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Article ; Online: ApoE4 expression disrupts tau uptake, trafficking, and clearance in astrocytes.

Eisenbaum, Maxwell / Pearson, Andrew / Ortiz, Camila / Mullan, Michael / Crawford, Fiona / Ojo, Joseph / Bachmeier, Corbin

Glia

2023 Volume 72, Issue 1, Page(s) 184–205

Abstract: Tauopathies are a collection of neurodegenerative diseases characterized by the accumulation of pathogenic aggregates of the microtubule-associated protein tau. Despite the prevalence and diversity of tau astrogliopathy in tauopathies, the interactions ... ...

Abstract	Tauopathies are a collection of neurodegenerative diseases characterized by the accumulation of pathogenic aggregates of the microtubule-associated protein tau. Despite the prevalence and diversity of tau astrogliopathy in tauopathies, the interactions between astrocytes and tau in the brain, and the influence of neurodegenerative genetic risk factors like the apolipoprotein E4 (apoE4) isoform, are largely unknown. Here, we leveraged primary and immortalized astrocytes expressing humanized apoE isoforms to characterize the mechanisms by which astrocytes interact with and eliminate extracellular tau, and the influence of apoE genotype on these processes. Our work indicates that astrocytes rapidly internalize, process, and release tau via an exosomal secretory mechanism under physiological conditions. However, we found that apoE4 disrupted these processes in comparison to apoE3, resulting in an astrocytic phenotype prone to intracellular tau accumulation. Furthermore, exposure to repetitive mild traumatic brain injuries exacerbated the apoE4-induced impairments in tau processing and elimination by astrocytes in apoE4 targeted-replacement mice. The diminished ability of apoE4 astrocytes to eliminate extracellular tau can lead to an accumulation of pathogenic tau, which induces mitochondrial dysfunction, as demonstrated by our studies. In total, our findings suggest that the apoE4 isoform lowers the threshold of astrocytic resilience to pathogenic tau, rendering them susceptible to bioenergetic deficits in the early stages of neurodegenerative diseases such as traumatic brain injury, potentially contributing to neurological decline.
MeSH term(s)	Mice ; Animals ; Apolipoprotein E4/genetics ; Astrocytes/metabolism ; Mice, Transgenic ; Apolipoproteins E/genetics ; Apolipoproteins E/metabolism ; Tauopathies/pathology ; Neurodegenerative Diseases/metabolism ; Protein Isoforms/genetics ; Protein Isoforms/metabolism
Chemical Substances	Apolipoprotein E4 ; Apolipoproteins E ; Protein Isoforms
Language	English
Publishing date	2023-09-05
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	639414-0
ISSN	1098-1136 ; 0894-1491
ISSN (online)	1098-1136
ISSN	0894-1491
DOI	10.1002/glia.24469
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Zs.A 2345: Show issues

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Article ; Online: Repetitive head trauma and apoE4 induce chronic cerebrovascular alterations that impair tau elimination from the brain.

Eisenbaum, Maxwell / Pearson, Andrew / Ortiz, Camila / Koprivica, Milica / Cembran, Arianna / Mullan, Michael / Crawford, Fiona / Ojo, Joseph / Bachmeier, Corbin

Experimental neurology

2024 Volume 374, Page(s) 114702

Abstract: Repetitive mild traumatic brain injuries (r-mTBI) sustained in the military or contact sports have been associated with the accumulation of extracellular tau in the brain, which may contribute to the pathogenesis of neurodegenerative tauopathies. The ... ...

