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Article ; Online: Three-dimensional object geometry of mitochondria-associated signal: 3-D analysis pipeline for two-photon image stacks of cerebrovascular endothelial mitochondria.

Gonzales, Christopher R / Moca, Eric N / Chandra, Partha K / Busija, David W / Rutkai, Ibolya

American journal of physiology. Heart and circulatory physiology

2024 Volume 326, Issue 5, Page(s) H1291–H1303

Abstract: Increasing evidence indicates the role of mitochondrial and vascular dysfunction in aging and aging-associated pathologies; however, the exact mechanisms and chronological processes remain enigmatic. High-energy demand organs, such as the brain, depend ... ...

Abstract	Increasing evidence indicates the role of mitochondrial and vascular dysfunction in aging and aging-associated pathologies; however, the exact mechanisms and chronological processes remain enigmatic. High-energy demand organs, such as the brain, depend on the health of their mitochondria and vasculature for the maintenance of normal functions, therefore representing vulnerable targets for aging. This methodology article describes an analysis pipeline for three-dimensional (3-D) mitochondria-associated signal geometry of two-photon image stacks of brain vasculature. The analysis methods allow the quantification of mitochondria-associated signals obtained in real time in their physiological environment. In addition, signal geometry results will allow the extrapolation of fission and fusion events under normal conditions, during aging, or in the presence of different pathological conditions, therefore contributing to our understanding of the role mitochondria play in a variety of aging-associated diseases with vascular etiology.
MeSH term(s)	Mitochondria/metabolism ; Imaging, Three-Dimensional ; Animals ; Microscopy, Fluorescence, Multiphoton/methods ; Endothelial Cells/metabolism ; Mitochondrial Dynamics ; Brain/blood supply ; Brain/metabolism ; Mice ; Aging/metabolism
Language	English
Publishing date	2024-03-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	603838-4
ISSN	1522-1539 ; 0363-6135
ISSN (online)	1522-1539
ISSN	0363-6135
DOI	10.1152/ajpheart.00101.2024
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Article ; Online: Targeting mitochondria in the aged cerebral vasculature with SS-31, a proteomic study of brain microvessels.

Seman, Abigail / Chandra, Partha K / Byrum, Stephanie D / Mackintosh, Samuel G / Gies, Allen J / Busija, David W / Rutkai, Ibolya

GeroScience

2023 Volume 45, Issue 5, Page(s) 2951–2965

Abstract: Cognitive impairment and dementias during aging such as Alzheimer's disease are linked to functional decline and structural alterations of the brain microvasculature. Although mechanisms leading to microvascular changes during aging are not clear, loss ... ...

Abstract	Cognitive impairment and dementias during aging such as Alzheimer's disease are linked to functional decline and structural alterations of the brain microvasculature. Although mechanisms leading to microvascular changes during aging are not clear, loss of mitochondria, and reduced efficiency of remaining mitochondria appear to play a major role. Pharmacological agents, such as SS-31, which target mitochondria have been shown to be effective during aging and diseases; however, the benefit to mitochondrial- and non-mitochondrial proteins in the brain microvasculature has not been examined. We tested whether attenuation of aging-associated changes in the brain microvascular proteome via targeting mitochondria represents a therapeutic option for the aging brain. We used aged male (> 18 months) C57Bl6/J mice treated with a mitochondria-targeted tetrapeptide, SS-31, or vehicle saline. Cerebral blood flow (CBF) was determined using laser speckle imaging during a 2-week treatment period. Then, isolated cortical microvessels (MVs) composed of end arterioles, capillaries, and venules were used for Orbitrap Eclipse Tribrid mass spectrometry. CBF was similar among the groups, whereas bioinformatic analysis revealed substantial differences in protein abundance of cortical MVs between SS-31 and vehicle. We identified 6267 proteins, of which 12% were mitochondria-associated. Of this 12%, 107 were significantly differentially expressed and were associated with oxidative phosphorylation, metabolism, the antioxidant defense system, or mitochondrial dynamics. Administration of SS-31 affected many non-mitochondrial proteins. Our findings suggest that mitochondria in the microvasculature represent a therapeutic target in the aging brain, and widespread changes in the proteome may underlie the rejuvenating actions of SS-31 in aging.
MeSH term(s)	Mice ; Animals ; Male ; Proteome/metabolism ; Proteome/pharmacology ; Proteomics/methods ; Mitochondria/metabolism ; Brain/metabolism ; Microvessels/metabolism
Chemical Substances	Proteome
Language	English
Publishing date	2023-07-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2886586-8
ISSN	2509-2723 ; 2509-2715
ISSN (online)	2509-2723
ISSN	2509-2715
DOI	10.1007/s11357-023-00845-y
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Article ; Online: Fibrinogen in mice cerebral microvessels induces blood-brain barrier dysregulation with aging via a dynamin-related protein 1-dependent pathway.

