Expression Of Phosphorylated Tau Research Articles

Treatment of Parkinson's disease model with human umbilical cord mesenchymal stem cell-derived exosomes loaded with BDNF

AimsParkinson's disease (PD) is a common neurodegenerative disease that has received widespread attention; however, current clinical treatments can only relieve its symptoms, and do not effectively protect dopaminergic neurons. The purpose of the present study was to investigate the therapeutic effects of human umbilical cord mesenchymal stem cell-derived exosomes loaded with brain-derived neurotrophic factor (BDNF-EXO) on PD models and to explore the underlying mechanisms of these effects. Main methods6-Hydroxydopamine was used to establish in vivo and in vitro PD models. Western blotting, flow cytometry, and immunofluorescence were used to detect the effects of BDNF-EXO on apoptosis and ferroptosis in SH-SY5Y cells. The in vivo biological distribution of BDNF-EXO was detected using a small animal imaging system, and dopaminergic neuron improvements in brain tissue were detected using western blotting, immunofluorescence, immunohistochemistry, and Nissl and Prussian blue staining. Key findingsBDNF-EXO effectively suppressed 6-hydroxydopamine-induced apoptosis and ferroptosis in SH-SY5Y cells. Following intravenous administration, BDNF-EXO crossed the blood–brain barrier to reach afflicted brain regions in mice, leading to a notable enhancement in neuronal survival. Furthermore, BDNF-EXO modulated microtubule-associated protein 2 and phosphorylated tau expression, thereby promoting neuronal cytoskeletal stability. Additionally, BDNF-EXO bolstered cellular antioxidant defense mechanisms through the activation of the nuclear factor erythroid 2-related factor 2 signaling pathway, thereby conferring neuroprotection against damage. SignificanceThe novel drug delivery system, BDNF-EXO, had substantial therapeutic effects in both in vivo and in vitro PD models, and may represent a new treatment strategy for PD.

Granulocyte‐Macrophage Colony‐Stimulating Factor Reduces Two Major Pathological Hallmarks of Alzheimer’s Disease and Astrogliosis in the TgF344‐AD Rat Model

AbstractBackgroundGranulocyte‐macrophage colony‐stimulating factor (GM‐CSF), a hematopoietic growth factor and the innate immune system modulator, has shown therapeutic and neuroprotective effects in animal models of Alzheimer’s disease (AD), Parkinson’s disease, Down syndrome, stroke, and normal aging. Recently, Potter et al. (2021) published the results of a Phase2 clinical trial in mild‐to‐moderate AD subjects showing that recombinant human GM‐CSF (sargramostim) treatment shifted both MMSE scores and plasma biomarkers of neurodegeneration toward normal. Cohen et al. (2013) developed a transgenic rat model (TgF344‐AD) that expresses the Swedish mutant human APP (APPsw) and mutant human presenilin 1 (PSEN1 deltaE9) genes that cause familial AD. In addition to cerebral amyloidosis, neuronal loss, and cognitive deficits, TgF344‐AD rats also show age‐dependent tauopathy including overexpression of phosphorylated tau and neurofibrillary tangle formation, which are not present in mouse models of AD. To evaluate the potential ability of GM‐CSF to reverse and/or prevent the full range of AD pathology, we treated ∼20‐month‐old TgF344‐AD rats with GM‐CSF or saline, and investigated AD pathology in the brain and retina. We also analyzed biomarkers in plasma using MSD and SIMOA neuroinflammation panels.MethodTgF344‐AD rats were injected subcutaneously with GM‐CSF (83.3ug/kg/day; 5days/week) or with saline (200ul/day) for 24 injections total over 32 days. On day 32, blood samples were collected, plasma samples were used for biomarkers assays, and brain and retinal tissues were processed for immunohistochemistry and immunoblotting.ResultTgF344‐AD rats treated with GM‐CSF showed a significant reduction in amyloid plaque deposition in the cortex and a strong trend towards reduced plaque deposition in the hippocampal CA region compared to saline‐treated TgF344‐AD rats. We also observed a trend of reduced phosphorylated tau expression in the cortex and hippocampal region in GM‐CSF‐treated TgF344‐AD rats. In addition, GM‐CSF treatment significantly reduced astrogliosis in the CA1 and dentate gyrus/hilus regions of TgF344‐AD rats.ConclusionAlthough experiments are ongoing, our findings indicate that GM‐CSF treatment rescues two major pathological hallmarks of AD and neuroinflammation (astrogliosis) in TgF344‐AD rats. Our results suggest that GM‐CSF/sargramostim/Leukine® may be a potential therapeutic not only for reducing amyloidosis, but also for reducing levels of hyperphosphorylated tau and other relevant pathological manifestations of AD.

