Alzheimer's disease (AD) is the leading cause of dementia. Amyloid plaques in the brain remain a pathological feature of AD. These plaques are primarily composed of amyloid β-protein (Aβ). It has been postulated that glycogen synthase kinase-3β (GSK3β) activity might exert a central role in the development of AD. GSK3β activity has been implicated in tau phosphorylation, APP processing, Aβ production and neurodegeneration. Quetiapine is frequently used to treat psychoses in AD patients at the late stage and has inhibitory effects on GSK3β activity in mouse brains after acute/subchronic treatment. Therefore, the proposed hypothesis is that chronic quetiapine administration after amyloid plaque onset reduces AD like pathology and alleviates AD like behaviours in APP/PS1 transgenic mice by inhibiting GSK3β activity. APP/PS1 transgenic mice were treated with quetiapine (2.5, 5 mg/kg/day) in drinking water starting from 3.5 months of age, for a period of 8 months. One week after behaviour testing, mice were sacrificed at 12 months of age. Half of the hemispheres were rapidly frozen for immunoblot and ELISA analyses and the other half were fixed with 4% paraformaldehyde for histological analyses. Quetiapine treatment reduced amyloid plaques formation in the cortex and hippocampus of AD mice. It also improved the behavioural deficits in these mice, including attenuating impaired memory and anxiety-like phenotypes. In addition, chronic quetiapine administration inhibited GSK3β, which resulted in reduced production of Aβ in cortices and hippocampi of transgenic mice. Quetiapine treatment also significantly decreased the activation of astrocytes and attenuated synapse integrity impairment in transgenic mice. These findings suggest that early application of quetiapine can alleviate memory deficits and pathological changes in the APP/PS1 transgenic mouse model of AD, and further support that modulation of GSK3β activity by quetiapine may be a therapeutic option for AD.

Alzheimer's disease (AD) is the leading cause of dementia. Amyloid plaques in the brain remain a pathological feature of AD. These plaques are primarily composed of amyloid β-protein (Aβ). It has been postulated that glycogen synthase kinase-3β (GSK3β) activity might exert a central role in the development of AD. GSK3β activity has been implicated in tau phosphorylation, APP processing, Aβ production and neurodegeneration. Quetiapine is frequently used to treat psychoses in AD patients at the late stage and has inhibitory effects on GSK3β activity in mouse brains after acute/subchronic treatment. Therefore, the proposed hypothesis is that chronic quetiapine administration after amyloid plaque onset reduces AD like pathology and alleviates AD like behaviours in APP/PS1 transgenic mice by inhibiting GSK3β activity. APP/PS1 transgenic mice were treated with quetiapine (2.5, 5 mg/kg/day) in drinking water starting from 3.5 months of age, for a period of 8 months. One week after behaviour testing, mice were sacrificed at 12 months of age. Half of the hemispheres were rapidly frozen for immunoblot and ELISA analyses and the other half were fixed with 4% paraformaldehyde for histological analyses. Quetiapine treatment reduced amyloid plaques formation in the cortex and hippocampus of AD mice. It also improved the behavioural deficits in these mice, including attenuating impaired memory and anxiety-like phenotypes. In addition, chronic quetiapine administration inhibited GSK3β, which resulted in reduced production of Aβ in cortices and hippocampi of transgenic mice. Quetiapine treatment also significantly decreased the activation of astrocytes and attenuated synapse integrity impairment in transgenic mice. These findings suggest that early application of quetiapine can alleviate memory deficits and pathological changes in the APP/PS1 transgenic mouse model of AD, and further support that modulation of GSK3β activity by quetiapine may be a therapeutic option for AD.