Abstract	Repetitive mild traumatic brain injuries (r-mTBI) sustained in the military or contact sports have been associated with the accumulation of extracellular tau in the brain, which may contribute to the pathogenesis of neurodegenerative tauopathies. The expression of the apolipoprotein E4 (apoE4) isoform has been associated with higher levels of tau in the brain, and worse clinical outcomes after r-mTBI, though the influence of apoE genotype on extracellular tau dynamics in the brain is poorly understood. We recently demonstrated that extracellular tau can be eliminated across blood-brain barrier (BBB), which is progressively impaired following r-mTBI. The current studies investigated the influence of repetitive mild TBI (r-mTBI) and apoE genotype on the elimination of extracellular solutes from the brain. Following intracortical injection of biotin-labeled tau into humanized apoE-Tr mice, the levels of exogenous tau residing in the brain of apoE4 mice were elevated compared to other isoforms, indicating reduced tau elimination. Additionally, we found exposure to r-mTBI increased tau residence in apoE2 mice, similar to our observations in E2FAD animals. Each of these findings may be the result of diminished tau efflux via LRP1 at the BBB, as LRP1 inhibition significantly reduced tau uptake in endothelial cells and decreased tau transit across an in vitro model of the BBB (basolateral-to-apical). Notably, we showed that injury and apoE status, (particularly apoE4) resulted in chronic alterations in BBB integrity, pericyte coverage, and AQP4 polarization. These aberrations coincided with an atypical reactive astrocytic gene signature indicative of diminished CSF-ISF exchange. Our work found that CSF movement was reduced in the chronic phase following r-mTBI (>18 months post injury) across all apoE genotypes. In summary, we show that apoE genotype strongly influences cerebrovascular homeostasis, which can lead to age-dependent deficiencies in the elimination of toxic proteins from the brain, like tau, particularly in the aftermath of head trauma.
MeSH term(s)	Mice ; Animals ; Apolipoprotein E4/genetics ; Apolipoprotein E4/metabolism ; Mice, Transgenic ; Endothelial Cells/metabolism ; Brain/metabolism ; Apolipoproteins E/genetics ; Apolipoproteins E/metabolism ; Brain Concussion/metabolism
Chemical Substances	Apolipoprotein E4 ; Apolipoproteins E
Language	English
Publishing date	2024-01-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	207148-4
ISSN	1090-2430 ; 0014-4886
ISSN (online)	1090-2430
ISSN	0014-4886
DOI	10.1016/j.expneurol.2024.114702
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Zs.A 184: Show issues

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Article ; Online: Deletion of PTEN in microglia ameliorates chronic neuroinflammation following repetitive mTBI.

Pearson, Andrew / Ortiz, Camila / Eisenbaum, Max / Arrate, Clara / Browning, Mackenzie / Mullan, Michael / Bachmeier, Corbin / Crawford, Fiona / Ojo, Joseph O

Molecular and cellular neurosciences

2023 Volume 125, Page(s) 103855

Abstract: Traumatic brain injury is a leading cause of morbidity and mortality in adults and children in developed nations. Following the primary injury, microglia, the resident innate immune cells of the CNS, initiate several inflammatory signaling cascades and ... ...

Abstract	Traumatic brain injury is a leading cause of morbidity and mortality in adults and children in developed nations. Following the primary injury, microglia, the resident innate immune cells of the CNS, initiate several inflammatory signaling cascades and pathophysiological responses that may persist chronically; chronic neuroinflammation following TBI has been closely linked to the development of neurodegeneration and neurological dysfunction. Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that have been shown to regulate several key mechanisms in the inflammatory response to TBI. Increasing evidence has shown that the modulation of the PI3K/AKT signaling pathway has the potential to influence the cellular response to inflammatory stimuli. However, directly targeting PI3K signaling poses several challenges due to its regulatory role in several cell survival pathways. We have previously identified that the phosphatase and tensin homolog deleted on chromosome 10 (PTEN), the major negative regulator of PI3K/AKT signaling, is dysregulated following exposure to repetitive mild traumatic brain injury (r-mTBI). Moreover, this dysregulated PI3K/AKT signaling was correlated with chronic microglial-mediated neuroinflammation. Therefore, we interrogated microglial-specific PTEN as a therapeutic target in TBI by generating a microglial-specific, Tamoxifen inducible conditional PTEN knockout model using a CX3CR1 Cre recombinase mouse line PTEN
MeSH term(s)	Animals ; Mice ; Brain Injuries, Traumatic/metabolism ; Disease Models, Animal ; Inflammation/metabolism ; Mice, Inbred C57BL ; Microglia/metabolism ; Neuroinflammatory Diseases ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism
Chemical Substances	Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Pten protein, mouse (EC 3.1.3.67)
Language	English
Publishing date	2023-04-20
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1046640-x
ISSN	1095-9327 ; 1044-7431
ISSN (online)	1095-9327
ISSN	1044-7431
DOI	10.1016/j.mcn.2023.103855
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Zs.A 3035: Show issues

