Cerebrolysin decreases amyloid-beta production by regulating amyloid protein precursor maturation in a transgenic model of Alzheimer's disease

Cerebrolysin is a peptide mixture with neurotrophic effects that might reduce the neurodegenerative pathology in Alzheimer's disease (AD). We have previously shown in an amyloid protein precursor (APP) transgenic (tg) mouse model of AD-like neuropathology that Cerebrolysin ameliorates behavioral deficits, is neuroprotective, and decreases amyloid burden; however, the mechanisms involved are not completely clear. Cerebrolysin might reduce amyloid deposition by regulating amyloid-beta (Abeta) degradation or by modulating APP expression, maturation, or processing. To investigate these possibilities, APP tg mice were treated for 6 months with Cerebrolysin and analyzed in the water maze, followed by RNA, immunoblot, and confocal microscopy analysis of full-length (FL) APP and its fragments, beta-secretase (BACE1), and Abeta-degrading enzymes [neprilysin (Nep) and insulin-degrading enzyme (IDE)]. Consistent with previous studies, Cerebrolysin ameliorated the performance deficits in the spatial learning portion of the water maze and reduced the synaptic pathology and amyloid burden in the brains of APP tg mice. These effects were associated with reduced levels of FL APP and APP C-terminal fragments, but levels of BACE1, Notch1, Nep, and IDE were unchanged. In contrast, levels of active cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3beta [GSK-3beta; but not stress-activated protein kinase-1 (SAPK1)], kinases that phosphorylate APP, were reduced. Furthermore, Cerebrolysin reduced the levels of phosphorylated APP and the accumulation of APP in the neuritic processes. Taken together, these results suggest that Cerebrolysin might reduce AD-like pathology in the APP tg mice by regulating APP maturation and transport to sites where Abeta protein is generated. This study clarifies the mechanisms through which Cerebrolysin might reduce Abeta production and deposition in AD and further supports the importance of this compound in the potential treatment of early AD.     

Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer's disease

Impaired amyloid-β clearance from the brain is a core pathological event in Alzheimer's disease.The therapeutic effect of current pharmacotherapies is unsatisfactory,and some treatments cause severe side effects.The meningeal lymphatic vessels might be a new route for amyloid-β clearance.This study investigated whether promoting dural lymphangiogenesis facilitated the clearance of amyloid-β from the brain.First,human lymphatic endothelial cells were treated with 100 ng/m L recombinant human vascular endothelial growth factor-C(rh VEGF-C) protein.Light microscopy verified that rh VEGF-C,a specific ligand for vascular endothelial growth factor receptor-3(VEGFR-3),significantly promoted tube formation of human lymphatic endothelial cells in vitro.In an in vivo study,200 μg/m L rh VEGF-C was injected into the cisterna magna of APP/PS1 transgenic mice,once every 2 days,four times in total.Immunofluorescence staining demonstrated high levels of dural lymphangiogenesis in Alzheimer's disease mice.One week after rh VEGF-C administration,enzyme-linked immunosorbent assay results showed that levels of soluble amyloid-β were decreased in cerebrospinal fluid and brain.The Morris water maze test demonstrated that spatial cognition was restored.These results indicate that the upregulation of dural lymphangiogenesis facilities amyloid-β clearance from the brain of APP/PS1 mice,suggesting the potential of the VEGF-C/VEGFR-3 signaling pathway as a therapeutic target for Alzheimer's disease.     

Cerebrolysin modulates pronerve growth factor/nerve growth factor ratio and ameliorates the cholinergic deficit in a transgenic model of Alzheimer's disease