Clinical findings have linked multiple risk factors and associated pathologies to Alzheimer\'s disease (AD). Amongst them are vascular risk factors such as hypertension and pathologies such as stroke. Coexistence of AD and these associated pathologies worsenes dementia, the clinical hallmark of the disease, as compared to pure AD. One general common denominator of these associated pathologies is the presence of hypoxic tissue conditions. It was asked the question, whether there exists a mutual, causal interaction between hypoxia and AD pathology, that could explain the clinical observations. Alternatively, the worsened clinical state of multiple brain pathologies could \"simply\" be the consequence of multimorbidity, i.e. accumulated disease load, without any causal interaction between the constituents. To approach this question whether hypoxia influences AD progression, use was made of a murine animal model of AD (transgenic mice: APPswe, PSEN1dE). Animals of two ages (8 and 14 months, \"young\" and \"old\" respectively) and two genotypes (transgenic and wild- type) were either treated under hypoxia or normoxia, corresponding to 8% and 21% oxygen, for 20 consecutive days. The resulting changes in the brain were assessed with a variety of techniques, namely by histology, ELISA, dot and Western blotting. Additional experiments in primary cell cultures were performed. Animals exposed to hypoxia showed an increased hematocrit (HCT), weight loss, reactive angiogenesis, but no infarctions. This illustrates that our hypoxic treatment put significant stress on the animals, without causing major pathologies. A large number of variables exists that could potentially be measured to assess the effect of hypoxia on AD. The focus was put on three of them: First, there is the Abeta1-42- protein, known to be the Abeta- isoform associated with the most detrimental disease progression. In AD, the self-combinatory Amyloid- beta peptide (Abeta) accumulates in the brain in so- called plaques, which is a main histologic finding of the disease. Its quantity was determined through histology and ELISA. Secondly, it was attempted to estimate the structural quality of the Abeta- protein by assessing the amount of A!- oligomers present. Abeta- protein does self- accumulate in various grades of complexity, i.e. as monomer, oligomer or fibril. Since oligomers are known to be the most neurotoxic \"species\" of the Abeta- protein, it was hypothesized that under hypoxic treatment their quantity could increase. And third, the organism\'s response to the Abeta- protein stimulus was investigated. Microglial cells have been described as the first cells to encounter the Abeta- protein \"threat\" in the shape of plaques, i.e. Abeta- protein aggregates. They then try to encapsulate and subsequently degrade them. Therefore, the attention was put on this cellular population. It was asked whether hypoxia could change the Abeta- protein quantity in the brain. This was assessed in two ways: First histologically, by staining for Abeta- protein depositions and quantifying them. Second, an ELISA was performed. Our findings state that hypoxic treatment does not alter the Abeta1-42 protein load in the brain, neither in young nor old animals, as assessed by histology and by total ELISA quantification of Abeta1-42 protein. Since hypoxia did not alter the quantity of the Abeta- protein, it was asked whether it influenced it qualitatively? If hypoxia increased oligomer formation, this change in the spectrum of the Abeta- species could, without any change in total Abeta- protein load, lead to increased neurotoxicity in animals under hypoxia. Initial experiments showed that oligomer formation in the brain seems to increase. However, this was not statistically significant and future experiments are necessary to evaluate this hypothesis further. It was then asked, whether hypoxia alters the cellular response to the protein. The total number of microglia in the hippocampal dentate gyrus, our structure of interest for practical purposes, and, it can be argued, by extension the brain, changes dynamically with various factors. First, transgenic animals present an increase in microglia. Second, microglia increase with age. Third, microglia decrease under hypoxia, but only do so significantly in old animals. Next, a parameter called \"plaque occupancy\" was coined to assess the microglia function to confront Abeta- plaques. Plaque occupancy is defined as the number of microglia in spatial proximity to one square millimeter of Abeta- plaque. This means, that microglia restricting one plaque are counted, and then normalized to this plaque\'s area. It was hypothesized that hypoxia would decrease plaque occupancy. Indeed, plaque occupancy roughly halved under hypoxia. Summarizing, our results demonstrate that long- term exposure to hypoxia significantly reduces the number of microglia. The reduced number results in significantly reduced plaque occupancy and compromizes the function of microglia to confront Abeta- plaques. The Abeta1-42 load, however, is not affected. On the other hand, Abeta shows an increased trend towards oligomer formation. A variety of possible explanations to these phenomena have been presented, that in our opinion deserve further investigation.

