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Choroba Alzheimera jako efekt niezdrowej diety: rola insulinooporoności mózgu

100%
Domanska J., Mietelska-Porowska A., Wojda U.
Wszechświat
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2023
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tom 124
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nr 01-03
2

Influence of systemic inflammation and fluctuations of blood glucose level on amyloidopathy progression in mouse model of sporadic Alzheimer’s disease

100%
Wieckowska A., Wydrych M., Mietelska-Porowska A., Wojda U.
Acta Neurobiologiae Experimentalis
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2017
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tom 77
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nr Suppl.1
INTRODUCTION: Prominent neuropathologic features of Alzheimer’s Disease (AD) are the appearance of senile plaques composed of amyloid peptides and neurofibrillary tangles derived from Tau protein. Induction of main risk factors before the appearance of typical neuropathological AD hallmarks can help to track the sequence of different and complicated early molecular mechanisms of the sporadic form of human AD (SAD). AIM(S): Our aim is to establish a mouse model that would mimic molecular mechanisms leading to SAD by induction of systemic neuroinflammation and insulin resistance in transgenic mice with mutated human gene encoding amyloid precursor protein (Tg APP). Additionally, we would like to check whether the same experimental conditions may induce AD hallmarks in wild type mice, that may be a proof of lifestyle factors influence on AD development. METHOD(S): In order to induce neuroinflammation and evaluate the influence of insulin dysregulation in the brain, Tg APP and C57BL mice were injected with LPS, and diabetes was induced by high-fat diet feeding, or streptozocin injection. Every two weeks blood glucose level and body weight were checked. To characterize the metabolic phenotype and immunostaining pattern of neuroinflammatory markers and amyloid β, mice blood and brain tissue were used. RESULTS: We show effects of systemic administration of infectious agent in neuroinflammation in the brain and body weight and blood biochemical pattern related to high-fat diet and their relation with amyloidopathy progression in the brain. CONCLUSIONS: The data verify if lifestyle conditions including ongoing systemic inflammation and metabolic changes related to unhealthy diet may accelerate amyloidopathy progression. Studied factors may cause changes not only in Tg APP mice but also lead to the development of AD hallmarks in brain of mice without mutations in APP gene. Results might provide the evidence that the proposed animal model may be an effective tool to study the molecular mechanisms of early stages of SAD progression. FINANCIAL SUPPORT: Polish National Science Centre Grant 2014/15/D/NZ4/04361.
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Involvement of the CacyBP/SIP protein in tauopaty

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Schneider G., Mietelska-Porowska A., Filipek A., Niewiadomska G.
Acta Neurobiologiae Experimentalis
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2009
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tom 69
|
nr 3
The CacyBP/SIP protein is highly expressed in brain neurons, where it localizes in somata and in neuronal processes. The role of CacyBP/SIP is not clear at present but recently it has been suggested that the interaction between CacyBP/SIP and tubulin might be important for stability of microtubules in neuronal cells. Particularly, it was found that CacyBP/SIP changes its localization in an age-dependent way. Moreover, these changes in localization are similar to those observed for tau, a well known tubulin binding protein. Since it is known that changes in localization of tau during aging are similar to those observed in tauopaties (such as Alzheimer’s disease), in this work we examined the localization and possible role of CacyBP/SIP in mouse model of tauopathy (mice overexpressing the tau protein). We found that in young tauopathic mice CacyBP/SIP and tau are mainly present in neuronal somata whereas in wild type animals both proteins are localized in somata and in neuronal processes. Moreover, the tubulin staining pattern in transgenic mice was different than in wild animals. This might suggest that translocation of tau together with CacyBP/SIP affects stability of microtubules in neuronal cells. At present we examine whether posttranslational modifi cation(s) of CacyBP/SIP, such as phosphorylation, might be responsible for the observed translocation of CacyBP/SIP during tauopathy. This work was supported by statutory funds from the Nencki Institute of Experimental Biology.
4

Lipopolysaccharide accelerates neuroinflammation in a mouse model of Alzheimer's disease