Alzheimer's disease (AD) is characterized by degeneration of neocortex, limbic system, and basal forebrain, accompanied by accumulation of amyloid‐β and tangle formation. Cerebrolysin (CBL), a peptide mixture with neurotrophic‐like effects, is reported to improve cognition and activities of daily living in patients with AD. Likewise, CBL reduces synaptic and behavioral deficits in transgenic (tg) mice overexpressing the human amyloid precursor protein (hAPP). The neuroprotective effects of CBL may involve multiple mechanisms, including signaling regulation, control of APP metabolism, and expression of neurotrophic factors. We investigate the effects of CBL in the hAPP tg model of AD on levels of neurotrophic factors, including pro‐nerve growth factor (NGF), NGF, brain‐derived neurotrophic factor (BDNF), neurotropin (NT)‐3, NT4, and ciliary neurotrophic factor (CNTF). Immunoblot analysis demonstrated that levels of pro‐NGF were increased in saline‐treated hAPP tg mice. In contrast, CBL‐treated hAPP tg mice showed levels of pro‐NGF comparable to control and increased levels of mature NGF. Consistently with these results, immunohistochemical analysis demonstrated increased NGF immunoreactivity in the hippocampus of CBL‐treated hAPP tg mice. Protein levels of other neurotrophic factors, including BDNF, NT3, NT4, and CNTF, were unchanged. mRNA levels of NGF and other neurotrophins were also unchanged. Analysis of neurotrophin receptors showed preservation of the levels of TrKA and p75^NTR immunoreactivity per cell in the nucleus basalis. Cholinergic cells in the nucleus basalis were reduced in the saline‐treated hAPP tg mice, and treatment with CBL reduced these cholinergic deficits. These results suggest that the neurotrophic effects of CBL might involve modulation of the pro‐NGF/NGF balance and a concomitant protection of cholinergic neurons. © 2012 Wiley Periodicals, Inc.     

Effects of oral aluminum exposure on behavior and neurogenesis in a transgenic mouse model of Alzheimer's disease

The effects of a very low oral dose of Al on spatial learning and neurogenesis were evaluated in a transgenic mouse (Tg 2576) model of Alzheimer disease. At 5 months of age, wild and Tg 2576 mice received a diet supplemented with Al lactate at 0 and 1 mg/g of diet for 120 days. The experimental groups (n =  7–8) were: control wild, Al-treated wild, control transgenic, and Al-treated transgenic. After 3 months of Al exposure, activity in an open-field and learning in a water maze were evaluated. At the end of the behavioral testing, in order to study cell proliferation and differentiation in the hippocampus, mice were injected with 5-bromo-2-deoxyuridine (BrdU) and sacrificed 1 or 28 days after the last BrdU injection. Tg 2576 mice were impaired in both acquisition and retention of the water maze task, showing higher amounts of β-amyloid fragments in brain. Aluminum exposure impaired learning and memory in wild mice and increased the total number of proliferating cells in the dentate gyrus of hippocampus. The low Al doses here experimented suggest that this element might impair cognition in the general population at doses comparable to current levels of human exposure. Although these doses are not enough to interact with the amyloidogenic pathway, an increase in cell proliferation can indicate a reactive response of the brain to Al insult. Further investigations should be performed to corroborate the effects observed at very low doses of Al and to study the potential effects derived from a longer exposure period.     

Neuronal and astrocytic metabolism in a transgenic rat model of Alzheimer's disease

Regional hypometabolism of glucose in the brain is a hallmark of Alzheimer''s disease (AD). However, little is known about the specific alterations of neuronal and astrocytic metabolism involved in homeostasis of glutamate and GABA in AD. Here, we investigated the effects of amyloid β (Aβ) pathology on neuronal and astrocytic metabolism and glial-neuronal interactions in amino acid neurotransmitter homeostasis in the transgenic McGill-R-Thy1-APP rat model of AD compared with healthy controls at age 15 months. Rats were injected with [1-¹³C]glucose and [1,2-¹³C]acetate, and extracts of the hippocampal formation as well as several cortical regions were analyzed using ¹H- and ¹³C nuclear magnetic resonance spectroscopy and high-performance liquid chromatography. Reduced tricarboxylic acid cycle turnover was evident for glutamatergic and GABAergic neurons in hippocampal formation and frontal cortex, and for astrocytes in frontal cortex. Pyruvate carboxylation, which is necessary for de novo synthesis of amino acids, was decreased and affected the level of glutamine in hippocampal formation and those of glutamate, glutamine, GABA, and aspartate in the retrosplenial/cingulate cortex. Metabolic alterations were also detected in the entorhinal cortex. Overall, perturbations in energy- and neurotransmitter homeostasis, mitochondrial astrocytic and neuronal metabolism, and aspects of the glutamate–glutamine cycle were found in McGill-R-Thy1-APP rats.     

