TY  - JOUR
AU  - Jovanović Macura, Irena
AU  - Živanović, Ana
AU  - Perović, Milka
AU  - Ćirić, Jelena
AU  - Major, Tamara
AU  - Kanazir, Selma
AU  - Ivković, Sanja
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/6548
AB  - Cerebral amyloid angiopathy (CAA) is characterized by amyloid (A ) accumulation in the blood vessels and is associated with cognitive impairment in Alzheimer’s disease (AD). The increased accumulation of A is also present in the retinal blood vessels and a significant correlation between retinal and brain amyloid deposition was demonstrated in living patients and animal AD models. The A accumulation in the retinal blood vessels can be the result of impaired transcytosis and/or the dysfunctional ocular glymphatic system in AD and during aging. We analyzed the changes in the mRNA and protein expression of major facilitator superfamily domain-containing protein2a (Mfsd2a), the major regulator of transcytosis, and of Aquaporin4 (Aqp4), the key player implicated in the functioning of the glymphatic system, in the retinas of 4- and 12-month-old WT and 5xFAD female mice. A strong decrease in the Mfsd2a mRNA and protein expression was observed in the 4 Mand12M5xFADand12MWTretinas. Theincrease in the expression of srebp1-c could be at least partially responsible for the Mfsd2a decrease in the 4 M 5xFAD retinas. The decrease in the pericyte (CD13+) coverage of retinal blood vessels in the 4 M and 12 M 5xFAD retinas and in the 12 MWTretinas suggests that pericyte loss could be associated with the Mfsd2a downregulation in these experimental groups. The observed increase in Aqp4 expression in 4 M and 12 M 5xFAD and 12 M WT retinas accompanied by the decreased perivascular Aqp4 expression is indicative of the impaired glymphatic system. The findings in this study reveal the impaired Mfsd2a and Aqp4 expression and Aqp4 perivascular mislocalization in retinal blood vessels during physiolog ical (WT) and pathological (5xFAD) aging, indicating their importance as putative targets for the development of new treatments that can improve the regulation of transcytosis or the function of the glymphatic system.
PB  - Basel: MDPI
T2  - International Journal of Molecular Sciences
T1  - The Expression of Major Facilitator Superfamily  Domain-Containing Protein2a (Mfsd2a) and Aquaporin 4 Is  Altered in the Retinas of a 5xFAD Mouse Model of  Alzheimer’s Disease
IS  - 18
VL  - 24
DO  - 10.3390/ijms241814092
SP  - 14092
ER  - 

@article{
author = "Jovanović Macura, Irena and Živanović, Ana and Perović, Milka and Ćirić, Jelena and Major, Tamara and Kanazir, Selma and Ivković, Sanja",
year = "2023",
abstract = "Cerebral amyloid angiopathy (CAA) is characterized by amyloid (A ) accumulation in the blood vessels and is associated with cognitive impairment in Alzheimer’s disease (AD). The increased accumulation of A is also present in the retinal blood vessels and a significant correlation between retinal and brain amyloid deposition was demonstrated in living patients and animal AD models. The A accumulation in the retinal blood vessels can be the result of impaired transcytosis and/or the dysfunctional ocular glymphatic system in AD and during aging. We analyzed the changes in the mRNA and protein expression of major facilitator superfamily domain-containing protein2a (Mfsd2a), the major regulator of transcytosis, and of Aquaporin4 (Aqp4), the key player implicated in the functioning of the glymphatic system, in the retinas of 4- and 12-month-old WT and 5xFAD female mice. A strong decrease in the Mfsd2a mRNA and protein expression was observed in the 4 Mand12M5xFADand12MWTretinas. Theincrease in the expression of srebp1-c could be at least partially responsible for the Mfsd2a decrease in the 4 M 5xFAD retinas. The decrease in the pericyte (CD13+) coverage of retinal blood vessels in the 4 M and 12 M 5xFAD retinas and in the 12 MWTretinas suggests that pericyte loss could be associated with the Mfsd2a downregulation in these experimental groups. The observed increase in Aqp4 expression in 4 M and 12 M 5xFAD and 12 M WT retinas accompanied by the decreased perivascular Aqp4 expression is indicative of the impaired glymphatic system. The findings in this study reveal the impaired Mfsd2a and Aqp4 expression and Aqp4 perivascular mislocalization in retinal blood vessels during physiolog ical (WT) and pathological (5xFAD) aging, indicating their importance as putative targets for the development of new treatments that can improve the regulation of transcytosis or the function of the glymphatic system.",
publisher = "Basel: MDPI",
journal = "International Journal of Molecular Sciences",
title = "The Expression of Major Facilitator Superfamily  Domain-Containing Protein2a (Mfsd2a) and Aquaporin 4 Is  Altered in the Retinas of a 5xFAD Mouse Model of  Alzheimer’s Disease",
number = "18",
volume = "24",
doi = "10.3390/ijms241814092",
pages = "14092"
}

