechanism by which a diet enriched in the sFFA palmitate and deficient in the PUFA linoleate exacerbates AD-like pathology involving signaling cross-talk between oxidative stress and NF-κB activation as a critical underlying factor in upregulating BACE1 activity and increasing Aβ burden.

Inhibition of HDAC3 reverses Alzheimer’s disease-related pathologies in vitro and in the 3xTg-AD mouse model

Alzheimer's disease (AD) is the leading cause of age-related dementia. Neuropathological hallmarks of AD include brain deposition of β-amyloid (Aβ) plaques and accumulation of both hyperphosphorylated and acetylated tau. RGFP-966, a brain-penetrant and selective HDAC3 inhibitor, or HDAC3 silencing, increases BDNF expression, increases histone H3 and H4 acetylation, decreases tau phosphorylation and tau acetylation at disease-associated sites, reduces β-secretase cleavage of the amyloid precursor protein (APP), and decreases Aβ1-42 accumulation in HEK-293 cells overexpressing APP with the double Swedish mutation (HEK/APPsw). In the triple transgenic AD mouse model (3xTg-AD), repeated administration of 3 and 10 mg/kg of RGFP-966 reverses pathological tau phosphorylation at Thr181, Ser202, and Ser396, increases levels of the Aβ degrading enzyme Neprilysin in plasma, decreases Aβ1-42 protein levels in the brain and periphery, and improves spatial learning and memory. Finally, we show that RGFP-966 decreases Aβ1-42 accumulation and both tau acetylation and phosphorylation at disease residues in neurons derived from induced pluripotent stem cells obtained from APOEε4-carrying AD patients. These data indicate that HDAC3 plays an important regulatory role in the expression and regulation of proteins associated with AD pathophysiology, supporting the notion that HDAC3 may be a disease-modifying therapeutic target.

Sex Differences in Neuropathology and Cognitive Behavior in APP/PS1/tau Triple-Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation in the brain, as well as impaired cognitive behaviors. A sex difference in the prevalence of AD has been noted, while sex differences in the cerebral pathology and relevant molecular mechanisms are not well clarified. In the present study, we systematically investigated the sex differences in pathological characteristics and cognitive behavior in 12-month-old male and female APP/PS1/tau triple-transgenic AD mice (3×Tg-AD mice) and examined the molecular mechanisms. We found that female 3×Tg-AD mice displayed more prominent amyloid plaques, neurofibrillary tangles, neuroinflammation, and spatial cognitive deficits than male 3×Tg-AD mice. Furthermore, the expression levels of hippocampal protein kinase A-cAMP response element-binding protein (PKA-CREB) and p38-mitogen-activated protein kinases (MAPK) also showed sex difference in the AD mice, with a significant increase in the levels of p-PKA/p-CREB and a decrease in the p-p38 in female, but not male, 3×Tg-AD mice. We suggest that an estrogen deficiency-induced PKA-CREB-MAPK signaling disorder in 12-month-old female 3×Tg-AD mice might be involved in the serious pathological and cognitive damage in these mice. Therefore, sex differences should be taken into account in investigating AD biomarkers and related target molecules, and estrogen supplementation or PKA-CREB-MAPK stabilization could be beneficial in relieving the pathological damage in AD and improving the cognitive behavior of reproductively-senescent females.

Selenium positively affects the proteome of 3 × Tg-AD mice cortex by altering the expression of various key proteins: unveiling the mechanistic role of selenium in AD prevention.

Selenium (Se) deficiency is believed to be involved in pathogenesis of Alzheimer's disease (AD) due to failure of antioxidant system. Its supplementation may restore the antioxidant system and compensate the impairments caused by AD. Present study reveals the effect of Se on the proteomic changes in cortex within triple transgenic male AD mice (3 × Tg-AD) after 4 months sodium selenate supplementation. Using iTRAQ comparative proteomics approach, 142 proteins found significant alterations with 96 down-regulated and 46 up-regulated proteins in the cortices of AD mice in comparison with the wild non-transgenic type mice. On treatment with sodium selenate, 41 proteins showed reverse expression, that is, thirty three proteins were down-regulated in AD mice but up-regulated in selenate treated AD mice while eight up-regulated proteins in AD mice showed lower expression in selenate treated mice. OmicsBean bioinformatics analysis revealed that Se positively affected the proteins vital in biological process, structural cores, and molecular functions, which include metabolic proteins, structural proteins, signaling molecules, oxidative stress balancers, and proteosomal degradation proteins. Results of mass spectrometry (MS) were further confirmed by Western blot analysis of five important proteins, prompting the authenticity of the MS results. This paper fills the protein-based molecular gap between AD and Se-treatment, and it provides a full view of Se in reversing the change of cortical protein levels during AD formation.

