CD36 gene polymorphism is associated with Alzheimer's disease

Šerý, Omar; Janoutová, Jana; Ewerlingová, Laura; Hálová, Alice; Lochman, Jan; Janout, Vladimí­r; Khan, Naim Akhtar; Balcar, Vladimír J.

doi:10.1016/j.biochi.2017.01.009

Cited by 32 publications

(16 citation statements)

References 49 publications

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“…Previous reports have shown that CD36 is closely involved in phagocytosis of fAb [39]. Together, Šerý et al reported that CD36 polymorphism related to AD develop [57]. We found that miR485-3p ASO was able to promote Aβ phagocytosis by increasing the expression of CD36 receptors.…”

Section: Discussionsupporting

confidence: 67%

Reducing miR485-3p ameliorates Alzheimer`s disease pathology by regulation of amyloid beta and neuro-inflammation

Koh¹,

Jang²,

Tae³

et al. 2020

Preprint

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Background Alzheimer`s disease (AD) is a progressive neurodegenerative disease worldwide. Accumulation of amyloid-β (Aβ), neurofibrillary tangles and neuroinflammation play the important neuro-pathology in patients with AD. miRNA is multifunctional and involved in physiological and pathological processes. Recently, microRNAs have been linked to neurodegenerative diseases. However, it is little known whether miRNA dysregulation contributes to AD pathology progression such as Ab processing, phagocytosis and neuroinflammation. Here, we identify miR485-3p as a novel modulator of AD pathology in 5XFAD mice. Methods To study the role of miR485-3p in AD, we used in control or miR485-3p antisense oligonucleotides (miR485-3p ASO) injected 5XFAD mouse model. Changes of Ab processing, clearance and inflammation were analyzed by biochemical method in vitro and in vivo. Results This study suggests that miR485-3p, a novel miRNA targeting SIRT1 may contribute to pathogenesis in an AD mouse. We found SIRT1 is significantly reduced in the precentral gyrus of Alzheimer patient`s and in 5XFAD mice. To determine whether the inhibition of miRNA 485-3p would affect AD pathology, we studied the effect of the antisense oligo in the brain of 5XFAD mice through direct intracerebral ventricular injection with miR485-3p ASO. We demonstrated that miR485-3p ASO significantly reduced Aβ plaque and amyloid biosynthetic enzyme. Importantly, the attenuation of Aβ plaques through miR485-3p ASO was mediated through Aβ phagocytic activity of glial cells, by which it can directly target CD36. MiR485-3p ASO also decreased inflammatory responses. Collectively, these responses inhibited neuronal loss caused by Aβ lead to improvements of cognitive impairment. Conclusion Our data provide evidence for the molecular mechanisms which underlie the miR485-3p ASO responses in an AD mouse model. These results suggest that attenuating miRNA 485-3p levels might represent a novel therapeutic approach in AD.

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Section: Discussionsupporting

confidence: 67%

Reducing miR485-3p ameliorates Alzheimer`s disease pathology by regulation of amyloid beta and neuro-inflammation

Koh¹,

Jang²,

Tae³

et al. 2020

Preprint

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“…Here, we show that treatment with miR485-3p ASO increases glial recruitment around A plaques and enhanced glial Auptake in vitro and in vivo. Previous reports have shown that CD36 is closely involved in phagocytosis of fA [39]TogetherŠerý et al reported that CD36 polymorphism related to AD develop [57]. We found that miR485-3p ASO was able to promote A phagocytosis by increasing the expression of CD36 receptors.…”

Section: Discussionsupporting

confidence: 54%

Reducing miR485-3p ameliorates Alzheimer`s disease pathology by regulation of amyloid beta and neuro-inflammation