No evidence of aberrant amyloid β and phosphorylated tau expression in herpes simplex virus-infected neurons of the trigeminal ganglia and brain.

Increasing evidence supports the role of neurotropic herpes simplex virus 1 (HSV‐1) in the pathogenesis of Alzheimer's disease (AD). However, it is unclear whether previously reported findings in HSV‐1 cell culture and animal models can be translated to humans. Here, we analyzed clinical specimens from latently HSV‐1 infected individuals and individuals with lytic HSV infection of the brain (herpes simplex encephalitis; HSE). Latent HSV‐1 DNA load and latency‐associated transcript (LAT) expression were identical between trigeminal ganglia (TG) of AD patients and controls. Amyloid β (Aβ) and hyperphosphorylated tau (pTau) were not detected in latently HSV‐infected TG neurons. Aging‐related intraneuronal Aβ accumulations, neurofibrillary tangles (NFT), and/or extracellular Aβ plaques were observed in the brain of some HSE patients, but these were neither restricted to HSV‐infected neurons nor brain regions containing virus‐infected cells. Analysis of unique brain material from an AD patient with concurrent HSE showed that HSV‐infected cells frequently localized close to Aβ plaques and NFT, but were not associated with exacerbated AD‐related pathology. HSE‐associated neuroinflammation was not associated with specific Aβ or pTau phenotypes. Collectively, we observed that neither latent nor lytic HSV infection of human neurons is directly associated with aberrant Aβ or pTau protein expression in ganglia and brain.

Mangostanaxanthone IV Ameliorates Streptozotocin-Induced Neuro-Inflammation, Amyloid Deposition, and Tau Hyperphosphorylation via Modulating PI3K/Akt/GSK-3β Pathway.

Simple SummaryMangostanaxanthone IV (MX-IV) is a major constituent in Garcinia mangostana. It induced neuro-protective effects in the ICV-STZ mouse model through diminishing ICV-STZ-induced oxidative stress, neuro-inflammation, and apoptosis which was reflected by a significant reduction in malondialdehyde (MDA), hydrogen peroxide (H2O2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) brain contents contrary to increased glutathione (GSH) content. It also decreased amyloid plaques’ number and phosphorylated tau expression via the PI3K/Akt/GSK-3β pathway.Alzheimer’s disease (AD), a progressive neurodegenerative disorder, is characterized by amyloid deposition and neurofibrillary tangles formation owing to tau protein hyperphosphorylation. Intra-cerebroventricular (ICV) administration of streptozotocin (STZ) has been widely used as a model of sporadic AD as it mimics many neuro-pathological changes witnessed in this form of AD. In the present study, mangostanaxanthone IV (MX-IV)-induced neuro-protective effects in the ICV-STZ mouse model were investigated. STZ (3 mg/kg, ICV) was injected once, followed by either MX-IV (30 mg/kg/day, oral) or donepezil (2.5 mg/kg/day, oral) for 21 days. Treatment with MX-IV diminished ICV-STZ-induced oxidative stress, neuro-inflammation, and apoptosis which was reflected by a significant reduction in malondialdehyde (MDA), hydrogen peroxide (H2O2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) brain contents contrary to increased glutathione (GSH) content. Moreover, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase content and cleaved caspase-3 activity were reduced together with a marked decrement in amyloid plaques number and phosphorylated tau expression via PI3K/Akt/GSK-3β pathway modulation, leading to obvious enhancement in neuronal survival and cognition. Therefore, MX-IV is deemed as a prosperous nominee for AD management with obvious neuro-protective effects that were comparable to the standard drug donepezil.