Jovanović Macura, I., Živanović, A., Perović, M., Ćirić, J., Major, T., Kanazir, S.,& Ivković, S.. (2023). The Expression of Major Facilitator Superfamily  Domain-Containing Protein2a (Mfsd2a) and Aquaporin 4 Is  Altered in the Retinas of a 5xFAD Mouse Model of  Alzheimer’s Disease. in International Journal of Molecular Sciences
Basel: MDPI., 24(18), 14092.
https://doi.org/10.3390/ijms241814092

Jovanović Macura I, Živanović A, Perović M, Ćirić J, Major T, Kanazir S, Ivković S. The Expression of Major Facilitator Superfamily  Domain-Containing Protein2a (Mfsd2a) and Aquaporin 4 Is  Altered in the Retinas of a 5xFAD Mouse Model of  Alzheimer’s Disease. in International Journal of Molecular Sciences. 2023;24(18):14092.
doi:10.3390/ijms241814092 .

Jovanović Macura, Irena, Živanović, Ana, Perović, Milka, Ćirić, Jelena, Major, Tamara, Kanazir, Selma, Ivković, Sanja, "The Expression of Major Facilitator Superfamily  Domain-Containing Protein2a (Mfsd2a) and Aquaporin 4 Is  Altered in the Retinas of a 5xFAD Mouse Model of  Alzheimer’s Disease" in International Journal of Molecular Sciences, 24, no. 18 (2023):14092,
https://doi.org/10.3390/ijms241814092 . .

TY  - CONF
AU  - Jovanović Macura, Irena
AU  - Đuričić, Ivana
AU  - Major, Tamara
AU  - Milanović, Desanka
AU  - Brkić, Marjana
AU  - Sobajić, Slađana
AU  - Kanazir, Selma
AU  - Ivković, Sanja
PY  - 2023
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5858
AB  - Mfsd2a is expressed mainly in the endothelial cells and is an essential regulator of 
blood vessel transcytosis. Therefore, decrease in Mfsd2a expression can be a risk 
factor for developing leaky blood vessels. Mfsd2a is also the main docosahexaenoic 
acid (DHA, C22:6n3) transporter. DHA, an omega-3 fatty acid, is one of the main 
structural lipids of the neuronal and vascular retina, crucial for the normal functioning 
of photoreceptors (PRs). However, the capacity of the retina to synthesize DHA is 
limited, and the maintenance of retinal DHA content relies on the uptake from blood borne lipids. The currently recommended FO doses yielded low PUFAs tissue 
bioavailability, and supplementation with higher doses has been increasingly 
recommended. Nevertheless, the effects of higher FO doses on retinal Mfsd2a 
expression and blood vessels coverage are unknown.
Western blot and qPCR analyses showed that high dose FO supplementation increased 
Mfsd2a expression in the retina. Immunohistochemical analyses of Mfsd2a expression 
on retinal blood vessels (labeled with 488-conjugated Lycopersicon esculentum, 
lectin) and subsequent ImageJ analyses revealed 1.32-fold increase in the Mfsd2a 
retinal blood vessel coverage. In the same time the pericyte blood vessel coverage 
(CD13+ cells) was not affected with FO supplementation, and the increase in Mfsd2a 
blood vessel expression is not the result of the increased pericyte coverage. 
Therefore, the high-dose FO supplementation emerges as the prophylactic fortifier of 
the retinal blood vessels that can serve either as prophylaxis in the healthy eye or as an 
adjuvant in developing targeted manipulations of the barrier during diseases.
PB  - Belgrade: Serbian Neuroscience Society
C3  - Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
T1  - The high-dose fish oil (FO) supplementation increased Mfsd2a expression in the retina of healthy mice
SP  - 66
UR  - https://hdl.handle.net/21.15107/rcub_ibiss_5858
ER  - 