Chandra, Partha K / Panner Selvam, Manesh Kumar / Castorena-Gonzalez, Jorge A / Rutkai, Ibolya / Sikka, Suresh C / Mostany, Ricardo / Busija, David W

GeroScience

2023 Volume 46, Issue 1, Page(s) 395–415

Abstract: We previously reported evidence that oxidative stress during aging leads to adverse protein profile changes of brain cortical microvessels (MVs: end arterioles, capillaries, and venules) that affect mRNA/protein stability, basement membrane integrity, ... ...

Abstract	We previously reported evidence that oxidative stress during aging leads to adverse protein profile changes of brain cortical microvessels (MVs: end arterioles, capillaries, and venules) that affect mRNA/protein stability, basement membrane integrity, and ATP synthesis capacity in mice. As an extension of our previous study, we also found that proteins which comprise the blood-brain barrier (BBB) and regulate mitochondrial quality control were also significantly decreased in the mice's cortical MVs with aging. Interestingly, the neuroinflammatory protein fibrinogen (Fgn) was increased in mice brain MVs, which corresponds with clinical reports indicating that the plasma Fgn concentration increased progressively with aging. In this study, protein-protein interaction network analysis indicated that high expression of Fgn is linked with downregulated expression of both BBB- and mitochondrial fission/fusion-related proteins in mice cortical MVs with aging. To investigate the mechanism of Fgn action, we observed that 2 mg/mL or higher concentration of human plasma Fgn changed cell morphology, induced cytotoxicity, and increased BBB permeability in primary human brain microvascular endothelial cells (HBMECs). The BBB tight junction proteins were significantly decreased with increasing concentration of human plasma Fgn in primary HBMECs. Similarly, the expression of phosphorylated dynamin-related protein 1 (pDRP1) and other mitochondrial fission/fusion-related proteins were also significantly reduced in Fgn-treated HBMECs. Interestingly, DRP1 knockdown by shRNA(h) resulted in the reduction of both BBB- and mitochondrial fission/fusion-related proteins in HBMECs. Our results suggest that elevated Fgn downregulates DRP1, leading to mitochondrial-dependent endothelial and BBB dysfunction in the brain microvasculature.
MeSH term(s)	Mice ; Humans ; Animals ; Blood-Brain Barrier/metabolism ; Endothelial Cells ; Fibrinogen/metabolism ; Microvessels/metabolism ; Dynamins/metabolism
Chemical Substances	Fibrinogen (9001-32-5) ; Dynamins (EC 3.6.5.5)
Language	English
Publishing date	2023-10-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2886586-8
ISSN	2509-2723 ; 2509-2715
ISSN (online)	2509-2723
ISSN	2509-2715
DOI	10.1007/s11357-023-00988-y
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Article ; Online: Detrimental effects of transient cerebral ischemia on middle cerebral artery mitochondria in female rats.

Rutkai, Ibolya / Merdzo, Ivan / Wunnava, Sanjay / McNulty, Catherine / Chandra, Partha K / Katakam, Prasad V / Busija, David W

American journal of physiology. Heart and circulatory physiology

2022 Volume 323, Issue 6, Page(s) H1343–H1351

Abstract: Mitochondrial numbers and dynamics in brain blood vessels differ between young male and female rats under physiological conditions, but how these differences are affected by stroke is unclear. In males, we found that mitochondrial numbers, possibly due ... ...