Insulin deficiency, but not resistance, exaggerates cognitive deficits in transgenic mice expressing human amyloid and tau proteins. Reversal by Exendin-4 treatment.

Epidemiological studies have pointed at diabetes as a risk factor for Alzheimer's disease (AD) and this has been supported by several studies in animal models of both type 1 and type 2 diabetes. However, side-by-side comparison of the two types of diabetes is limited. We investigated the role of insulin deficiency and insulin resistance in the development of memory impairments and the effect of Exendin-4 (Ex4) treatment in a mouse model of AD. Three-4-month-old female wild type (WT) mice and mice overexpressing human tau and amyloid precursor protein (TAPP) were injected with streptozotocin (STZ) or fed a high-fat diet (HFD). A second study was performed in TAPP-STZ mice treated with Ex4, a long-lasting analog of GLP-1. Plasma and brain were collected at study termination for ELISA, Western blot, and immunohistochemistry analysis. Learning and memory deficits were impaired in TAPP transgenic mice compared with WT mice at the end of the study. Deficits were exaggerated by insulin deficiency in TAPP mice but 12weeks of insulin resistance did not affect memory performances in either WT or TAPP mice. Levels of phosphorylated tau were increased in the brain of WT-STZ and TAPP-STZ mice but not in the brain of WT or TAPP mice on HFD. In the TAPP-STZ mice, treatment with Ex4 initiated after established cognitive deficits ameliorated learning, but not memory, impairments. This was accompanied by the reduction of amyloid β and phosphorylated tau expression. Theses studies support the role of Ex4 in AD, independently from its actions on diabetes.

Protective effects of Coenzyme Q10 against sevoflurane-induced cognitive impairment through regulating apolipoprotein E and phosphorylated Tau expression in young mice.

Children with multiple exposures to anesthesia and surgery may be more likely to develop the learning disability. Coenzyme Q10 (CoQ10) was reported to reduce the multiple sevoflurane treatment-induced cognitive deficiency in 6-day-old young mice. However, its specific mechanisms have not yet been found. This research aimed to reveal the role of ApoE in the pathogenesis of cognitive deficiency caused by sevoflurane anesthesia and the protective mechanism of CoQ10 in a multiple sevoflurane treatment model of young mice. The mice were randomly divided into four groups: Control+corn oil, Sevoflurane+corn oil, Control+CoQ10, and Sevoflurane+CoQ10. Sevoflurane group mice were anesthetized with 3% sevoflurane and 60% oxygen 2hr a day for 3days, while control group mice received only 60% oxygen. Mice received an intraperitoneal injection of 50mg/kg CoQ10 or the same volume of corn oil 30min before the inhalation of oxygen or sevoflurane for 3days. Mice received sevoflurane anesthesia or control treatment from the 6th to 8th day after birth. The cortex and hippocampus were harvested on the 8th day. The ATP, MMP, ApoE mRNA, total ApoE, ApoE fragments, Aβ1-40, Aβ1-42, Tau5, AT8, and PHF levels were detected. The Morris water maze (MWM) tests were performed from P30 to p36 after anesthesia or control treatment. The results indicated that the injection of CoQ10 ahead of sevoflurane treatment could reverse the anesthesia-induced energy deficiency, mitochondrial dysfunction, ApoE, and its fragments expression, Aβ1-42 generation, Tau phosphorylation, and cognitive impairment in young mice. These data reveal that the ApoE and its fragments enhancement may play an important role in the pathogenesis of cognitive deficiency caused by sevoflurane anesthesia. CoQ10 could reduce ApoE expression by improving energy replenishment and mitochondrial functions, thereby alleviating sevoflurane-induced brain damage and cognitive impairment.