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Article: Human amnionic progenitor cell secretome mitigates the consequence of traumatic optic neuropathy in a mouse model.

McCartan, Robyn / Gratkowski, Arissa / Browning, Mackenzie / Hahn-Townsend, Coral / Ferguson, Scott / Morin, Alexander / Bachmeier, Corbin / Pearson, Andrew / Brown, Larry / Mullan, Michael / Crawford, Fiona / Tzekov, Radouil / Mouzon, Benoit

Molecular therapy. Methods & clinical development

2023 Volume 29, Page(s) 303–318

Abstract: Traumatic optic neuropathy (TON) is a condition in which acute injury to the optic nerve from direct or indirect trauma results in vision loss. The most common cause of TON is indirect injury to the optic nerve caused by concussive forces that are ... ...

Abstract	Traumatic optic neuropathy (TON) is a condition in which acute injury to the optic nerve from direct or indirect trauma results in vision loss. The most common cause of TON is indirect injury to the optic nerve caused by concussive forces that are transmitted to the optic nerve. TON occurs in up to 5% of closed-head trauma patients and there is currently no known effective treatment. One potential treatment option for TON is ST266, a cell-free biological solution containing the secretome of amnion-derived multipotent progenitor (AMP) cells. We investigated the efficacy of intranasal ST266 in a mouse model of TON induced by blunt head trauma. Injured mice treated with a 10-day regimen of ST266 showed an improvement in spatial memory and learning, a significant preservation of retinal ganglion cells, and a decrease in neuropathological markers in the optic nerve, optic tract, and dorsal lateral geniculate nucleus. ST266 treatment effectively downregulated the NLRP3 inflammasome-mediated neuroinflammation pathway after blunt trauma. Overall, treatment with ST266 was shown to improve functional and pathological outcomes in a mouse model of TON, warranting future exploration of ST266 as a cell-free therapeutic candidate for testing in all optic neuropathies.
Language	English
Publishing date	2023-04-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2872938-9
ISSN	2329-0501 ; 2329-0501
ISSN (online)	2329-0501
ISSN	2329-0501
DOI	10.1016/j.omtm.2023.04.002
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Zs.A 7107: Show issues

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Article ; Online: Apolipoprotein E-mediated Modulation of ADAM10 in Alzheimer's Disease.

Shackleton, Ben / Crawford, Fiona / Bachmeier, Corbin

Current Alzheimer research

2017 Volume 14, Issue 6, Page(s) 578–585

Abstract: Background: The APOE4 allele is the strongest genetic risk factor for Alzheimer's disease (AD). It has been associated with an accumulation of amyloid-β (Aβ) in the brain, which is produced through the sequential cleavage of the amyloid-β precursor ... ...