Abstract	Mitochondrial numbers and dynamics in brain blood vessels differ between young male and female rats under physiological conditions, but how these differences are affected by stroke is unclear. In males, we found that mitochondrial numbers, possibly due to mitochondrial fission, in large middle cerebral arteries (MCAs) increased following transient middle cerebral artery occlusion (tMCAO). However, mitochondrial effects of stroke on MCAs of female rats have not been studied. To address this disparity, we conducted morphological, biochemical, and functional studies using electron microscopy, Western blot, mitochondrial respiration, and Ca
MeSH term(s)	Female ; Male ; Rats ; Animals ; Ischemic Attack, Transient ; Middle Cerebral Artery ; Rats, Sprague-Dawley ; Stroke
Language	English
Publishing date	2022-11-11
Publishing country	United States
Document type	Journal Article
ZDB-ID	603838-4
ISSN	1522-1539 ; 0363-6135
ISSN (online)	1522-1539
ISSN	0363-6135
DOI	10.1152/ajpheart.00346.2022
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Book: THE EFFECT OF HYPEROXIA ON CEREBRAL BLOOD FLOW IN THE UNANESTHETIZED PONY

BUSIJA, DAVID W.

1978

Title variant	EFFECT OF HYPEROXIA ON CEREBRAL BLOOD FLOW IN THE UNANESTHETIZED PONY
Size	70 BL.
Document type	Book
Note	LAWRENCE, KAN., UNIV. OF KANSAS, DISS., 1978
HBZ-ID	HT002743021
Database	Catalogue ZB MED Medicine, Health

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Article ; Online: Mitochondrial mechanisms in cerebral vascular control: shared signaling pathways with preconditioning.

Busija, David W / Katakam, Prasad V

Journal of vascular research

2014 Volume 51, Issue 3, Page(s) 175–189

Abstract: Mitochondrial-initiated events protect the neurovascular unit against lethal stress via a process called preconditioning, which independently promotes changes in cerebrovascular tone through shared signaling pathways. Activation of adenosine triphosphate ...

Abstract	Mitochondrial-initiated events protect the neurovascular unit against lethal stress via a process called preconditioning, which independently promotes changes in cerebrovascular tone through shared signaling pathways. Activation of adenosine triphosphate (ATP)-dependent potassium channels on the inner mitochondrial membrane (mitoKATP channels) is a specific and dependable way to induce protection of neurons, astroglia, and cerebral vascular endothelium. Through the opening of mitoKATP channels, mitochondrial depolarization leads to activation of protein kinases and transient increases in cytosolic calcium (Ca(2+)) levels that activate terminal mechanisms that protect the neurovascular unit against lethal stress. The release of reactive oxygen species from mitochondria has similar protective effects. Signaling elements of the preconditioning pathways also are involved in the regulation of vascular tone. Activation of mitoKATP channels in cerebral arteries causes vasodilation, with cell-specific contributions from the endothelium, vascular smooth muscles, and nerves. Preexisting chronic conditions, such as insulin resistance and/or diabetes, prevent preconditioning and impair relaxation to mitochondrial-centered responses in cerebral arteries. Surprisingly, mitochondrial activation after anoxic or ischemic stress appears to protect cerebral vascular endothelium and promotes the restoration of blood flow; therefore, mitochondria may represent an important, but underutilized target in attenuating vascular dysfunction and brain injury in stroke patients.
MeSH term(s)	Benzimidazoles/pharmacology ; Brain/blood supply ; Brain Ischemia/drug therapy ; Brain Ischemia/physiopathology ; Cerebral Arteries ; Ischemic Preconditioning ; Membrane Potential, Mitochondrial/drug effects ; Membrane Potential, Mitochondrial/physiology ; Mitochondria/drug effects ; Mitochondria/physiology ; Mitochondria/ultrastructure ; Muscle, Smooth, Vascular/drug effects ; Potassium Channels/physiology ; Reactive Oxygen Species/metabolism ; Signal Transduction
Chemical Substances	Benzimidazoles ; Potassium Channels ; Reactive Oxygen Species ; mitochondrial K(ATP) channel ; NS 1619 (153587-01-0)
Language	English
Publishing date	2014-05-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1105259-4
ISSN	1423-0135 ; 1018-1172
ISSN (online)	1423-0135
ISSN	1018-1172
DOI	10.1159/000360765
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Zs.A 513: Show issues

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Article ; Online: Circulating Plasma Exosomal Proteins of Either SHIV-Infected Rhesus Macaque or HIV-Infected Patient Indicates a Link to Neuropathogenesis.