Clinical findings have linked multiple risk factors and associated pathologies to Alzheimer\''s disease (AD). Amongst them are vascular risk factors such as hypertension and pathologies such as stroke. Coexistence of AD and these associated pathologies worsenes dementia, the clinical hallmark of the disease, as compared to pure AD. One general common denominator of these associated pathologies is the presence of hypoxic tissue conditions. It was asked the question, whether there exists a mutual, causal interaction between hypoxia and AD pathology, that could explain the clinical observations. Alternatively, the worsened clinical state of multiple brain pathologies could \"simply\" be the consequence of multimorbidity, i.e. accumulated disease load, without any causal interaction between the constituents. To approach this question whether hypoxia influences AD progression, use was made of a murine animal model of AD (transgenic mice: APPswe, PSEN1dE). Animals of two ages (8 and 14 months, \"young\" and \"old\" respectively) and two genotypes (transgenic and wild- type) were either treated under hypoxia or normoxia, corresponding to 8% and 21% oxygen, for 20 consecutive days. The resulting changes in the brain were assessed with a variety of techniques, namely by histology, ELISA, dot and Western blotting. Additional experiments in primary cell cultures were performed. Animals exposed to hypoxia showed an increased hematocrit (HCT), weight loss, reactive angiogenesis, but no infarctions. This illustrates that our hypoxic treatment put significant stress on the animals, without causing major pathologies. A large number of variables exists that could potentially be measured to assess the effect of hypoxia on AD. The focus was put on three of them: First, there is the Abeta1-42- protein, known to be the Abeta- isoform associated with the most detrimental disease progression. In AD, the self-combinatory Amyloid- beta peptide (Abeta) accumulates in the brain in so- called plaques, which is a main histologic finding of the disease. Its quantity was determined through histology and ELISA. Secondly, it was attempted to estimate the structural quality of the Abeta- protein by assessing the amount of A!- oligomers present. Abeta- protein does self- accumulate in various grades of complexity, i.e. as monomer, oligomer or fibril. Since oligomers are known to be the most neurotoxic \"species\" of the Abeta- protein, it was hypothesized that under hypoxic treatment their quantity could increase. And third, the organism\''s response to the Abeta- protein stimulus was investigated. Microglial cells have been described as the first cells to encounter the Abeta- protein \"threat\" in the shape of plaques, i.e. Abeta- protein aggregates. They then try to encapsulate and subsequently degrade them. Therefore, the attention was put on this cellular population. It was asked whether hypoxia could change the Abeta- protein quantity in the brain. This was assessed in two ways: First histologically, by staining for Abeta- protein depositions and quantifying them. Second, an ELISA was performed. Our findings state that hypoxic treatment does not alter the Abeta1-42 protein load in the brain, neither in young nor old animals, as assessed by histology and by total ELISA quantification of Abeta1-42 protein. Since hypoxia did not alter the quantity of the Abeta- protein, it was asked whether it influenced it qualitatively? If hypoxia increased oligomer formation, this change in the spectrum of the Abeta- species could, without any change in total Abeta- protein load, lead to increased neurotoxicity in animals under hypoxia. Initial experiments showed that oligomer formation in the brain seems to increase. However, this was not statistically significant and future experiments are necessary to evaluate this hypothesis further. It was then asked, whether hypoxia alters the cellular response to the protein. The total number of microglia in the hippocampal dentate gyrus, our structure of interest for practical purposes, and, it can be argued, by extension the brain, changes dynamically with various factors. First, transgenic animals present an increase in microglia. Second, microglia increase with age. Third, microglia decrease under hypoxia, but only do so significantly in old animals. Next, a parameter called \"plaque occupancy\" was coined to assess the microglia function to confront Abeta- plaques. Plaque occupancy is defined as the number of microglia in spatial proximity to one square millimeter of Abeta- plaque. This means, that microglia restricting one plaque are counted, and then normalized to this plaque\''s area. It was hypothesized that hypoxia would decrease plaque occupancy. Indeed, plaque occupancy roughly halved under hypoxia. Summarizing, our results demonstrate that long- term exposure to hypoxia significantly reduces the number of microglia. The reduced number results in significantly reduced plaque occupancy and compromizes the function of microglia to confront Abeta- plaques. The Abeta1-42 load, however, is not affected. On the other hand, Abeta shows an increased trend towards oligomer formation. A variety of possible explanations to these phenomena have been presented, that in our opinion deserve further investigation.

Alzheimer’s disease (AD) is a devastating neurodegenerative condition in which a patient’s cognitive functioning, memory, and physical health progressively deteriorate. In order to treat physiological deterioration in AD, a neuroprotective recombinant human- erythropoietin (EPO) fusion protein was used. In addition to its ability to target amyloid beta (Aβ) aggregation, EPO has been shown to reduce inflammation, oxidative stress and synaptic loss. Recombinant human-erythropoietin (EPO) was combined with a chimeric transferrin receptor (TfR) monoclonal antibody (cTfRMAb) to form a fusion protein (cTfRMAb-EPO) that is able to cross the blood-brain barrier (BBB) by binding to the TfR expressed on the luminal side of the BBB. Thirty eight male APPswePSEN1dE9 (APP/PS1) mice were separated into four treatment groups (wildtype (WT) treated with saline, APP/PS1 treated with saline (TG), APP/PS1 treated with cTfRMAb-EPO (cTfRMAb-EPO), and APP/PS1 treated with rHu-EPO alone (rhu-EPO)) and were subcutaneously injected with their respective treatments twice a week for six weeks. Recognition memory and locomotive behavior were tested through the novel object recognition (NOR) task and open field (OF) test when the mice were 8 months old and again at 11 months old (after 8 weeks of treatment) to determine treatment effects. Both behavioral tests demonstrated a clear age effect in mice between 8- and 11-months old. In the NOR task, no significant differences in recognition memory were observed in TG, cTfRMAb-EPO, or rHu-EPO groups. Lastly, the OF test demonstrated no significant behavioral differences among treatment groups.