88%
Dlugosz J., Wieckowska A., Koperski M., Mietelska-Porowska A., Wojda U.
Acta Neurobiologiae Experimentalis
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2019
|
tom 79
|
nr Suppl.1
INTRODUCTION: The amyloid hypothesis postulates that the main cause of Alzheimer’s disease (AD) is amyloidogenic cleavage of amyloid precursor protein (APP) and deposition of amyloid‑beta. Recently, another hypothesis was formulated that neuroinflammation may precede amyloid generation in AD development. It was also demonstrated that systemic inflammation may impair brain homeostasis and function. AIM(S): Based on these data we hypothesized that systemic inflammation impairs brain homeostasis and leads to neuroinflammation that later causes AD development. METHOD(S): To verify this hypothesis, we compared effects of systemic inflammation induced by intraperitoneal injection of lipopolysaccharide (LPS) in transgenic mice expressing human APP with Swedish AD-causing mutation (APPswe) to untreated APPswe mice. To assess AD neuropathological hallmarks, brain tissue from 4, 8, and 12‑month old animals were analyzed by immunohistochemical staining and immunoblotting. RESULTS: We found that LPS shortly after peripheral administration to APPswe mice induced astrogliosis and dysregulation of pro- and anti-inflammatory cytokines in brains already in young 4‑month old animals and these effects were also detected in 8-month old mice. In control mice not treated with APPswe, the development of signs of neuroinflammation was slower. We also compared the signs of neuroinflammation in the hippocampus and entorhinal cortex to levels of APP full-length protein and its pathologically truncated CTFs forms. CONCLUSIONS: Obtained results indicate that systemic inflammation accelerates and intensifies neuroinflammation as reflected by astrogliosis and pro-inflammatory reaction during AD development. It suggests that systemic inflammation can be considered as a common civilization risk factor of AD progression. These data became the reference for the next hypothesis and studies of our group (abstracts by A. Mietelska‑Porowska and by A. Więckowska). FINANCIAL SUPPORT: Financed by National Science Center grants no. 2014/15/D/NZ4/04361, 2018/29/N/ NZ7/01724.
5

Diet-derived changes in insulin metabolism in brain accelerate the development of Alzheimer's disease neuropathological features

88%
Mietelska-Porowska A., Wieckowska A., Dlugosz J., Koperski M., Wojda U.
Acta Neurobiologiae Experimentalis
|
2019
|
tom 79
|
nr Suppl.1
INTRODUCTION: The western diet (WD), enriched in saturated fatty acids, cholesterol, and simple carbohydrates., is known to cause metabolic syndrome related to insulin metabolism impairment. On the other hand, metabolic syndrome is described as a potential risk factor for Alzheimer’s disease (AD). Main early AD features in brain are altered proteolysis of amyloid precursor protein (APP) and hyperphosphorylation of tau protein. AIM(S): Our aim was to verify our hypothesis that the WD causes insulin metabolism disturbances and may accelerate development of early AD hallmarks. METHOD(S): To verify this hypothesis, we compared effects of WD feeding (from 3rd month of age) in transgenic mice expressing human APP with Swedish AD-causing mutation (APPswe) compared to APPswe mice in which systemic inflammation was induced by injection of lipopolysaccharide (LPS; the model described in the abstract by J. Dlugosz), and to untreated APPswe mice. To assess AD neuropathological hallmarks, all groups were analysed at the ages of 4, 8, and 12‑months by immunohistochemical and immunoblotting analysis. RESULTS: Our results demonstrate levels of insulin resistance marker and insulin/Aβ degrading enzyme in relation to characteristic neuropathological AD hallmarks, such as occurrence, intensity of staining, and neuronal compartmentalisation of phosphorylated isoform of Tau protein, and the level of APP full-length protein and its pathologically truncated CTFs forms, in the hippocampus and cortex of mice brains. CONCLUSIONS: Obtained results indicate that WD is linked to insulin metabolism impairment and leads to accelerated over-phosphorylation of tau protein and proteolysis of APP. This suggests that the WD, via impairment in insulin metabolism, may accelerate the development of AD. FINANCIAL SUPPORT: Financed by National Science Center grant no. 2014/15/D/NZ4/04361.
6

Western diet - from metabolic disturbances to acceleration of glia activation and development of Alzheimer’s disease