Koh¹,

Jang²,

Tae³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Alzheimer`s disease (AD) is a progressive neurodegenerative disease worldwide. Accumulation of amyloid-β (Aβ), neurofibrillary tangles and neuroinflammation play the important neuro-pathology in patients with AD. miRNA is multifunctional and involved in physiological and pathological processes. Recently, microRNAs have been linked to neurodegenerative diseases. However, it is little known whether miRNA dysregulation contributes to AD pathology progression such as Aβ processing, phagocytosis and neuroinflammation. Here, we identify miR485-3p as a novel modulator of AD pathology in 5XFAD mice. Methods To study the role of miR485-3p in AD, we used in control or miR485-3p antisense oligonucleotides (miR485-3p ASO) injected 5XFAD mouse model. Changes of Aβ processing and clearance and inflammation were analyzed by biochemical method in vitro and in vivo. Result This study suggests that miR485-3p, a novel miRNA targeting SIRT1 may contribute to pathogenesis in an AD mouse. We found SIRT1 is significantly reduced in the precentral gyrus of Alzheimer patient`s and in 5XFAD mice. To determine whether the inhibition of miRNA 485-3p would affect AD pathology, we studied the effect of the antisense oligo in the brain of 5XFAD mice through direct intracerebral ventricular injection with miR485-3p ASO. We demonstrated that miR485-3p ASO significantly reduced Aβ plaque and amyloid biosynthetic enzyme. Importantly, the attenuation of Aβ plaques through miR485-3p ASO was mediated through Aβ phagocytic activity of glial cells, by which it can directly target CD36. MiR485-3p ASO also decreased inflammatory responses. Collectively, these responses inhibited neuronal loss caused by Aβ lead to improvements of cognitive impairment. Conclusion Our data provide evidence for the molecular mechanisms which underlie the miR485-3p ASO responses in an AD mouse model. These results suggest that attenuating miRNA 485-3p levels might represent a novel therapeutic approach in AD.

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“…On the other hand, increasing evidence suggests a role of innate immunity cells and receptors in AD pathogenesis 62 . While microglial cells, resident brain immune cells, may degrade Aβ and shield the brain from the deleterious effects of amyloid 62, 65 , innate immunity receptors, including CR1, TREM2, CD33, and CD36, among others, have been linked to increased AD susceptibility in genome-wide association studies 22, 62 . However, it remained unclear how innate immunity exerts its harmful effects in AD 36 .…”

Section: Discussionmentioning

confidence: 99%

“…For example, Aβ suppresses the increase in CBF evoked by synaptic activity, a vital homeostatic response that matches oxygen and glucose delivery to the energy needs of the active brain, and disrupts endothelial function 16–21 . These neurovascular alterations are mediated by the innate immunity receptor CD36, polymorphisms of which are linked to AD susceptibility 22 . CD36 binds Aβ and leads to Nox2-dependent production of reactive oxygen species (ROS) 23–27 .…”

Section: Introductionmentioning

confidence: 99%

Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides

Park

Uekawa

García-Bonilla

et al. 2017

Circulation Research

189

213

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Rationale Increasing evidence indicates that alterations of the cerebral microcirculation may play a role in Alzheimer’s disease (AD), the leading cause of late-life dementia. The amyloid-β peptide (Aβ), a key pathogenic factor in AD, induces profound alterations in neurovascular regulation through the innate immunity receptor CD36, which, in turn, activates a Nox2-containing NADPH oxidase leading to cerebrovascular oxidative stress. Brain perivascular macrophages (PVM) located in the perivascular space, a major site of brain Aβ collection and clearance, are juxtaposed to the wall of intracerebral resistance vessels and are a powerful source of reactive oxygen species (ROS). Objective We tested the hypothesis that PVM are the main source of ROS responsible for the cerebrovascular actions of Aβ, and that CD36 and Nox2 in PVM are the molecular substrates of the effect. Methods and Results Selective depletion of PVM using intracerebroventricular injection of clodronate abrogates the ROS production and cerebrovascular dysfunction induced by Aβ applied directly to the cerebral cortex, administered intravascularly or overproduced in the brain of transgenic mice expressing mutated forms of the amyloid precursor protein (Tg2576 mice). In addition, using bone marrow chimeras we demonstrate that PVM are the cells expressing CD36 and Nox2 responsible for the dysfunction. Thus, deletion of CD36 or Nox2 from PVM abrogates the deleterious vascular effects of Aβ, whereas wild-type PVM reconstitute the vascular dysfunction in CD36-null mice. Conclusions The data identify PVM as a previously unrecognized effector of the damaging neurovascular actions of Aβ and unveil a new mechanism by which brain-resident innate immune cells and their receptors may contribute to the pathobiology of AD.

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CD36 gene polymorphism is associated with Alzheimer's disease

Cited by 32 publications

References 49 publications

Reducing miR485-3p ameliorates Alzheimer`s disease pathology by regulation of amyloid beta and neuro-inflammation

Reducing miR485-3p ameliorates Alzheimer`s disease pathology by regulation of amyloid beta and neuro-inflammation

Reducing miR485-3p ameliorates Alzheimer`s disease pathology by regulation of amyloid beta and neuro-inflammation

Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides

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