@conference{
author = "Jovanović Macura, Irena and Đuričić, Ivana and Major, Tamara and Milanović, Desanka and Brkić, Marjana and Sobajić, Slađana and Kanazir, Selma and Ivković, Sanja",
year = "2023",
abstract = "Mfsd2a is expressed mainly in the endothelial cells and is an essential regulator of 
blood vessel transcytosis. Therefore, decrease in Mfsd2a expression can be a risk 
factor for developing leaky blood vessels. Mfsd2a is also the main docosahexaenoic 
acid (DHA, C22:6n3) transporter. DHA, an omega-3 fatty acid, is one of the main 
structural lipids of the neuronal and vascular retina, crucial for the normal functioning 
of photoreceptors (PRs). However, the capacity of the retina to synthesize DHA is 
limited, and the maintenance of retinal DHA content relies on the uptake from blood borne lipids. The currently recommended FO doses yielded low PUFAs tissue 
bioavailability, and supplementation with higher doses has been increasingly 
recommended. Nevertheless, the effects of higher FO doses on retinal Mfsd2a 
expression and blood vessels coverage are unknown.
Western blot and qPCR analyses showed that high dose FO supplementation increased 
Mfsd2a expression in the retina. Immunohistochemical analyses of Mfsd2a expression 
on retinal blood vessels (labeled with 488-conjugated Lycopersicon esculentum, 
lectin) and subsequent ImageJ analyses revealed 1.32-fold increase in the Mfsd2a 
retinal blood vessel coverage. In the same time the pericyte blood vessel coverage 
(CD13+ cells) was not affected with FO supplementation, and the increase in Mfsd2a 
blood vessel expression is not the result of the increased pericyte coverage. 
Therefore, the high-dose FO supplementation emerges as the prophylactic fortifier of 
the retinal blood vessels that can serve either as prophylaxis in the healthy eye or as an 
adjuvant in developing targeted manipulations of the barrier during diseases.",
publisher = "Belgrade: Serbian Neuroscience Society",
journal = "Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia",
title = "The high-dose fish oil (FO) supplementation increased Mfsd2a expression in the retina of healthy mice",
pages = "66",
url = "https://hdl.handle.net/21.15107/rcub_ibiss_5858"
}

Jovanović Macura, I., Đuričić, I., Major, T., Milanović, D., Brkić, M., Sobajić, S., Kanazir, S.,& Ivković, S.. (2023). The high-dose fish oil (FO) supplementation increased Mfsd2a expression in the retina of healthy mice. in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia
Belgrade: Serbian Neuroscience Society., 66.
https://hdl.handle.net/21.15107/rcub_ibiss_5858

Jovanović Macura I, Đuričić I, Major T, Milanović D, Brkić M, Sobajić S, Kanazir S, Ivković S. The high-dose fish oil (FO) supplementation increased Mfsd2a expression in the retina of healthy mice. in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia. 2023;:66.
https://hdl.handle.net/21.15107/rcub_ibiss_5858 .

Jovanović Macura, Irena, Đuričić, Ivana, Major, Tamara, Milanović, Desanka, Brkić, Marjana, Sobajić, Slađana, Kanazir, Selma, Ivković, Sanja, "The high-dose fish oil (FO) supplementation increased Mfsd2a expression in the retina of healthy mice" in Book of abstracts: 8th Congress of Serbian neuroscience society with international participation; 2023 May 31 - Jun 2; Belgrade, Serbia (2023):66,
https://hdl.handle.net/21.15107/rcub_ibiss_5858 .