76%
Wieckowska A., Mietelska-Porowska A., Wydrych M., Dlugosz J., Chutoranski D., Wojda U.
Acta Neurobiologiae Experimentalis
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2019
|
tom 79
|
nr Suppl.1
INTRODUCTION: A diet enriched in fat, cholesterol, and sugar – called the Western diet (WD) – was shown to induce systemic inflammation, obesity, and metabolic syndrome and results directly and indirectly in an impact on brain structure and function. The WD has not been examined yet in the context of Alzheimer’s disease (AD), characterised by altered cleavage of amyloid precursor protein (APP) and deposits of toxic amyloid. AIM(S): We aimed to verify the hypothesis that WD by inducing metabolic syndrome and systemic inflammation may accelerate brain glia activation events and the onset of AD. METHOD(S): To verify this hypothesis, transgenic mice expressing human APP with Swedish AD-causing mutation (APPswe) were fed with WD from 3rd month of age. These mice were compared to APPswe mice in which systemic inflammation was induced by injection of lipopolysaccharide (LPS) and to untreated APPswe mice. All animal groups were subsequently analysed at the age of 4, 8, and 12‑months by immunohistochemical and immunoblotting analysis. RESULTS: Already one month of WD feeding induces metabolic disturbances including hypercholesterolemia and hyperglycaemia and accelerates the brain pathological events in young APPswe mice. After one month of WD feeding, we observed enhanced astrogliosis, altered profile of microglia activation state, and enhanced cleavage of APP in mice brains. Moreover, we observed obesity, enhanced liver weight, and non-alcoholic fatty liver disease (NAFLD) after 3 months of the WD, which suggest that the WD causes alterations in the brain even earlier than in peripheral organs. CONCLUSIONS: These results suggest that the WD leads to brain neuroinflammation and accelerates the development of AD. Therefore, the WD can be considered as a newly identified common civilian AD risk factor. FINANCIAL SUPPORT: Supported by National Science Center grants: 2014/15/D/NZ4/04361, 2018/29/N/ NZ7/01724.
7

Beyond amyloid:altered cell cycle regulation in Alzheimer's disease:comparison of P21 signaling in patients lymphocytes and brain neurons

76%
Mietelska-Porowska A., Wojsiat J., Laskowska-Kaszub K., Stepien T., Wierzba-Bobrowicz T., Wojda U.
Acta Neurobiologiae Experimentalis
|
2015
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tom 75
|
nr Supl.
BACKGROUND AND AIMS: Alzheimer’s disease (AD) develops for decades, but the molecular mechanism of pathogenesis is poorly understood. In result, an effective AD cure is still missing. According to the cell cycle (CC) hypothesis, one of the AD causes is CC reactivation in mature neurons. We aimed at elucidation if similar CC alterations occur in AD brain neurons and in peripheral blood cells. METHODS: As the study materials, we used 40 lines of immortalized lymphoblasts from sporadic AD (SAD) patients and 40 lines from healthy non-demented individuals (controls)1-4. CC in lymphocytes was analyzed by real-time PCR-arrays, immunoblotting, and flow cytometry. Human post mortem brain tissue from AD patients was prepared by paraffin embedding and microscopic tissue slides of hippocampus and enthorinal cortex was analyzed by antip21 immunohistochemical staining. RESULTS: Our data demonstrated aberrant CC in SAD lymphoblasts that involved a prolongation of the G1 phase driven by a marked increase of levels of p21 protein (Walf1/Cip1/Sid1), the key regulator of the G1/S CC checkpoint and of apoptosis. Consistently, we also found differences in p21 levels and its signaling pathway in apoptotic response of SAD lymphoblasts to redox stess. The analysis of p21 protein levels and related signaling in AD brain neurons will also be presented. CONCLUSIONS: In summary, these studies indicate that p21-related molecular changes underlie altered cell cycle and apoptosis in AD pathology and may represent novel therapeutic targets. Moreover, our data show that AD have a features of a systemic disease with CC alterations in peripheral lymphoblasts which thus have a potential diagnostic value. Support: CEPT, Polish National Science Centre grant NN401 596840, and JPND grant 2/BIOMARKAPD/JPND/2012.
8

Transmembrane intraneuronal delivery of Tau protein in rat may serve as an animal model of human tauopathy

76%
Mietelska-Porowska A., Koss D., Baksalerska-Pazera M., Robakiewicz L., Nosecka E., Riedel G., Niewiadomska G.
Acta Neurobiologiae Experimentalis
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2009
|
tom 69
|
nr 3
Filamentous inclusions of tau protein are hallmarks of tauopathies including Alzheimer’s disease. Here a rat model for tauopathies was developed using pore-forming halitoxin Poly-APS. Tau protein was delivered through the membrane into the neurons where it is metabolized. Rats were injected with recombinant human Tau441 only (controls), Tau+Poly-APS (double) and Tau+PolyAPS+Okadaic Acid (triple). Cognitive and neurodegenerative changes were examined with Morrris water maze behavioral test and immunohistochemistry, respectively. Acquisition of the spatial reference memory was unaffected by administration of Tau or Tau+Poly-APS. However, enhanced phosphorylation of exogenously delivered tau with the triple infusion impaired learning. Hippocampal tau was visualized using antibodies against Tau441 and phosphorylated Tau-S404. The higher intensity of Tau441 immunostaining in double and triple groups suggests that exogenous tau is sequestered from the infusion solution into the cells. With respect to phospho-tau izoform we observed different cellular compartmentalization of P-Tau-S404 in double and triple treated rats. In double treated rats P-TauS401 was distributed both in the cell bodies and neuronal fi bers, while in triple group presence of OA caused redistribution of phospho-tau staining from neuronal processes to the perikaryon. This is similar to age-dependent tau redistribution between cellular compartments and could be a result of hyperphosphorylation.
9