Quetiapine, an atypical antipsychotic drug, is effective in treating the behavioural and the psychological symptoms of dementia (BPSD). The objective of this study was to examine the effects of quetiapine on anxiety-like behaviour in the amyloid precursor protein (APP)/ presenilin 1 (PS1) double transgenic mouse model of Alzheimers disease (AD). The mice were treated with quetiapine (0, 2.5, or 5 mg/kg/day) orally in drinking water for 7 or 10 months starting from 2 months of age. Conditioned anxiety was measured using the elevated T-maze (ETM). To measure memory, the Y-maze and the Morris Water maze were employed. After behavioural testing, â-amyloid (Aâ) plaques in the hippocampus and cortex of transgenic mice were stained using Congo Red. Brain-derived neurotrophic factor (BDNF) in the basolateral amygdala (BLA) and the hippocampus of mice was examined using immunohistochemical methods. The statistics revealed an interaction between quetiapine and APP/PS1 double transgenic mice in the avoidance phase of the ETM. Quetiapine modulates anxiety-like behaviours in the ETM. The anxiety-like behaviours were associated with reductions in BDNF levels in the BLA and hippocampus of the transgenic mice. This was reversed by treatment with quetiapine. Furthermore, chronic administration of quetiapine attenuated the memory impairment and decreased the Aâ plaque load in the brain. This study demonstrates that quetiapine normalizes anxiety-like behaviour and up-regulates cerebral BDNF levels in the APP/PS1 mice, suggesting that quetiapine may function as a neuroprotectant as well as an antipsychotic in treating the BPSD associated with AD.

Quetiapine, an atypical antipsychotic drug, is effective in treating the behavioural and the psychological symptoms of dementia (BPSD). The objective of this study was to examine the effects of quetiapine on anxiety-like behaviour in the amyloid precursor protein (APP)/ presenilin 1 (PS1) double transgenic mouse model of Alzheimers disease (AD). The mice were treated with quetiapine (0, 2.5, or 5 mg/kg/day) orally in drinking water for 7 or 10 months starting from 2 months of age. Conditioned anxiety was measured using the elevated T-maze (ETM). To measure memory, the Y-maze and the Morris Water maze were employed. After behavioural testing, â-amyloid (Aâ) plaques in the hippocampus and cortex of transgenic mice were stained using Congo Red. Brain-derived neurotrophic factor (BDNF) in the basolateral amygdala (BLA) and the hippocampus of mice was examined using immunohistochemical methods. The statistics revealed an interaction between quetiapine and APP/PS1 double transgenic mice in the avoidance phase of the ETM. Quetiapine modulates anxiety-like behaviours in the ETM. The anxiety-like behaviours were associated with reductions in BDNF levels in the BLA and hippocampus of the transgenic mice. This was reversed by treatment with quetiapine. Furthermore, chronic administration of quetiapine attenuated the memory impairment and decreased the Aâ plaque load in the brain. This study demonstrates that quetiapine normalizes anxiety-like behaviour and up-regulates cerebral BDNF levels in the APP/PS1 mice, suggesting that quetiapine may function as a neuroprotectant as well as an antipsychotic in treating the BPSD associated with AD.

No description available.

Yes / A key aim of Alzheimer disease research is to develop efficient therapies to prevent and/or delay the irreversible progression of cognitive impairments. Early deficits in long-term potentiation (LTP) are associated with the accumulation of amyloid beta in rodent models of the disease; however, less is known about how mGluR-mediated long-term depression (mGluR-LTD) is affected. In this study, we have found that mGluR-LTD is enhanced in the APPswe /PS1dE9 mouse at 7 but returns to wild-type levels at 13 months of age. This transient over-activation of mGluR signalling is coupled with impaired LTP and shifts the dynamic range of synapses towards depression. These alterations in synaptic plasticity are associated with an inability to utilize cues in a spatial learning task. The transient dysregulation of plasticity can be prevented by genetic deletion of the MAP kinase-activated protein kinase 2 (MK2), a substrate of p38 MAPK, demonstrating that manipulating the mGluR-p38 MAPK-MK2 cascade at 7 months can prevent the shift in synapse dynamic range. Our work reveals the MK2 cascade as a potential pharmacological target to correct the over-activation of mGluR signalling. / Wellcome Trust, Grant/Award Number: 200646/Z/16/Z

No description available.