Abstract	Background: The APOE4 allele is the strongest genetic risk factor for Alzheimer's disease (AD). It has been associated with an accumulation of amyloid-β (Aβ) in the brain, which is produced through the sequential cleavage of the amyloid-β precursor protein (AβPP) by β - and γ-secretases. Alternatively, AβPP is also cleaved by α -secretases such as A Disintegrin and Metalloproteinase Domain-containing Protein 10 (ADAM10). Objective: While several studies have investigated the impact of apoE on β- and γ-secretase, interactions between apoE and α-secretases have not been fully examined. We investigated the effect of each apoE isoform on ADAM10 in vitro and in human cortex samples. Method: ADAM10 activity and kinetics was assessed in cell-free assays and the biological activity of ADAM10 further investigated in 7WCHO cells over-expressing wild type AβPP through ELISA. Finally, ADAM10 expression and activity was observed in the soluble fraction of both control and Alzheimer's Disease human cortex samples through ELISA. Results: In a cell free assay, ADAM10 activity was found to be significantly lower in apoE4 samples compared to apoE2. 7WCHO cells over expressing wild type AβPP exposed to apoE4 demonstrated reduced formation of sAβPPα compared to other apoE isoforms. We also identified APOE and AD dependent changes in ADAM10 activity and expression in the soluble brain fraction of human brain cortex. Conclusion: Overall, our data demonstrates an apoE isoform-dependent effect on ADAM10 function and AβPP processing which may describe the elevated amyloid levels in the brains of AD subjects carrying the APOE4 allele.
MeSH term(s)	ADAM10 Protein/metabolism ; Aged ; Aged, 80 and over ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Protein Precursor ; Animals ; Apolipoproteins E/genetics ; CHO Cells ; Cerebral Cortex/metabolism ; Cricetulus ; Female ; Gene Expression Regulation/genetics ; Humans ; Male ; Membrane Proteins/metabolism ; Middle Aged ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Transfection
Chemical Substances	Amyloid beta-Protein Precursor ; Apolipoproteins E ; Membrane Proteins ; Protein Isoforms ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; ADAM10 Protein (EC 3.4.24.81) ; ADAM10 protein, human (EC 3.4.24.81)
Language	English
Publishing date	2017-02-03
Publishing country	United Arab Emirates
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2205170-3
ISSN	1875-5828 ; 1567-2050
ISSN (online)	1875-5828
ISSN	1567-2050
DOI	10.2174/1567205014666170203093219
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Zs.A 6235: Show issues

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Article ; Online: MMP9 modulation improves specific neurobehavioral deficits in a mouse model of Alzheimer's disease.

Ringland, Charis / Schweig, Jonas Elias / Eisenbaum, Maxwell / Paris, Daniel / Ait-Ghezala, Ghania / Mullan, Michael / Crawford, Fiona / Abdullah, Laila / Bachmeier, Corbin

BMC neuroscience

2021 Volume 22, Issue 1, Page(s) 39

Abstract: Background: Matrix metallopeptidase 9 (MMP9) has been implicated in a variety of neurological disorders, including Alzheimer's disease (AD), where MMP9 levels are elevated in the brain and cerebrovasculature. Previously our group demonstrated ... ...