GONADAL HORMONES MODULATE HIPPOCAMPAL NUCLEAR DEK EXPRESSION IN ADULT MICE AND RATS

Alzheimer’s Disease (AD) is currently the 6th leading cause of death in the United States, and is the most common cause of dementia. Women are more likely than men to be diagnosed with AD. The cause of this discrepancy is not known; however, the loss of circulating estrogen after menopause is hypothesized to be a leading factor for women’s increased risk of AD. Estrogen is considered neuroprotective; it can ameliorate the effects of brain injury, contribute to DNA repair in mitochondria, and maintain synapse number and spine density in the hippocampus. Our laboratory is investigating the role of an estrogen receptor alpha (ERα) target gene, DEK, as a novel player in Alzheimer’s disease and age‐related dementias. DEK is a nuclear chromatin phosphoprotein that is expressed throughout the brain, and is prominently expressed in the hippocampus, a brain region important for learning and memory. Preliminary data indicate that DEK loss in vitro and in vivo results in AD and dementia‐like phenotypes, such as cell death, increased total tau and phosphorylated tau expression, DNA damage, and decreased hippocampal microtubule associated protein (MAP2) expression. These findings suggest a neuroprotective role of DEK. Given that DEK is an ERα target gene, we postulated that DEK expression in the brain would be modulated by circulating levels of estrogen. We specifically hypothesized that loss of estrogens would decrease DEK expression in the hippocampus. To study this, we used a surgical rodent model of menopause, ovariectomy (OVX), to remove the main source of circulating estrogen in female rats. OVX was performed in 3‐month‐old Sprague Dawley rats. Cell counts and optical density analysis were done using NIH Image J. We found that following two months ovariectomy, DEK expression was decreased in the hippocampus of adult female rats. Besides estrogen, the gonadal hormones testosterone and progesterone can exhibit neuroprotective effects as well. Therefore, we included males in our next experiment in order to determine if gonadal hormone depletion in males would also affect DEK expression. Similar to rats, gonadectomy decreased hippocampal DEK expression in adult male and female mice. Interestingly, OVX significantly decreased DEK expression relative to castration in the CA1 and CA3 regions of the hippocampus. These findings suggest that the impact of gonadal hormone loss on DEK expression is evident across species. We do not yet know the effect of specific gonadal hormonal administration (e.g., E2 or testosterone) on central DEK expression in castrated males and OVX females; therefore, future studies will explore this. Our results suggest that biological factors such as circulating hormones can affect the expression of DEK, whose deficiency may be linked with neurodegeneration and brain aging in dementia and AD.Support or Funding InformationL.I.F.E. Foundation

Combined vildagliptin and memantine treatment downregulates expression of amyloid precursor protein, and total and phosphorylated tau in a rat model of combined Alzheimer's disease and type 2 diabetes.

There is increasing evidence of a link between type 2 diabetes mellitus (T2DM) and cognitive decline. T2DM has been recognized as a risk factor for Alzheimer's disease (AD). The aim of this research was to investigate the biochemical and physiological effects of vildagliptin treatment alone, and in combination with memantine, in a rat model of combined T2DM and AD. The experimental study was carried out on 75 male Wistar rats weighing 180-200g. The rats were divided into five groups (n = 15): normal group, Alzheimer diabetic control, treated with vildagliptin (10mg/kg/day), treated with memantine (30mg/kg/day), and treated with combination of drugs. Serum glucose, lipid profile, acetylcholinesterase (AChE), homocysteine (Hcy), and amyloid beta peptide (Aβ) were determined. Lipid peroxidation was measured in brain tissue. Expression of amyloid precursor protein (APP) in the brain was assessed by q-PCR, and expression of total and phosphorylated tau was determined by Western Blotting. Vildagliptin alone and in combination with memantine caused a decrease in blood glucose, HOMA-IR, lipid profile, Hcy, malanodialdhyde, and acetylcholinesterase, and an increase in apolipoprotein E. Expression of APP and phosphorylated tau protein was decreased with combined vildagliptin and memantine treatment. In conclusion, vildagliptin treatment, either alone or in combination with memantine, modulates AD-associated biochemical changes and downregulates amyloid precursor protein and phosphorylated tau expression in diabetic rats.

Protective roles of isoastilbin against Alzheimer's disease via Nrf2‑mediated antioxidation and anti‑apoptosis.