Chandra, Partha K / Braun, Stephen E / Maity, Sudipa / Castorena-Gonzalez, Jorge A / Kim, Hogyoung / Shaffer, Jeffrey G / Cikic, Sinisa / Rutkai, Ibolya / Fan, Jia / Guidry, Jessie J / Worthylake, David K / Li, Chenzhong / Abdel-Mageed, Asim B / Busija, David W

Viruses

2023 Volume 15, Issue 3

Abstract: Despite the suppression of human immunodeficiency virus (HIV) replication by combined antiretroviral therapy (cART), 50-60% of HIV-infected patients suffer from HIV-associated neurocognitive disorders (HAND). Studies are uncovering the role of ... ...

Abstract	Despite the suppression of human immunodeficiency virus (HIV) replication by combined antiretroviral therapy (cART), 50-60% of HIV-infected patients suffer from HIV-associated neurocognitive disorders (HAND). Studies are uncovering the role of extracellular vesicles (EVs), especially exosomes, in the central nervous system (CNS) due to HIV infection. We investigated links among circulating plasma exosomal (crExo) proteins and neuropathogenesis in simian/human immunodeficiency virus (SHIV)-infected rhesus macaques (RM) and HIV-infected and cART treated patients (Patient-Exo). Isolated EVs from SHIV-infected (SHIV-Exo) and uninfected (CTL-Exo) RM were predominantly exosomes (particle size < 150 nm). Proteomic analysis quantified 5654 proteins, of which 236 proteins (~4%) were significantly, differentially expressed (DE) between SHIV-/CTL-Exo. Interestingly, different CNS cell specific markers were abundantly expressed in crExo. Proteins involved in latent viral reactivation, neuroinflammation, neuropathology-associated interactive as well as signaling molecules were expressed at significantly higher levels in SHIV-Exo than CTL-Exo. However, proteins involved in mitochondrial biogenesis, ATP production, autophagy, endocytosis, exocytosis, and cytoskeleton organization were significantly less expressed in SHIV-Exo than CTL-Exo. Interestingly, proteins involved in oxidative stress, mitochondrial biogenesis, ATP production, and autophagy were significantly downregulated in primary human brain microvascular endothelial cells exposed with HIV+/cART+ Patient-Exo. We showed that Patient-Exo significantly increased blood-brain barrier permeability, possibly due to loss of platelet endothelial cell adhesion molecule-1 protein and actin cytoskeleton structure. Our novel findings suggest that circulating exosomal proteins expressed CNS cell markers-possibly associated with viral reactivation and neuropathogenesis-that may elucidate the etiology of HAND.
MeSH term(s)	Animals ; Humans ; Macaca mulatta ; HIV Infections/complications ; Simian Acquired Immunodeficiency Syndrome/complications ; HIV-1 ; Endothelial Cells ; Proteomics ; Disease Models, Animal ; Simian Immunodeficiency Virus ; Adenosine Triphosphate ; Viral Load
Chemical Substances	Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2023-03-21
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2516098-9
ISSN	1999-4915 ; 1999-4915
ISSN (online)	1999-4915
ISSN	1999-4915
DOI	10.3390/v15030794
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Article ; Online: Transcriptome analysis reveals sexual disparities in gene expression in rat brain microvessels.