Abstract	Background: Matrix metallopeptidase 9 (MMP9) has been implicated in a variety of neurological disorders, including Alzheimer's disease (AD), where MMP9 levels are elevated in the brain and cerebrovasculature. Previously our group demonstrated apolipoprotein E4 (apoE4) was less efficient in regulating MMP9 activity in the brain than other apoE isoforms, and that MMP9 inhibition facilitated beta-amyloid (Aβ) elimination across the blood-brain barrier (BBB) METHODS: In the current studies, we evaluated the impact of MMP9 modulation on Aβ disposition and neurobehavior in AD using two approaches, (1) pharmacological inhibition of MMP9 with SB-3CT in apoE4 x AD (E4FAD) mice, and (2) gene deletion of MMP9 in AD mice (MMP9KO/5xFAD) RESULTS: Treatment with the MMP9 inhibitor SB-3CT in E4FAD mice led to reduced anxiety compared to placebo using the elevated plus maze. Deletion of the MMP9 gene in 5xFAD mice also reduced anxiety using the open field test, in addition to improving sociability and social recognition memory, particularly in male mice, as assessed through the three-chamber task, indicating certain behavioral alterations in AD may be mediated by MMP9. However, neither pharmacological inhibition of MMP9 or gene deletion of MMP9 affected spatial learning or memory in the AD animals, as determined through the radial arm water maze. Moreover, the effect of MMP9 modulation on AD neurobehavior was not due to changes in Aβ disposition, as both brain and plasma Aβ levels were unchanged in the SB-3CT-treated E4FAD animals and MMP9KO/AD mice compared to their respective controls. Conclusions: In total, while MMP9 inhibition did improve specific neurobehavioral deficits associated with AD, such as anxiety and social recognition memory, modulation of MMP9 did not alter spatial learning and memory or Aβ tissue levels in AD animals. While targeting MMP9 may represent a therapeutic strategy to mitigate aspects of neurobehavioral decline in AD, further work is necessary to understand the nature of the relationship between MMP9 activity and neurological dysfunction.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/psychology ; Amyloid beta-Peptides/genetics ; Animals ; Anxiety/drug therapy ; Anxiety/genetics ; Anxiety/metabolism ; Anxiety/psychology ; Brain/metabolism ; Female ; Heterocyclic Compounds, 1-Ring/pharmacology ; Heterocyclic Compounds, 1-Ring/therapeutic use ; Male ; Matrix Metalloproteinase 9/deficiency ; Matrix Metalloproteinase 9/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Motor Activity/drug effects ; Motor Activity/physiology ; Presenilin-1/genetics ; Social Interaction/drug effects ; Spatial Learning/drug effects ; Spatial Learning/physiology ; Sulfones/pharmacology ; Sulfones/therapeutic use
Chemical Substances	Amyloid beta-Peptides ; Heterocyclic Compounds, 1-Ring ; Presenilin-1 ; SB 3CT compound ; Sulfones ; presenilin 1, mouse ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; Mmp9 protein, mouse (EC 3.4.24.35)
Language	English
Publishing date	2021-05-25
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2041344-0
ISSN	1471-2202 ; 1471-2202
ISSN (online)	1471-2202
ISSN	1471-2202
DOI	10.1186/s12868-021-00643-2
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Article ; Online: Influence of traumatic brain injury on extracellular tau elimination at the blood-brain barrier.

Eisenbaum, Maxwell / Pearson, Andrew / Gratkowski, Arissa / Mouzon, Benoit / Mullan, Michael / Crawford, Fiona / Ojo, Joseph / Bachmeier, Corbin

Fluids and barriers of the CNS

2021 Volume 18, Issue 1, Page(s) 48

Abstract: Repetitive head trauma has been associated with the accumulation of tau species in the brain. Our prior work showed brain vascular mural cells contribute to tau processing in the brain, and that these cells progressively degenerate following repetitive ... ...

Abstract	Repetitive head trauma has been associated with the accumulation of tau species in the brain. Our prior work showed brain vascular mural cells contribute to tau processing in the brain, and that these cells progressively degenerate following repetitive mild traumatic brain injury (r-mTBI). The current studies investigated the role of the cerebrovasculature in the elimination of extracellular tau from the brain, and the influence of r-mTBI on these processes. Following intracranial injection of biotin-labeled tau, the levels of exogenous labeled tau residing in the brain were elevated in a mouse model of r-mTBI at 12 months post-injury compared to r-sham mice, indicating reduced tau elimination from the brain following head trauma. This may be the result of decreased caveolin-1 mediated tau efflux at the blood-brain barrier (BBB), as the caveolin inhibitor, methyl-β-cyclodextrin, significantly reduced tau uptake in isolated cerebrovessels and significantly decreased the basolateral-to-apical transit of tau across an in vitro model of the BBB. Moreover, we found that the upstream regulator of endothelial caveolin-1, Mfsd2a, was elevated in r-mTBI cerebrovessels compared to r-sham, which coincided with a decreased expression of cerebrovascular caveolin-1 in the chronic phase following r-mTBI (> 3 months post-injury). Lastly, angiopoietin-1, a mural cell-derived protein governing endothelial Mfsd2a expression, was secreted from r-mTBI cerebrovessels to a greater extent than r-sham animals. Altogether, in the chronic phase post-injury, release of angiopoietin-1 from degenerating mural cells downregulates caveolin-1 expression in brain endothelia, resulting in decreased tau elimination across the BBB, which may describe the accumulation of tau species in the brain following head trauma.
MeSH term(s)	Animals ; Blood-Brain Barrier/metabolism ; Brain Injuries, Traumatic/metabolism ; Disease Models, Animal ; Female ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; tau Proteins/metabolism
Chemical Substances	tau Proteins
Language	English
Publishing date	2021-10-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2595406-4
ISSN	2045-8118 ; 2045-8118
ISSN (online)	2045-8118
ISSN	2045-8118
DOI	10.1186/s12987-021-00283-y
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Article ; Online: Influence of Matrix Metallopeptidase 9 on Beta-Amyloid Elimination Across the Blood-Brain Barrier.