Nasal administration of amyloid-beta peptide decreases cerebral amyloid burden in a mouse model of Alzheimer's disease

Progressive cerebral deposition of amyloid-beta (Abeta) peptide, an early and essential feature of Alzheimer's disease (AD), is accompanied by an inflammatory reaction marked by microgliosis, astrocytosis, and the release of proinflammatory cytokines. Mucosal administration of disease-implicated proteins can induce antigen-specific anti-inflammatory immune responses in mucosal lymphoid tissue which then act systemically. We hypothesized that chronic mucosal administration of Abeta peptide might induce an anti-inflammatory process in AD brain tissue that could beneficially affect the neuropathological findings. To test this hypothesis, we treated PDAPP mice, a transgenic line displaying numerous neuropathological features of AD, between the ages of approximately 5 and approximately 12 months with human Abeta synthetic peptide mucosally each week. We found significant decreases in the cerebral Abeta plaque burden and Abeta42 levels in mice treated intranasally with Abeta peptide versus controls treated with myelin basic protein or left untreated. This lower Abeta burden was associated with decreased local microglial and astrocytic activation, decreased neuritic dystrophy, serum anti-Abeta antibodies of the IgG1 and IgG2b classes, and mononuclear cells in the brain expressing the anti-inflammatory cytokines interleukin-4, interleukin-10, and tumor growth factor-beta. Our results demonstrate that chronic nasal administration of Abeta peptide can induce an immune response to Abeta that decreases cerebral Abeta deposition, suggesting a novel mucosal immunological approach for the treatment and prevention of AD.     

Autoantibodies to amyloid-beta and Alzheimer's disease.

Immunization against amyloid-beta has been suggested as a possible preventive or therapeutic treatment for Alzheimer's disease. We hypothesized that some individuals may have autoantibodies to amyloid-beta and that this may be protective. We analyzed the plasma of 365 individuals, drawn from a larger longitudinal epidemiological study, for the presence of antibodies to amyloid-beta. There were detectable but very low levels of anti-amyloid-beta antibodies in just over 50% of all samples and modest levels in under 5% of all samples. However, neither the presence nor the level of anti-amyloid-beta antibodies correlated with the likelihood of developing dementia or with plasma levels of amyloid-beta peptide. These data suggest that low levels of anti-amyloid-beta autoantibodies are frequent in the elderly population but do not confer protection against developing dementia.     

Stereological analysis of microvascular parameters in a double transgenic model of Alzheimer's disease

Morphological alterations in microvasculature occur as a common finding in the brains of non-demented aged persons and patients with Alzheimer's disease. Quantifying the extent of this vascular pathology, however, has been complicated by systematic error (bias) associated with the applications of assumption- and model-based morphometric techniques to human and animal tissues. The current study used novel assumption- and model-free stereological approaches to quantify capillary parameters in the corpus callosum of a double amyloid precursor protein/presenilin-1 transgenic murine model of Alzheimer's disease. The results revealed significant reductions in the total number of capillary segments in white matter of transgenic mice compared to non-transgenic littermates, with no differences in total capillary length. These findings support the view that the expression of mutant human genes for beta-amyloid peptides alters the normal architecture of cerebral capillary vessels in the white matter of mouse brain, which may model microvasculature changes reported in Alzheimer's disease.     

铁和老年斑在阿尔茨海默病转基因小鼠脑内的沉积及其对磁共振T2弛豫时间的影响

目的 观察老年斑和铁在阿尔茨海默病(AD)转基因小鼠脑内皮质和海马处的沉积及其对磁共振活体扫描T2弛豫时间的影响.方法 2、4、6、8、10、12、14、16月龄的AD转基因小鼠各2只,分为幼龄组、成龄组和老龄组,8月龄野生型C57BL/6J小鼠2只作为对照,依次进行磁共振活体扫描,测量皮质、海马、丘脑、胼胝体、纹状体等结构的T2弛豫时间,扫描完成后,进行铁和老年斑的组织学染色,计算皮质和海马处老年斑的数目及含量、铁颗粒的数目及含量.结果 各组皮质及海马T2弛豫时间(ms)分别为:野生组:49.5±2.1、51.6±1.1;幼龄组(2、4月龄):49.7±0.5、50.7±0.7;成龄组(6、8、10月龄):47.2±0.8、47.7±0.9;老龄组(12、14、16月龄):44.6±0.8、45.3±0.4.各组皮质及海马T2弛豫时间差异有统计学意义(皮质F=18.620,海马F=67.925,均P＜0.01).组间比较示成龄组较幼龄组(皮质q=4.284,海马q=7.902;均P＜0.01)及野生组(皮质q=4.424,P＜0.05,海马q=11.450,P＜0.01)小鼠皮质及海马T2弛豫时间缩短;而老龄组较成龄组小鼠皮质及海马T2弛豫时间缩短(皮质q=4.812,海马q=7.034,均P＜0.01).组织学染色示4月龄转基因小鼠皮质和海马开始出现老年斑的沉积,6月龄开始出现铁的沉积,并且随着小鼠月龄的增加,皮质和海马处老年斑和铁的数目及含量均明显增加.老年斑和铁的沉积具有明显的正相关(r=0.931,P＜0.01),老年斑的含量、铁的含量与T2弛豫时间均具有明显的负相关(分别r=-0.884、-0.827,均P＜0.01).结论 老年斑和铁的沉积可能共同影响T2弛豫时间,提示T2弛豫时间可以作为早期诊断AD和抗痴呆药物筛选的一个敏感性指标.     