Phosphorylation of Tau protein correlates with changes in hippocampal theta oscillations and reduces hippocampal excitability in Alzheimer's model

Tau hyperphosphorylation at several sites, including those close to the microtubule domain region (MDr), is considered a key pathological event in the development of Alzheimer's disease (AD). Recent studies indicate that at the very early stage of this disease, increased phosphorylation in Tau's MDr domain correlates with reduced levels of neuronal excitability. Mechanistically, we show that pyramidal neurons and some parvalbumin-positive interneurons in 1-month-old triple-transgenic AD mice accumulate hyperphosphorylated Tau protein and that this accumulation correlates with changes in theta oscillations in hippocampal neurons. Pyramidal neurons from young triple-transgenic AD mice exhibited less spike accommodation and power increase in subthreshold membrane oscillations. Furthermore, triple-transgenic AD mice challenged with the potassium channel blocker 4-aminopyridine had reduced theta amplitude compared with 4-aminopyridine-treated control mice and, unlike these controls, displayed no seizure-like activity after this challenge. Collectively, our results provide new insights into AD pathogenesis and suggest that increases in Tau phosphorylation at the initial stages of the disease represent neuronal responses that compensate for brain circuit overexcitation.

Inflammation, neurodegeneration and protein aggregation in the retina as ocular biomarkers for Alzheimer\u2019s disease in the 3xTg-AD mouse model

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. In the pathogenesis of AD a pivotal role is played by two neurotoxic proteins that aggregate and accumulate in the central nervous system: amyloid beta and hyper-phosphorylated tau. Accumulation of extracellular amyloid beta plaques and intracellular hyper-phosphorylated tau tangles, and consequent neuronal loss begins 10–15 years before any cognitive impairment. In addition to cognitive and behavioral deficits, sensorial abnormalities have been described in AD patients and in some AD transgenic mouse models. Retina can be considered a simple model of the brain, as some pathological changes and therapeutic strategies from the brain may be observed or applicable to the retina. Here we propose new retinal biomarkers that could anticipate the AD diagnosis and help the beginning and the follow-up of possible future treatments. We analyzed retinal tissue of triple-transgenic AD mouse model (3xTg-AD) for the presence of pathological hallmarks during disease progression. We found the presence of amyloid beta plaques, tau tangles, neurodegeneration, and astrogliosis in the retinal ganglion cell layer of 3xTg-AD mice, already at pre-symptomatic stage. Moreover, retinal microglia in pre-symptomatic mice showed a ramified, anti-inflammatory phenotype which, during disease progression, switches to a pro-inflammatory, less ramified one, becoming neurotoxic. We hypothesize retina as a window through which monitor AD-related neurodegeneration process.

Se-Methylselenocysteine Ameliorates Neuropathology and Cognitive Deficits by Attenuating Oxidative Stress and Metal Dyshomeostasis in Alzheimer Model Mice.

Se-methylselenocysteine (SMC) is a major selenocompound in selenium (Se)-enriched plants. Se is vital for proper brain function, and Se-deficient is considered to be related with cognitive impairment and Alzheimer's disease (AD). The potential of SMC in intervening cognitive deficits and neuropathology of triple transgenic AD (3 × Tg-AD) mice is evaluated for the first time. AD mice are treated with SMC (0.75 mg kg-1 BW per day) in their drinking water for 10 months. Results reveal that SMC 1) reduces oxidative stress and neuro-inflammation; 2) modulates the distribution and levels of several metal ions; 3) decreases amyloid-β peptide (Aβ) generation by inhibiting the expression of its precursor protein APP and β-secretase (BACE1); and 4) attenuates tau hyperphosphorylation and neurofibrillary tangles (NFT) formation via promoting protein phosphatase 2A (PP2A) activity, thereby preserving synaptic proteins and neuron activities and finally improving spatial learning and memory deficits in AD model mice. The authors suggest that the inhibitory effect of SMC on MEK/ERK activation may play a critical role in intervening AD progression. These results reveal that SMC is powerful in ameliorating AD-related neuropathology and cognitive deficits via modulating oxidative stress, metal homeostasis, and extracellular signal-regulated kinase (ERK) activation.