Shackleton, Ben / Ringland, Charis / Abdullah, Laila / Mullan, Michael / Crawford, Fiona / Bachmeier, Corbin

Molecular neurobiology

2019 Volume 56, Issue 12, Page(s) 8296–8305

Abstract: Lipoprotein receptor transport across the blood-brain barrier (BBB) mediates beta-amyloid (Aβ) accumulation in the brain and may be a contributing factor in Alzheimer's disease (AD) pathogenesis. Lipoprotein receptors are susceptible to proteolytic ... ...

Abstract	Lipoprotein receptor transport across the blood-brain barrier (BBB) mediates beta-amyloid (Aβ) accumulation in the brain and may be a contributing factor in Alzheimer's disease (AD) pathogenesis. Lipoprotein receptors are susceptible to proteolytic shedding at the cell surface, which precludes the endocytic transport of ligands. A ligand that closely interacts with the lipoprotein receptors is apolipoprotein E (apoE), which exists as three isoforms (apoE2, apoE3, apoE4). Our prior work showed an inverse relationship between lipoprotein receptor shedding and Aβ transport across the BBB, which was apoE-isoform dependent. To interrogate this further, the current studies investigated an enzyme implicated in lipoprotein receptor shedding, matrix metalloproteinase 9 (MMP9). Treatment with MMP9 dose-dependently elevated lipoprotein receptor shedding in brain endothelial cells and freshly isolated mouse cerebrovessels. Furthermore, treatment with a MMP9 inhibitor (SB-3CT) mitigated Aβ-induced lipoprotein receptor shedding in brain endothelial cells and the brains of apoE4 animals. In terms of BBB transit, SB-3CT treatment increased the transport of Aβ across an in vitro model of the BBB. In vivo, administration of SB-3CT to apoE4 animals significantly enhanced Aβ clearance from the brain to the periphery following intracranial administration of Aβ. The current studies show that MMP9 impacts lipoprotein receptor shedding and Aβ transit across the BBB, in an apoE isoform-specific manner. In total, MMP9 inhibition can facilitate Aβ clearance across the BBB, which could be an effective approach to lowering Aβ levels in the brain and mitigating the AD phenotype, particularly in subjects carrying the apoE4 allele.
MeSH term(s)	Amyloid beta-Peptides/blood ; Amyloid beta-Peptides/metabolism ; Animals ; Apolipoproteins E/metabolism ; Blood-Brain Barrier/enzymology ; Endothelial Cells/enzymology ; Female ; Glial Fibrillary Acidic Protein/blood ; Humans ; Male ; Matrix Metalloproteinase 9/metabolism ; Mice, Transgenic ; Models, Biological ; Receptors, Lipoprotein/metabolism ; Solubility ; Transcytosis
Chemical Substances	Amyloid beta-Peptides ; Apolipoproteins E ; Glial Fibrillary Acidic Protein ; Receptors, Lipoprotein ; Matrix Metalloproteinase 9 (EC 3.4.24.35)
Language	English
Publishing date	2019-06-18
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/s12035-019-01672-z
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Zs.A 2411: Show issues

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Article ; Online: APOE genotype dependent molecular abnormalities in the cerebrovasculature of Alzheimer's disease and age-matched non-demented brains.