The effect of metals on spatial memory in a transgenic mouse model of Alzheimer's disease

The amyloid-β protein (Aβ) is a metalloprotein with affinity for the metal ions zinc (Zn), copper (Cu), and iron (Fe), which are found in high concentrations in the plaques of Alzheimer's disease (AD). Increasing attention is focused on the role of these metals in AD, and much of the evidence suggests a dyshomeostasis between these metal ions may significantly affect Aβ aggregation and deposition in the brain. While the effect of these metals on Aβ has been shown in vitro, there is less behavioral data supporting a direct role in cognitive impairment. In order to investigate the cognitive consequences of metal dyshomeostasis, we sought to directly increase metal levels in the brain by dietary means in a transgenic mouse model (Tg2576). We have now examined the effect of increased Zn (10 ppm) and Fe (10 ppm) levels in the drinking water in the Tg2576 mouse. Since increased dietary Zn can lead to Cu deficiency, a Zn group supplemented with copper was also examined (Zn (10 ppm)+Cu (0.025 ppm)). Significant increases in latency and fewer platform crossings on probe trials, which are considered measures of spatial memory impairment, were seen in both Fe and Zn supplemented transgenic mice, compared to those raised on lab water. No significant differences were seen between the Zn + Cu group and in transgenic mice raised on lab water. These data suggest that the negative consequences of Zn may be due to a reduction in copper levels and, therefore, an imbalance between these metal ions rather than a direct effect of increased Zn.     

A cholesterol-lowering drug reduces beta-amyloid pathology in a transgenic mouse model of Alzheimer's disease

Clinical, epidemiological, and laboratory studies suggest that cholesterol may play a role in the pathogenesis of Alzheimer's disease (AD). Transgenic mice exhibiting an Alzheimer's beta-amyloid phenotype were treated with the cholesterol-lowering drug BM15.766 and tested for modulation of beta-amyloid levels. BM15.766 treatment reduced plasma cholesterol, brain Abeta peptides, and beta-amyloid load by greater than twofold. A strong, positive correlation between the amount of plasma cholesterol and Abeta was observed. Furthermore, drug treatment reduced the amyloidogenic processing of the amyloid precursor protein, suggesting alterations in processing in response to cholesterol modulation. This study demonstrates that hypocholesterolemia is associated with reduced Abeta accumulation suggesting that lowering cholesterol by pharmacological means may be an effective approach for reducing the risk of developing AD.     

Transplanted astrocytes internalize deposited beta-amyloid peptides in a transgenic mouse model of Alzheimer's disease

Alzheimer's disease (AD) is one of the most devastating neurodegenerative disorders. The neuropathological hallmarks include extracellular senile plaques consisting of deposited beta-amyloid (Abeta) peptides and intraneuronal neurofibrillary tangles. Neuroinflammation and activation of astrocytes are also well-established features of AD neuropathology; however, the relationships between astrocytes and Abeta deposition remain unclear. Previous studies have shown that adult mouse astrocytes internalize and degrade Abeta deposits in brain sections prepared from human amyloid precursor protein (APP) transgenic mice. In the present study, we demonstrate that cultured adult, but not neonatal mouse astrocytes, respond morphologically and degrade Abeta deposits present in human AD brain. We also transplanted astrocytes isolated from enhanced green fluorescent protein expressing adult and neonatal mice into the hippocampi of human Abeta plaque-bearing transgenic APPSwe+PS1dE9 (APdE9) mice and their wild-type littermates and followed the migration and localization of these astrocytes by confocal microscopy upto 7 days after transplantation. Posttransplantation the astrocytes localized as aggregates or thin strings of many cells within the hippocampi of APdE9 and wild-type mice and showed limited migration from the injection site. Interestingly, most of the transplanted astrocytes were found near Abeta deposits in the hippocampi of APdE9 mice. In contrast to findings in ex vivo degradation assay, confocal microscopy revealed that both adult and neonatal transplanted astrocytes internalized human Abeta immunoreactive material in vivo. These results support the role of astrocytes as active Abeta clearing cells in the CNS that may have important implications for future development of therapeutic strategies for AD.     

Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease

Astrocytes are fundamental for brain homeostasis and are at the fulcrum of neurological diseases including Alzheimer's disease (AD). Here, we monitored changes in astroglia morphology throughout the age‐dependent progression of AD. We used an immunohistochemical approach that allows us to determine the domain of glial cytoskeleton, by measuring the surface, volume, and the relationship between astrocytes and neuritic plaques. We investigated astroglia in the hippocampus of a triple transgenic mouse model of AD (3xTg‐AD) that mimics the progression of the human disease. The numerical density of astrocytes is affected neither by AD nor by age. We found reduction of surface and volume of GFAP profiles from early ages (6 months; 43.84 and 52.76%, respectively), persisting at 12 (40.73 and 45.39%) and 18 months (64.80 and 71.95%) in the dentate gyrus (DG) of 3xTg‐AD, whereas in CA1 it appears at 18 months (29.42 and 32.74%). This cytoskeleton atrophy is accompanied by a significant reduction of glial somata volume in DG at 12 and 18 months (40.46 and 75.55%, respectively), whereas in CA1 it is significant at 18 months (42.81%). However, while astroglial atrophy appears as a generalized process, astrocytes surrounding plaques are clearly hypertrophic as revealed by increased surface (48.06%; 66.66%), and volume (57.10%; 71.06%) of GFAP profiles in DG and CA1, respectively, at 18 months. We suggest differential effects of AD on astroglial populations depending on their association with plaques accounting for the progressive disruption of neural networks connectivity and neurotransmitters imbalance which underlie mnesic and cognitive impairments observed in AD. © 2010 Wiley‐Liss, Inc.     

Beta-amyloid plaques in a model for sporadic Alzheimer's disease based on transgenic anti-nerve growth factor antibodies

Cerebral deposition of beta-amyloid (Abeta) is an invariant event of Alzheimer's disease (AD). We recently described that the brain of aged transgenic mice expressing anti-nerve growth factor (NGF) antibodies (AD11 mice) show a dramatic neurodegenerative phenotype, reminiscent of AD, which includes neuronal loss, cholinergic deficit, and tau hyperphosphorylation, associated with neurofibrillary pathology. We now report that brains of aged transgenic mice contain large amounts of beta-amyloid plaques and describe their morphology by a variety of approaches. In conclusion, the chronic deprivation of NGF leads to the formation and deposition of Abeta in AD11 mice, suggesting a direct link between NGF signaling and abnormal processing of amyloid precursor protein.     

Brainstem Alzheimer's-like pathology in the triple transgenic mouse model of Alzheimer's disease

The triple transgenic mouse (3xTgAD), harboring human APP_Swe, PS1_M146V and Tau_P301L genes, develops age-dependent forebrain intraneuronal Aβ and tau as well as extraneuronal plaques. We evaluated brainstem AD-like pathology using 6E10, AT8, and Alz50 antibodies and unbiased stereology in young and old 3xTgAD mice. Intraneuronal Aβ occurred in the tectum, periaqueductal gray, substantia nigra, red nucleus, tegmentum and mesencephalic V nucleus at all ages. Aβ-positive neuron numbers significantly decreased in the superior colliculus and substantia nigra while AT8-positive superior colliculus, red nucleus, principal sensory V, vestibular nuclei, and tegmental neurons significantly increased between 2 and 12 months. Alz50-positive neuron numbers increased only in the inferior colliculus between these ages. Dual labeling revealed a few Aβ- and tau-positive neurons. Plaques occurred only in the pons of female 3xTgAD mice starting at 9 months. 3xTgAD mice provide a platform to define in vivo mechanisms of Aβ and tau brainstem pathology.     