Mitochondrial Molecular Abnormalities Revealed by Proteomic Analysis of Hippocampal Organelles of Mice Triple Transgenic for Alzheimer Disease.

Mitochondrial dysfunction is implicated in the pathogenesis of Alzheimer’s disease (AD). However, the precise mitochondrial molecular deficits in AD remain poorly understood. Mitochondrial and nuclear proteomic analysis in mature male triple transgenic AD mice (PS1M146V/APPSwe/TauP301L) by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with MALDI-TOF-MS/MS, bio-informatics analysis and immunofluorescent staining were performed in this study. In addition to impaired spatial memory impairment and intracellular accumulation of amyloid 1–42 (Aβ1–42) in the 3xTg-AD mice, a well-accepted mouse model of the human disease, we also found significantly increased DNA oxidative damage in entorhinal cortex, hippocampal CA1, CA3 and dental gyrus (DG), as evidenced by the positive staining of 8-hydroxyguanosine, a biomarker of mild cognitive impairment early in AD. We identified significant differences in 27 hippocampal mitochondrial proteins (11 increased and 16 decreased), and 37 hippocampal nuclear proteins (12 increased and 25 decreased) in 3xTg-AD mice compared with the wild-type (WT) mice. Differentially expressed mitochondrial and nuclear proteins were mainly involved in energy metabolism (>55%), synapses, DNA damage, apoptosis and oxidative stress. Two proteins were differentially expressed in both hippocampal mitochondria and nuclei, namely electron transport chain (ETC)-related protein ATP synthase subunit d (ATP5H) was significantly decreased, and apoptosis-related dynamin-1 (DYN1), a pre-synaptic and mitochondrial division-regulated protein that was significantly increased. In sum, perturbations of hippocampus mitochondrial energy metabolism-related proteins responsible for ATP generation via oxidation phosphorylation (OXPHOS), especially nuclear-encoded OXPHOS proteins, correlated with the amyloid-associated cognitive deficits of this murine AD model. The molecular changes in respiratory chain-related proteins and DYN1 may represent novel biomarkers of AD.

SLOH, a carbazole-based fluorophore, mitigates neuropathology and behavioral impairment in the triple-transgenic mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative dysfunction characterized by memory impairment and brings a heavy burden to old people both in developing and developed countries. Amyloid hypothesis reveals that aggregation and deposition of amyloid plaques are the cause of AD neurodegeneration. SLOH, a carbazole-based fluorophore, is reported to inhibit amyloid beta (Aβ) aggregation in vitro. In the current study, we intended to evaluate the protective effect of SLOH in a triple transgenic AD mouse model (3xTg-AD). 3xTg-AD (10-month-old) were treated with SLOH (0.5, 1 and 2 mg kg−1) for one month via intraperitoneal injection. After treatment, cognitive function was assessed by Morris Water Maze (MWM) and Y-maze tasks. In addition, biochemical estimations were used to examine the degree of Aβ deposition, tau hyperphosphorylation and neuroinflammation in the brains of 3xTg-AD mice. An in vitro study was conducted on human neuroblastoma (SH-SY5Y) cells to determine the activity of SLOH on tau and GSK-3β using western blot and immunofluorescence staining. One month treatment with SLOH significantly ameliorated memory impairments in 3xTg-AD mice in MWM and Y-maze tests. Moreover, SLOH treatment mitigated the level of amyloid plaques, tau hyperphosphorylation and neuroinflammation in the mouse brain. SLOH also reduced tau hyperphosphorylation and down-regulated GSK-3β activity in Aβ induced neurotoxic SH-SY5Y cells. The promising results in mitigating amyloid plaques, tau hyperphosphorylation, neuroinflammation and ameliorating cognitive deficits following one-month treatment suggest that SLOH could be a potential multi-target molecule for the AD treatment.