TY  - JOUR
AU  - Jovanović Macura, Irena
AU  - Đuričić, Ivana
AU  - Major, Tamara
AU  - Milanović, Desanka
AU  - Brkić, Marjana
AU  - Šobajić, Slađana
AU  - Kanazir, Selma
AU  - Ivković, Sanja
PY  - 2022
UR  - https://linkinghub.elsevier.com/retrieve/pii/S1756464622003723
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/5174
AB  - The recommended fish oil (FO) supplementation doses often yield low omega-3 polyunsaturated fatty acids (PUFAs) tissue bioavailability, and higher doses (up to 10 g per day) have been increasingly recommended. However, the exact effects of such FO supplementation on the healthy retina and retinal pigmented epithelium (RPE) are unknown. Our study showed that the high dose FO treatment did not imbalance the rigorous docosahexaenoic acid (DHA, C22:6n3) homeostasis in the retina and RPE in the three-month-old female B6/SLJ mice. Instead, we have found the significant increase in the expression of Mfsd2a, the main DHA transporter. Mfsd2a is also an essential regulator of blood vessel transcytosis and the decrease in Mfsd2a expression can be a risk factor for developing leaky blood vessels. Therefore, the high-dose FO supplementation emerges as the prophylactic fortifier of the retinal blood vessels.
T2  - Journal of Functional Foods
T1  - The high-dose fish oil supplementation increased Mfsd2a expression without altering DHA levels in the retina of healthy mice
VL  - 99
DO  - 10.1016/j.jff.2022.105302
SP  - 105302
ER  - 

@article{
author = "Jovanović Macura, Irena and Đuričić, Ivana and Major, Tamara and Milanović, Desanka and Brkić, Marjana and Šobajić, Slađana and Kanazir, Selma and Ivković, Sanja",
year = "2022",
abstract = "The recommended fish oil (FO) supplementation doses often yield low omega-3 polyunsaturated fatty acids (PUFAs) tissue bioavailability, and higher doses (up to 10 g per day) have been increasingly recommended. However, the exact effects of such FO supplementation on the healthy retina and retinal pigmented epithelium (RPE) are unknown. Our study showed that the high dose FO treatment did not imbalance the rigorous docosahexaenoic acid (DHA, C22:6n3) homeostasis in the retina and RPE in the three-month-old female B6/SLJ mice. Instead, we have found the significant increase in the expression of Mfsd2a, the main DHA transporter. Mfsd2a is also an essential regulator of blood vessel transcytosis and the decrease in Mfsd2a expression can be a risk factor for developing leaky blood vessels. Therefore, the high-dose FO supplementation emerges as the prophylactic fortifier of the retinal blood vessels.",
journal = "Journal of Functional Foods",
title = "The high-dose fish oil supplementation increased Mfsd2a expression without altering DHA levels in the retina of healthy mice",
volume = "99",
doi = "10.1016/j.jff.2022.105302",
pages = "105302"
}

Jovanović Macura, I., Đuričić, I., Major, T., Milanović, D., Brkić, M., Šobajić, S., Kanazir, S.,& Ivković, S.. (2022). The high-dose fish oil supplementation increased Mfsd2a expression without altering DHA levels in the retina of healthy mice. in Journal of Functional Foods, 99, 105302.
https://doi.org/10.1016/j.jff.2022.105302

Jovanović Macura I, Đuričić I, Major T, Milanović D, Brkić M, Šobajić S, Kanazir S, Ivković S. The high-dose fish oil supplementation increased Mfsd2a expression without altering DHA levels in the retina of healthy mice. in Journal of Functional Foods. 2022;99:105302.
doi:10.1016/j.jff.2022.105302 .

Jovanović Macura, Irena, Đuričić, Ivana, Major, Tamara, Milanović, Desanka, Brkić, Marjana, Šobajić, Slađana, Kanazir, Selma, Ivković, Sanja, "The high-dose fish oil supplementation increased Mfsd2a expression without altering DHA levels in the retina of healthy mice" in Journal of Functional Foods, 99 (2022):105302,
https://doi.org/10.1016/j.jff.2022.105302 . .