By analyzing the L-glutamic acid (L-Glu)-induced apoptosis of PC12 cells and an AlCl3 combined with D-galactose (D-gal)-developed Alzheimer's disease (AD) mouse model, the protective effects of isoastilbin (IAB) against AD were systematically investigated in the present study. Pre-incubation with IAB for 3 h prior to treatment with 25 mM L-Glu decreased cell viability and inhibited apoptosis, suppressed the accumulation of intracellular reactive oxygen species, and restored mitochondrial membrane potential in PC12 cells induced by L-Glu. In mice with AD, the reduced escape latency time in the water maze test, suppressed chronic movement in the center area of an open field test and enhanced ability to seek hidden food in a Y maze test indicated that abnormal behaviors had improved after 28 days of treatment with IAB. Furthermore, IAB reduced the deposition of amyloid β (Aβ) and the expression of phosphorylated-Tau in the mouse brain and enhanced the serum levels of Aβ. IAB ameliorated the oxidative stress via modulating the levels of associated enzymes and improved the functioning of the central cholinergic system, as indicated by an increase in acetylcholine and choline acetyltransferase concentrations. The expression levels of acetylcholine esterase were reduced in the mouse brain in response to IAB pre-treatment. In cells and brain tissue, IAB regulated the expression levels of pro- and anti-apoptotic proteins and enhanced the nuclear levels of NF-E2p45-related factor 2 (Nrf2); subsequently, IAB further enhanced the expression of superoxide dismutase 1, catalase, and heme oxygenase-1 and -2. The findings of the present study indicated that the protection of IAB against AD is at least partially associated with its antioxidation and anti-apoptotic properties.

Regenerating islet-derived 1α (REG-1α) protein increases tau phosphorylation in cell and animal models of tauopathies

REG-1α, a secreted protein containing a C-type lectin domain, is expressed in various organs and plays different roles in digestive system cells in physiological and pathological conditions. Like other members of the Reg family, REG-1α is expressed also in the brain where it has different functions. For instance, we previously reported that REG-1α regulates neurite outgrowth and is overexpressed during the very early stages of Alzheimer's disease (AD). However, REG-1α function in neural cells during neural degeneration remains unknown. First, REG-1α and phosphorylated tau expression were assessed in tissue sections from the hippocampus, representing neurofibrillary tangles (NFTs), from patients with AD, and from basal ganglia, representing subcortical NFTs, from patients with progressive supranuclear palsy (PSP). We found an association between REG-1α expression, tau hyperphosphorylation and NFTs in human brain samples from patients with these neurodegenerative diseases. Then, the effects of REG-1α overexpression on tau phosphorylation and axonal morphology were investigated i) in primary cultures of rat neurons that express human tau P301L and ii) in a transgenic zebrafish model of tauopathy that expresses human tau P301L. In the tau P301L cell model, REG-1α overexpression increased tau phosphorylation at the S202/T205 and S396 residues (early and late stages of abnormal phosphorylation, respectively) through the AKT/GSK3-β pathway. This effect was associated with axonal defects both in tau P301L-expressing rat neurons and zebrafish embryos. Our findings suggest a functional role for REG-1α during tauopathy development and progression and, specifically, its involvement in the modification of tau phosphorylation temporal sequence.

Intracerebroventricular injection of Aβ1-42 combined with two-vessel occlusion accelerate Alzheimer’s disease development in rats