Chandra, Partha K / Cikic, Sinisa / Baddoo, Melody C / Rutkai, Ibolya / Guidry, Jessie J / Flemington, Erik K / Katakam, Prasad Vg / Busija, David W

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

2021 Volume 41, Issue 9, Page(s) 2311–2328

Abstract: Sex is an important determinant of brain microvessels (MVs) function and susceptibility to cerebrovascular and neurological diseases, but underlying mechanisms are unclear. Using high throughput RNA sequencing analysis, we examined differentially ... ...

Abstract	Sex is an important determinant of brain microvessels (MVs) function and susceptibility to cerebrovascular and neurological diseases, but underlying mechanisms are unclear. Using high throughput RNA sequencing analysis, we examined differentially expressed (DE) genes in brain MVs from young, male, and female rats. Bioinformatics analysis of the 23,786 identified genes indicates that 298 (1.2%) genes were DE using False Discovery Rate criteria (FDR; p < 0.05), of which 119 (40%) and 179 (60%) genes were abundantly expressed in male and female MVs, respectively. Nucleic acid binding, enzyme modulator, and transcription factor were the top three DE genes, which were more highly expressed in male than female MVs. Synthesis of glycosylphosphatidylinositol (GPI), biosynthesis of GPI-anchored proteins, steroid and cholesterol synthesis, were the top three significantly enriched canonical pathways in male MVs. In contrast, respiratory chain, ribosome, and 3 ́-UTR-mediated translational regulation were the top three enriched canonical pathways in female MVs. Different gene functions of MVs were validated by proteomic analysis and western blotting. Our novel findings reveal major sex disparities in gene expression and canonical pathways of MVs and these differences provide a foundation to study the underlying mechanisms and consequences of sex-dependent differences in cerebrovascular and other neurological diseases.
MeSH term(s)	Animals ; Brain/physiopathology ; Female ; Gene Expression Profiling/methods ; Gene Expression Regulation/genetics ; Male ; Microvessels/physiopathology ; Proteomics/methods ; Rats ; Rats, Sprague-Dawley ; Sex Characteristics
Language	English
Publishing date	2021-03-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604628-9
ISSN	1559-7016 ; 0271-678X
ISSN (online)	1559-7016
ISSN	0271-678X
DOI	10.1177/0271678X21999553
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Zs.A 1663: Show issues

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Article ; Online: Effects of aging on protein expression in mice brain microvessels: ROS scavengers, mRNA/protein stability, glycolytic enzymes, mitochondrial complexes, and basement membrane components.

Chandra, Partha K / Cikic, Sinisa / Rutkai, Ibolya / Guidry, Jessie J / Katakam, Prasad V G / Mostany, Ricardo / Busija, David W

GeroScience

2021 Volume 44, Issue 1, Page(s) 371–388

Abstract: Differentially expressed (DE) proteins in the cortical microvessels (MVs) of young, middle-aged, and old male and female mice were evaluated using discovery-based proteomics analysis (> 4,200 quantified proteins/group). Most DE proteins (> 90%) showed no ...

Abstract	Differentially expressed (DE) proteins in the cortical microvessels (MVs) of young, middle-aged, and old male and female mice were evaluated using discovery-based proteomics analysis (> 4,200 quantified proteins/group). Most DE proteins (> 90%) showed no significant differences between the sexes; however, some significant DE proteins showing sexual differences in MVs decreased from young (8.3%), to middle-aged (3.7%), to old (0.5%) mice. Therefore, we combined male and female data for age-dependent comparisons but noted sex differences for examination. Key proteins involved in the oxidative stress response, mRNA or protein stability, basement membrane (BM) composition, aerobic glycolysis, and mitochondrial function were significantly altered with aging. Relative abundance of superoxide dismutase-1/-2, catalase and thioredoxin were reduced with aging. Proteins participating in either mRNA degradation or pre-mRNA splicing were significantly increased in old mice MVs, whereas protein stabilizing proteins decreased. Glycolytic proteins were not affected in middle age, but the relative abundance of these proteins decreased in MVs of old mice. Although most of the 41 examined proteins composing mitochondrial complexes I-V were reduced in old mice, six of these proteins showed a significant reduction in middle-aged mice, but the relative abundance increased in fourteen proteins. Nidogen, collagen, and laminin family members as well as perlecan showed differing patterns during aging, indicating BM reorganization starting in middle age. We suggest that increased oxidative stress during aging leads to adverse protein profile changes of brain cortical MVs that affect mRNA/protein stability, BM integrity, and ATP synthesis capacity.
MeSH term(s)	Animals ; Basement Membrane ; Brain/metabolism ; Female ; Glycolysis/genetics ; Male ; Mice ; Microvessels/metabolism ; Mitochondria/metabolism ; Protein Stability ; Proteomics ; RNA Stability ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Reactive Oxygen Species/metabolism
Chemical Substances	RNA, Messenger ; Reactive Oxygen Species
Language	English
Publishing date	2021-10-28
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2886586-8
ISSN	2509-2723 ; 2509-2715
ISSN (online)	2509-2723
ISSN	2509-2715
DOI	10.1007/s11357-021-00468-1
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Article ; Online: Latent HIV-Exosomes Induce Mitochondrial Hyperfusion Due to Loss of Phosphorylated Dynamin-Related Protein 1 in Brain Endothelium.

