Magga J.,University of Eastern Finland |
Magga J.,University of Oulu |
Savchenko E.,University of Eastern Finland |
Malm T.,University of Eastern Finland |
And 12 more authors.
Journal of Cellular and Molecular Medicine | Year: 2012
Accumulation of amyloid β (Aβ) is a major hallmark in Alzheimer's disease (AD). Bone marrow derived monocytic cells (BMM) have been shown to reduce Aβ burden in mouse models of AD, alleviating the AD pathology. BMM have been shown to be more efficient phagocytes in AD than the endogenous brain microglia. Because BMM have a natural tendency to infiltrate into the injured area, they could be regarded as optimal candidates for cell-based therapy in AD. In this study, we describe a method to obtain monocytic cells from BM-derived haematopoietic stem cells (HSC). Mouse or human HSC were isolated and differentiated in the presence of macrophage colony stimulating factor (MCSF). The cells were characterized by assessing the expression profile of monocyte markers and cytokine response to inflammatory stimulus. The phagocytic capacity was determined with Aβ uptake assay in vitro and Aβ degradation assay of natively formed Aβ deposits ex vivo and in a transgenic APdE9 mouse model of AD in vivo. HSC were lentivirally transduced with enhanced green fluorescent protein (eGFP) to determine the effect of gene modification on the potential of HSC-derived cells for therapeutic purposes. HSC-derived monocytic cells (HSCM) displayed inflammatory responses comparable to microglia and peripheral monocytes. We also show that HSCM contributed to Aβ reduction and could be genetically modified without compromising their function. These monocytic cells could be obtained from human BM or mobilized peripheral blood HSC, indicating a potential therapeutic relevance for AD. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
Heikkinen R.,University of Eastern Finland |
Malm T.,University of Eastern Finland |
Heikkila J.,Kuopio University Hospital |
Muona A.,Medeia Therapeutics Ltd |
And 4 more authors.
Aging and Disease | Year: 2014
Cerebral ischemia is a risk factor for Alzheimer's disease (AD). Moreover, recent evidence indicates that it is a two-way street as the incidence rate of stroke is significantly higher in AD patients than those without the disease. Here we investigated the interaction of ischemic brain insults and AD in 9-month-old ApdE9 mice, which show full-blown accumulation of Aβ deposits and microgliosis in the brain. Permanent occlusion of the middle cerebral artery (pMCAo) resulted in 36% larger infarct in ApdE9 mice compared to their wild-type (wt) controls. This was not due to differences in endothelium-dependent vascular reactivity. Treatment with human intravenous immunoglobulin (IVIG) reduced the infarct volumes and abolished the increased vulnerability of ApdE9 mice to pMCAo induced brain ischemia. When the mice were exposed to global brain ischemia (GI), an insult of hippocampal cells, ApdE9 mice showed increased neuronal loss in CA2 and CA3 subregions compared to their wt controls. GI was associated with increased microgliosis, astrogliosis, infiltration of blood-derived monocytic cells, and neurogenesis without clear differences between the genotypes. IVIG treatment prevented the GI-induced neuron loss in hippocampal CA1 and CA3 regions in ApdE9 mice. IVIG treatment increased microgliosis in wt but not in ApdE9 mice. Finally, GI induced 60% reduction in the hippocampal Aβ burden in ApdE9 mice, which was not affected by IVIG treatment. The results indicate that the AD pathology with Aβ deposits and microgliosis increases ischemic vulnerability in various brain areas. Moreover, IVIG treatment may be beneficial especially in patients suffering from both acute ischemic insult and AD.
Medeia Therapeutics Ltd | Date: 2013-01-11
The invention relates to novel heteroarylamide derivatives having formula (I) and N-oxides, stereoisomers and pharmaceutically acceptable salts thereof, where R_(A), R_(B), R1 1, R, R, z and X are as defined in the claims. The arylamide derivatives of formula (I) have antiandrogenic properties. The invention also relates to compounds of formula (I) for use as a medicament and to pharmaceutical compositions comprising them and to their preparation.
Medeia Therapeutics Ltd | Date: 2011-07-14
The invention relates to novel arylamide derivatives having formula (I) and stereoisomers and pharmaceutically acceptable salts thereof, where R1-R11, R, R, z and X are as defined in the claims. The arylamide derivatives of formula (I) have antiandrogenic properties. The invention also relates to compounds of formula (I) for use as a medicament and to pharmaceutical compositions comprising them and to their preparation.
Medeia Therapeutics Ltd | Date: 2011-01-07
The current invention relates to methods for stimulating mammalian cells to enhance their ability to cross the blood-brain-barrier and to phagocytose and degrade beta-amyloid plaques in the brain. The current invention also relates to cells obtained by the method of the invention. The current invention also relates to methods for prevention and treatment of amyloid-accumulating disorders.