Cerebrolysin in Alzheimer's disease: a randomized,double-blind,placebo-controlled trial with a neurotrophic agent

Summary. Summary. Cerebrolysin (Cere) is a compound with neurotrophic activity. It has been shown to be effective in the treatment of Alzheimer's disease (AD) in earlier trials. In this multicenter, randomized, double-blind, placebo-controlled, parallel-group study, patients were injected intravenously with placebo or 30 mL Cere five days per week for four weeks. Effects on cognition and global function were evaluated with the Alzheimer Disease Assessment Scale – Cognitive Subscale (ADAS-Cog) and the Clinicians Interview-based Impression of Change with Caregiver Input scale (CIBIC+) 4, 12, 24 weeks after the beginning of the injections. 192 patients were enrolled, 95 were randomized to placebo, and 97 to Cere. At baseline, there was a significant difference between groups for age, age of onset of dementia, and the number of patients with hallucinations. At week 12 there was a significant difference on the CIBIC+ (p = 0.033) in favor of Cere. The number of CIBIC+ responders (score ≤ 4), was significantly higher (p = 0.007), with 68 (76%) in the Cere group and 51 (57%) in the placebo group. Trends were noted in the Disability Assessment in Dementia scale and the Cornell Depression Scale. Adverse events were recorded in 73% of placebo and 64% of Cere patients. Most common adverse events were headaches, dizziness, weight loss and anxiety. Conclusions: Cere treatment was well tolerated and resulted in significant improvements in the global score two months after the end of active treatment. Received September 10, 2001; accepted November 15, 2001     

Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer's disease patients

The defective clearance of amyloid-beta (Abeta) in the brain of Alzheimer's disease (AD) patients is unexplained. The immunohistochemical studies of the frontal lobe and hippocampus show perivascular and intraplaque infiltration by blood-borne macrophages containing intracellular Abeta but only inefficient clearance of beta deposits. Neurons and neuronal nuclei, respectively, express interleukin-1beta and the chemokine RANTES, which could induce the inflammatory cell infiltration. To clarify the pathophysiology ofbeta clearance, we examined Abeta phagocytosis by monocytes and macrophages isolated from the blood of age-matched patients and controls. Control monocytes display excellent differentiation into macrophages and intracellular phagocytosis of Abeta followed by beta degradation or export. AD monocytes show poor differentiation and only surface uptake of Abeta and suffer apoptosis. HLA DR and cyclooxygenase-2 are abnormally expressed on neutrophils and monocytes of AD patients. AD patients have higher levels of intracellular cytokines compared to controls. Thus Abeta clearance is not restricted to brain microglia and involves systemic innate immune responses. In AD, however, macrophage phagocytosis is defective, which may elicit compensatory response by the adaptive immune system.     

Curcuminoids enhance amyloid-beta uptake by macrophages of Alzheimer's disease patients

Treatment of Alzheimer's disease (AD) is difficult due to ignorance of its pathogenesis. AD patients have defects in phagocytosis of amyloid-beta (1-42) (Abeta) in vitro by the innate immune cells, monocyte/macrophages and in clearance of Abeta plaques [5]. The natural product curcuminoids enhanced brain clearance of Abeta in animal models. We, therefore, treated macrophages of six AD patients and 3 controls by curcuminoids in vitro and measured Abeta uptake using fluorescence and confocal microscopy. At baseline, the intensity of Abeta uptake by AD macrophages was significantly lower in comparison to control macrophages and involved surface binding but no intracellular uptake. After treatment of macrophages with curcuminoids, Abeta uptake by macrophages of three of the six AD patients was significantly (P<0.001 to 0.081) increased. Confocal microscopy of AD macrophages responsive to curcuminoids showed surface binding in untreated macrophages but co-localization with phalloidin in an intracellular compartment after treatment. Immunomodulation of the innate immune system by curcuminoids might be a safe approach to immune clearance of amyloidosis in AD brain.     

Synaptic plasticity defect following visual deprivation in Alzheimer's disease model transgenic mice

Amyloid-β (Aβ)-induced changes in synaptic function in experimental models of Alzheimer's disease (AD) suggest that Aβ generation and accumulation may affect fundamental mechanisms of synaptic plasticity. To test this hypothesis, we examined the effect of APP overexpression on a well characterized, in vivo, developmental model of systems-level plasticity, ocular dominance plasticity. Following monocular visual deprivation during the critical period, mice that express mutant alleles of amyloid precursor protein (APPswe) and Presenilin1 (PS1dE9), as well as mice that express APPswe alone, lack ocular dominance plasticity in visual cortex. Defects in the spatial extent and magnitude of the plastic response are evident using two complementary approaches, Arc induction and optical imaging of intrinsic signals in awake mice. This defect in a classic paradigm of systems level synaptic plasticity shows that Aβ overexpression, even early in postnatal life, can perturb plasticity in cerebral cortex, and supports the idea that decreased synaptic plasticity due to elevated Aβ exposure contributes to cognitive impairment in AD.