Numerous experimental studies and clinical observations suggest that cerebral ischemia may contribute to the pathogenesis of Alzheimer’s disease (AD). Two-vessel occlusion caused cerebral ischemia model is often used in the study of vascular dementia (VaD). But how cerebral ischemia works on AD rat model which induced by intracerebroventricular injection of Aβ1-42 remains unclear. In the following study, we investigated the characteristics of rat model caused by intracerebroventricular injection of Aβ1-42 or two-vessel occlusion (2-VO) only and by both of the two operations. The animal cognitive functions were accessed by the Morris water maze. Regional cerebral blood flow was detected by Laser Doppler Blood Flowmeter. HE&Nissl staining, Congo red staining and immunohistochemistry were used to observe the status of neuronal loss, Aβ deposition and the phosphorylated tau expression in hippocampus, respectively. We also measured the contents of AchE and ChAT in serum and hippocampus by Enzyme Linked Immunosorbent Assay. The MWM results showed that rats of Aβ1–42+2-VO group had a disorder in cognitive functions, at an early stage of one week after modeling, comparing with rats of sham group. The regional cerebral blood flow (rCBF) was significantly reduced in Aβ1-42+2-VO and 2-VO group one week after modeling, and still maintained low perfusion levels four weeks after modeling. HE and Nissl staining showed that Aβ1-42+2-VO rats’ hippocampal CA1 neurons were in disorder, degeneration and necrosis, severe neuronal loss from the first week to the fourth week, while this phenomenon only appeared in the fourth week after modeling in rats of Aβ1-42 group and 2-VO group. Congo red staining showed that Aβ1-42 + 2-VO group rats’ hippocampus CA1 had amyloid deposits from the first week to the fourth week, Aβ1-42 group were not find amyloid deposition significantly until four weeks after modeling, however, 2-VO group had no significant amyloid deposition all the time. Notably, IHC showed that, two weeks after modeling, the p-tau positive total area and integrated optical density of hippocampal CA1 region were significantly increased in Aβ1-42 + 2-VO group rats, while 2-VO group and Aβ1-42 group rats had no significantly changes all the time. We also found that the content of AchE was increased both in serum and hippocampus of Aβ1-42 + 2-VO group rats, and ChAT was decreased. However, there was no significantly change in cortex of content of AchE: acetylcholinesterase (AchE) and choline acetylase (ChAT) all three groups. Together, our study suggest that intracerebroventricular injection of Aβ1-42 combined with two-vessel occlusion may accelerate Alzheimer’s disease development in rats. Also, this may serve as a less-time consuming new model to study the Alzheimer’s disease and especially AD accompanied by cerebral ischemia.

Hippocampal Aβ expression, but not phosphorylated tau, predicts cognitive deficits following repeated peripheral poly I:C administration

Alzheimer’s disease is marked by the accumulation of the amyloid-beta (Aβ) peptide, and increases in phosphorylation of the microtubule associated protein, tau. Changes in these proteins are considered responsible, in part, for the progressive neuronal degeneration and cognitive deficits seen in AD. We examined the effect of repeated consecutive peripheral poly I:C injections on cognitive deficits, central Aβ, and phosphorylated tau accumulation, following three treatment durations: 7, 14, and 21 days. Forty-eight hours after the final injection, animals were trained in a contextual fear-conditioning paradigm, and tested 24h later. Immediately after testing, the hippocampus was collected to quantify Aβ and phosphorylated tau accumulation. Results showed that, although poly I:C-induced Aβ was significantly elevated at all time points examined, poly I:C only disrupted cognition after 14 and 21 days of administration. Moreover, elevations in phosphorylated tau were not seen until the 14-day time point. Interestingly, phosphorylated tau expression then declined at the 21-day time point. Finally, we demonstrated that Aβ levels are a stronger predictor of cognitive dysfunction, explaining 37% of the variance, whereas phosphorylated tau levels only accounted for 0.2%. Taken together, these results support the hypothesis that inflammation-induced elevation in Aβ disrupts cognition, independently of phosphorylated tau, and suggest that long-term administration of poly I:C may provide a model to investigate the contribution of long-term inflammation toward the development of Alzheimer’s-like pathology.

Effect of sleep deprivation on cognitive function in rats undergoing propofol anesthesia

Objective To evaluate the effect of sleep deprivation on cognitive function in the rats undergoing propofol anesthesia. Methods Sixty healthy male Sprague Dawley rats, aged 14-18 weeks, weighing 200-250 g, were randomly assigned into 3 groups(n=20 each)using a random number table: control group(group C), propofol anesthesia group(group P), and sleep deprivation+ propofol anesthesia group(group SDP). Propofol was given as a bolus of 15 mg/kg followed by an infusion of 40 mg·kg-1·h-1 for 2 h in group P. After the rats were subjected to rapid eye movement sleep deprivation for 24 h, the rats received propofol anesthesia in group SDP.Before sleep deprivation, after sleep deprivation, and at 1, 3 and 7 days after anesthesia, Morris water maze test was used to assess the learning and memory function, and the escape latency and frequency of crossing the original platform were recorded.Ten rats randomly selected from each group at 1 and 7 days after anesthesia were sacrificed, and brains were removed to observe the morphology of nerve cells in the hippocampal CA1 region(by Nissl's staining)and to detect the expression of phosphorylated Tau at Thr231(Tau-pThr231)in the hippocampal CA1 region(by immunohistochemisty). Results Compared with group C, the escape latency was significantly prolonged, the frequency of crossing the original platform was decreased, the expression of Tau-pThr231in the hippocampal CA1 region was up-regulated at 1 day after anesthesia in P and SDP groups(P 0.05). The pathological changes were aggravated at 1 day after anesthesia in group SDP compared with group P, and there was no significant difference at 3 and 7 days after anesthesia between group SDP and group P. Conclusion Sleep deprivation can aggravate the transient cognitive dysfunction after propofol anesthesia, and the mechanism is related to promotion of Tau phosphorylation in the rats. Key words: Sleep deprivation; Propofol; Cognition disorders