Chandra, Partha K / Rutkai, Ibolya / Kim, Hogyoung / Braun, Stephen E / Abdel-Mageed, Asim B / Mondal, Debasis / Busija, David W

Molecular neurobiology

2021 Volume 58, Issue 6, Page(s) 2974–2989

Abstract: Damage to the cerebral vascular endothelium is a critical initiating event in the development of HIV-1-associated neurocognitive disorders. To study the role of mitochondria in cerebral endothelial dysfunction, we investigated how exosomes, isolated from ...

Abstract	Damage to the cerebral vascular endothelium is a critical initiating event in the development of HIV-1-associated neurocognitive disorders. To study the role of mitochondria in cerebral endothelial dysfunction, we investigated how exosomes, isolated from both cell lines with integrated provirus and HIV-1 infected primary cells (HIV-exosomes), accelerate the dysfunction of primary human brain microvascular endothelial cells (HBMVECs) by inducing mitochondrial hyperfusion, and reducing the expression of phosphorylated endothelial nitric oxide synthase (p-eNOS). The quantitative analysis of the extracellular vesicles (EVs) indicates that the isolated EVs were predominantly exosomes. It was further supported by the detection of exosomal markers, and the absence of large EV-related protein in the isolated EVs. The exosomes were readily taken up by primary HBMVECs. HIV-exosomes induce cellular and mitochondrial superoxide production but reduce mitochondrial membrane potential in HBMVECs. HIV-exosomes increase mitochondrial hyperfusion, possibly due to loss of phosphorylated dynamin-related protein 1 (p-DRP1). HIV-exosomes, containing the HIV-Tat protein, and viral Tat protein reduce the expression of p-DRP1 and p-eNOS, and accelerate brain endothelial dysfunction. Finally, exosomes isolated from HIV-1 infected primary human peripheral blood mononuclear cells (hPBMCs) produce more exosomes than uninfected controls and reduce both p-DRP1 and p-eNOS expressions in primary HBMVECs. Our novel findings reveal the significant role of HIV-exosomes on dysregulation of mitochondrial function, which induces adverse changes in the function of the brain microvascular endothelium.
MeSH term(s)	Brain/metabolism ; Dynamins/metabolism ; Endocytosis ; Endothelium, Vascular/metabolism ; Exosomes/metabolism ; Exosomes/ultrastructure ; HIV-1/metabolism ; Humans ; Jurkat Cells ; Membrane Potential, Mitochondrial ; Mitochondria/metabolism ; Models, Biological ; Nitric Oxide Synthase Type III/metabolism ; Phosphorylation ; Superoxides/metabolism ; Virus Replication ; tat Gene Products, Human Immunodeficiency Virus/metabolism
Chemical Substances	tat Gene Products, Human Immunodeficiency Virus ; Superoxides (11062-77-4) ; Nitric Oxide Synthase Type III (EC 1.14.13.39) ; DNM1L protein, human (EC 3.6.5.5) ; Dynamins (EC 3.6.5.5)
Language	English
Publishing date	2021-02-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-021-02319-8
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