Administration of clenbuterol improves morphology of cholinergic neurons and cognitive processes in aged rats

76%
Mazurkiewicz M., Mietelska-Porowska A., Robakiewicz L., Gasiorowska A., Baksalerska-Pazera M., Nieiwadomska G.
Acta Neurobiologiae Experimentalis
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2009
|
tom 69
|
nr 3
A defi cit in the cholinergic system of the basal forebrain (BF) is thought to contribute to the development of cognitive symptoms of dementia. Forebrain cholinergic neurons are highly dependent on nerve growth factor (NGF) for phenotype maintenance. Attempts to prevent age-associated cholinergic vulnerability and deterioration therefore represent a crucial point for pharmacotherapy in the elderly. The pharmacological induction of endogenous NGF synthesis in the brain could be an elegant way to overcome application problems. Therefore, the present experiment was undertaken to determine the infl uence of prolonged pharmacological stimulation of NGF biosynthesis on learning and memory in aged rats. To address these issues we used young (4-month-old) and aged (28-month-old) rats in which we stimulated endogenous NGF biosynthesis by treatment with clenbuterol (β2-adrenergic receptors agonist). The cognitive behavior of the young and aged rats was assessed in the long-lasting “Non-Matching to Position Test”. Our data suggest that in aged rats, clenbuterol positively affects cognitive processes related to formation of associations established in recognition memory and discrimination tasks. In addition, NGF signifi cantly improved morphological parameters of BF cholinergic cells in aged rats. These data suggest that endogenous NGF induction restores the age-related decline of the cholinergic system activity in rats, resulting in improvement of water maze performance in old animals.
10

Long-term effects of subdural injections of an antlerogenic cell homogenate (ACH) in a porcine model of spinal cord injury (SCI)

52%
Wrzosek M., Plonek M., Nicpon J., Chelmonska-Soyta A., Podgorski P., Cegielski M., Gebarowski T., Mietelska-Porowska A., Wojda U., Gajewska-Wozniak O., Skup M.
Acta Neurobiologiae Experimentalis
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2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: The potential use of stem cells in spinal cord regeneration is widely discussed. Xenogenic implantation of antlerogenic stem cell homogenate (ACH) was reported to improve cartilage and cornea regeneration. AIM(S): A multilevel spinal cord reaction assessment to an ACH implantation in a spinal cord injury (SCI) porcine model was undertaken. METHOD(S): ACH (cell line MIC-1; 10×106 cells/ml) was obtained using sonification. Five groups were studied: A-sham, B-negative control, C–E with subdural ACH injection, applied immediately after SCI (C), and 1h (D) and 24 h (E) after SCI. Before (P0), directly after (P1), 2 weeks (P2) and 8 weeks (P3) after contusion, CBC and standard blood biochemistry, TP and CSF pleocytosis, UCHL-1, TNF‑alfa, MBP, IL‑8, IL‑6, IL‑1β in the serum and CSF were compared. The degree of SCI on MRI (1.5T, Philips, Ingenia) and MR-DTI parameters (FA, ADC) were also evaluated. Post-mortem histopathology and IHC labeling for an astroglial (GFAP) and microglial (IBA) reaction were performed. All of the above analyses were double-blind and randomized. RESULTS: The majority of the CSF changes were found only in the late postlesion period (P3). The lack of serum IL‑1β changes during the entire experiment in all animals, together with the HP and IHC findings, point to a lack of pro‑inflammatory reaction to the subdural ACH implantation. Decreased levels of cell degeneration markers (MBP, TNF alfa, IL-8) in the CSF of the animals where ACH was used suggest that it has potential neuroprotective activity. CONCLUSIONS: MR and MR-DTI results and a small astrocyte and microglial response in group C (subdural ACH implantation directly after the SCI), suggest a potential beneficial influence of ACH on the neuronal tissue at the injury site. However, due to the data inhomogeneity, a longer observation on a larger group of animals should be conducted. FINANCIAL SUPPORT: This study was conducted in a National Center for Research and Development project (UOD-DEM-1-352/001) .
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