The Protective Effect of Icariin on Mitochondrial Transport and Distribution in Primary Hippocampal Neurons from 3× Tg-AD Mice.

Icariin, a pharmacologically active component isolated from the Chinese herb Epimedium, has been shown to improve spatial learning and memory abilities in Alzheimer’s disease (AD) rats through inhibition of Aβ production and tau protein hyperphosphorylation. However, the potential mechanism of icariin-induced protective effects against mitochondrial dysfunctions in AD still remains unclear. In the present study, we investigated the effect of icariin on the modulation of mitochondrial transport and distribution in primary hippocampal cultures from triple-transgenic (3× Tg) AD mice. The results showed that icariin enhanced mitochondrial motility and increased mitochondrial index and mitochondrial length and size in the diseased neurons. Additionally, the expression of the key mitochondrial enzyme, pyruvate dehydrogenase-E1α (PDHE1α), and the post synaptic density protein 95 (PSD95), was preserved in AD neurons after icariin treatment, accompanied by a downregulation of Aβ and phosphorylated tau expression in the corresponding areas. Further study showed that icariin treatment resulted in a decrease in mitochondrial fission protein dynamin-related protein 1 (Drp1) and an increase in fusion protein Mitofusin 2 (Mfn2). These data indicate that icariin can promote mitochondrial transport, protect mitochondria against fragmentation and preserve the expression of mitochondrial and synaptic functional proteins in AD neurons. Thus, icariin may be a potential therapeutic complement for AD and other mitochondrial malfunction-related neuronal degenerative diseases.

Hyperphosphorylation of tau protein by calpain regulation in retina of Alzheimer's disease transgenic mouse

Aim to investigate phosphorylated tau expression and its pathogenic mechanism in eye of Alzheimer's disease (AD) transgenic mice. Levels of tau, phosphorylated tau and other related factors (p35/p25, Cyclin-dependent kinase 5 (Cdk5), calpain) were observed by western blot. β-Amyloid (Aβ) plaques and neuron-fibrillary tangles (NFTs) in APP/PS1 double transgenic mice were detected by immuno-histochemistry. We found that hyper-expression of phosphorylated tau was detected in retina, and only a few or no expressed in optic nerve, cornea and lens of transgenic mice. Increased senile plaques (Aβ) and NFTs were observed in transgenic mice accompanying with increased tau phosphorylation. The increased tau phosphorylation was associated with a significant increase in production of p35 and p25, and up-regulation of calpain. In conclusion, phosphorylated tau level was highly expressed in retina of AD transgenic mice. The pathogenic mechanism of AD was triggered by accelerating tau pathology via calpain-mediated tau hyper-phosphorylation in retina of an AD mice model.

Age-Related Intraneuronal Elevation of αII-Spectrin Breakdown Product SBDP120 in Rodent Forebrain Accelerates in 3×Tg-AD Mice