TY  - JOUR
AU  - Ivković, Sanja
AU  - Major, Tamara
AU  - Mitić, Miloš
AU  - Lončarević-Vasiljković, Nataša
AU  - Jović, Milena
AU  - Adžić, Miroslav
PY  - 2022
UR  - https://linkinghub.elsevier.com/retrieve/pii/S0024320522001709
UR  - http://www.ncbi.nlm.nih.gov/pubmed/35283177
UR  - http://radar.ibiss.bg.ac.rs/handle/123456789/4942
AB  - The brain is the softest organ in the body, and any change in the mechanical properties of the tissue induces the activation of glial cells, astrocytes and microglia. Amyloid plaques, one of the main pathological features of Alzheimer's disease (AD), are substantially harder than the surrounding brain tissue and can activate astrocytes and microglia resulting in the glial engulfment of plaques. Durotaxis, a migratory preference towards stiffer tissue, is prompting microglia to form a mechanical barrier around plaques reducing amyloid β (Aβ) induced neurotoxicity. Mechanoreceptors are highly expressed in the brain, particularly in microglia. The large increase in the expression of the mechanoreceptor Piezo1 was observed in the brains from AD animal models and AD patients in plaque encompassing glia. Importantly, Piezo1 function is regulated via force-from-lipids through the lipid composition of the membrane and membranous incorporation of polyunsaturated fatty acids (PUFAs) can affect the function of Piezo1 altering mechanosensitive properties of the cell. On the other hand, PUFAs dietary supplementation can alter microglial polarization, the envelopment of amyloid plaques, and immune response and Piezo1 activity was implicated in the similar modulations of microglia behavior. Finally, PUFAs treatment is currently in use in medical trials as the therapy for sickle cell anemia, a disease linked with the mutations in Piezo1. Further studies are needed to elucidate the connection between PUFAs, Piezo1 expression, and microglia behavior in the AD brain. These findings could open new possibilities in harnessing microglia in AD and in developing novel therapeutic strategies.
T2  - Life sciences
T1  - Fatty acids as biomodulators of Piezo1 mediated glial mechanosensitivity in Alzheimer's disease.
VL  - 297
DO  - 10.1016/j.lfs.2022.120470
SP  - 120470
ER  - 

@article{
author = "Ivković, Sanja and Major, Tamara and Mitić, Miloš and Lončarević-Vasiljković, Nataša and Jović, Milena and Adžić, Miroslav",
year = "2022",
abstract = "The brain is the softest organ in the body, and any change in the mechanical properties of the tissue induces the activation of glial cells, astrocytes and microglia. Amyloid plaques, one of the main pathological features of Alzheimer's disease (AD), are substantially harder than the surrounding brain tissue and can activate astrocytes and microglia resulting in the glial engulfment of plaques. Durotaxis, a migratory preference towards stiffer tissue, is prompting microglia to form a mechanical barrier around plaques reducing amyloid β (Aβ) induced neurotoxicity. Mechanoreceptors are highly expressed in the brain, particularly in microglia. The large increase in the expression of the mechanoreceptor Piezo1 was observed in the brains from AD animal models and AD patients in plaque encompassing glia. Importantly, Piezo1 function is regulated via force-from-lipids through the lipid composition of the membrane and membranous incorporation of polyunsaturated fatty acids (PUFAs) can affect the function of Piezo1 altering mechanosensitive properties of the cell. On the other hand, PUFAs dietary supplementation can alter microglial polarization, the envelopment of amyloid plaques, and immune response and Piezo1 activity was implicated in the similar modulations of microglia behavior. Finally, PUFAs treatment is currently in use in medical trials as the therapy for sickle cell anemia, a disease linked with the mutations in Piezo1. Further studies are needed to elucidate the connection between PUFAs, Piezo1 expression, and microglia behavior in the AD brain. These findings could open new possibilities in harnessing microglia in AD and in developing novel therapeutic strategies.",
journal = "Life sciences",
title = "Fatty acids as biomodulators of Piezo1 mediated glial mechanosensitivity in Alzheimer's disease.",
volume = "297",
doi = "10.1016/j.lfs.2022.120470",
pages = "120470"
}

Ivković, S., Major, T., Mitić, M., Lončarević-Vasiljković, N., Jović, M.,& Adžić, M.. (2022). Fatty acids as biomodulators of Piezo1 mediated glial mechanosensitivity in Alzheimer's disease.. in Life sciences, 297, 120470.
https://doi.org/10.1016/j.lfs.2022.120470

Ivković S, Major T, Mitić M, Lončarević-Vasiljković N, Jović M, Adžić M. Fatty acids as biomodulators of Piezo1 mediated glial mechanosensitivity in Alzheimer's disease.. in Life sciences. 2022;297:120470.
doi:10.1016/j.lfs.2022.120470 .

Ivković, Sanja, Major, Tamara, Mitić, Miloš, Lončarević-Vasiljković, Nataša, Jović, Milena, Adžić, Miroslav, "Fatty acids as biomodulators of Piezo1 mediated glial mechanosensitivity in Alzheimer's disease." in Life sciences, 297 (2022):120470,
https://doi.org/10.1016/j.lfs.2022.120470 . .