Spectrins line the intracellular surface of plasmalemma and play a critical role in supporting cytoskeletal stability and flexibility. Spectrins can be proteolytically degraded by calpains and caspases, yielding breakdown products (SBDPs) of various molecular sizes, with SBDP120 being largely derived from caspase-3 cleavage. SBDPs are putative biomarkers for traumatic brain injury. The levels of SBDPs also elevate in the brain during aging and perhaps in Alzheimer’s disease (AD), although the cellular basis for this change is currently unclear. Here we examined age-related SBDP120 alteration in forebrain neurons in rats and in the triple transgenic model of AD (3×Tg-AD) relative to non-transgenic controls. SBDP120 immunoreactivity (IR) was found in cortical neuronal somata in aged rats, and was prominent in the proximal dendrites of the olfactory bulb mitral cells. Western blot and densitometric analyses in wild-type mice revealed an age-related elevation of intraneuronal SBDP120 in the forebrain which was more robust in their 3×Tg-AD counterparts. The intraneuronal SBDP120 occurrence was not spatiotemporally correlated with transgenic amyloid precursor protein (APP) expression, β-amyloid plaque development, or phosphorylated tau expression over various forebrain regions or lamina. No microscopically detectable in situ activated caspase-3 was found in the nuclei of SBDP120-containing neurons. The present study demonstrates the age-dependent intraneuronal presence of an αII-spectrin cleavage fragment in mammalian forebrain which is exacerbated in a transgenic model of AD. This novel neuronal alteration indicates that impairments in membrane protein metabolism, possibly due to neuronal calcium mishandling and/or enhancement of calcium sensitive proteolysis, occur during aging and in transgenic AD mice.

Cerebral ischemia aggravates cognitive impairment in a rat model of Alzheimer's disease

AimAutopsy evidence suggests that the presence of both Alzheimer's disease (AD) and cerebral infarction pathology is associated with more severe cognitive impairment than that produced by AD pathology alone. This study aims to investigate the effect of cerebral ischemia on cognitive function in rats with AD constructed by hippocampal injection and to determine its underlying mechanism, which is proposed to be of significance to the treatment of AD. Main methodsAD was modeled by injection of aggregated Aβ(1–40), either alone or followed by hippocampal endothelin-1 injection to mimic cerebral ischemia in hippocampus, into the right dentate gyrus (DG) of rats. The Morris water maze was used to evaluate cognitive function. Aβ deposition, neuronal loss and phosphorylated tau expression in hippocampus were examined by Congo red staining, Nissl's staining and immunohistochemistry, respectively. Reactive astrocytes, IL-1β and TNF-α expressions were measured by immunohistochemistry, in situ hybridization and reverse transcription–polymerase chain reaction. Key findingsCompared with rats treated with either Aβ or endothelin alone, rats treated with both Aβ and endothelin showed more aggravated cognitive impairment and more Aβ deposits, neuron loss, phosphorylated tau expression, reactive astrocytes, IL-1β and TNF-α expressions in hippocampus. SignificanceHippocampal ischemia aggravates cognitive impairment of AD rats by increasing Aβ deposits, neuron loss and tau phosphorylation in hippocampus. The enhanced inflammatory response may be responsible for cerebral ischemia-induced aggravation of cognitive impairment in AD rats. Based on these findings, prevention and treatment of cerebral ischemia may improve clinical symptoms of AD and suppress the progression of AD.

Analysis of neuronal cell death in the cerebral cortex of H-Tx rats with compensated hydrocephalus

Some cases of compensatory hydrocephalus have been reported in which cognitive deficiency progresses despite the absence of progressive ventricular dilation. In this study, the differentially expressed genes in compensated hydrocephalic H-Tx rat cortices were determined. A molecular mechanism that induces neuronal death in the cerebral cortex of compensated hydrocephalus is proposed. The cerebral cortices of 8-week-old H-Tx rats with spontaneously arrested hydrocephalus (hH-Tx) and nonhydrocephalic H-Tx (nH-Tx) control rats were subjected to cDNA microarray analysis followed by canonical pathway analysis. In the hH-Tx rats, many genes in the amyloidal processing pathway showed altered expression, including Akt3 and p38 MAPK. These latter genes are involved in tau protein phosphorylation, and their increased expression in hydrocephalus was confirmed by real-time polymerase chain reaction analysis. Immunohistological and immunoblot analysis revealed elevated phosphorylated tau expression in the cerebral cortex neurons of the hH-Tx rats. The accumulation of phosphorylated tau protein in the cerebral cortex may be one of the mechanisms by which later cognitive dysfunction develops in patients with compensated hydrocephalus. More work needs to be done to determine if the accumulation of phosphorylated tau in the cortex can help predict which patients may decompensate thus requiring more aggressive treatment for compensated hydrocephalus.