Ojo, Joseph O / Reed, Jon M / Crynen, Gogce / Vallabhaneni, Prashanthi / Evans, James / Shackleton, Benjamin / Eisenbaum, Maximillian / Ringland, Charis / Edsell, Anastasia / Mullan, Michael / Crawford, Fiona / Bachmeier, Corbin

Molecular brain

2021 Volume 14, Issue 1, Page(s) 110

Abstract: Cerebrovascular dysfunction is a hallmark feature of Alzheimer's disease (AD). One of the greatest risk factors for AD is the apolipoprotein E4 (E4) allele. The APOE4 genotype has been shown to negatively impact vascular amyloid clearance, however, its ... ...

Abstract	Cerebrovascular dysfunction is a hallmark feature of Alzheimer's disease (AD). One of the greatest risk factors for AD is the apolipoprotein E4 (E4) allele. The APOE4 genotype has been shown to negatively impact vascular amyloid clearance, however, its direct influence on the molecular integrity of the cerebrovasculature compared to other APOE variants (APOE2 and APOE3) has been largely unexplored. To address this, we employed a 10-plex tandem isobaric mass tag approach in combination with an ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method, to interrogate unbiased proteomic changes in cerebrovessels from AD and healthy control brains with different APOE genotypes. We first interrogated changes between healthy control cases to identify underlying genotype specific effects in cerebrovessels. EIF2 signaling, regulation of eIF4 and 70S6K signaling and mTOR signaling were the top significantly altered pathways in E4/E4 compared to E3/E3 cases. Oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction were the top significant pathways in E2E2 vs E3/E3cases. We also identified AD-dependent changes and their interactions with APOE genotype and found the highest number of significant proteins from this interaction was observed in the E3/E4 (192) and E4/E4 (189) cases. As above, EIF2, mTOR signaling and eIF4 and 70S6K signaling were the top three significantly altered pathways in E4 allele carriers (i.e. E3/E4 and E4/E4 genotypes). Of all the cerebrovascular cell-type specific markers identified in our proteomic analyses, endothelial cell, astrocyte, and smooth muscle cell specific protein markers were significantly altered in E3/E4 cases, while endothelial cells and astrocyte specific protein markers were altered in E4/E4 cases. These proteomic changes provide novel insights into the longstanding link between APOE4 and cerebrovascular dysfunction, implicating a role for impaired autophagy, ER stress, and mitochondrial bioenergetics. These APOE4 dependent changes we identified could provide novel cerebrovascular targets for developing disease modifying strategies to mitigate the effects of APOE4 genotype on AD pathogenesis.
MeSH term(s)	Aged ; Aged, 80 and over ; Aging/pathology ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Apolipoproteins E/genetics ; Brain/blood supply ; Brain/pathology ; Case-Control Studies ; Dementia/genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; Middle Aged ; Organ Size ; Proteome/metabolism ; Proteomics ; Subcellular Fractions/metabolism
Chemical Substances	Apolipoproteins E ; Proteome
Language	English
Publishing date	2021-07-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2436057-0
ISSN	1756-6606 ; 1756-6606
ISSN (online)	1756-6606
ISSN	1756-6606
DOI	10.1186/s13041-021-00803-9
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Article: Molecular Pathobiology of the Cerebrovasculature in Aging and in Alzheimers Disease Cases With Cerebral Amyloid Angiopathy.

Frontiers in aging neuroscience

2021 Volume 13, Page(s) 658605

Abstract: Cerebrovascular dysfunction and cerebral amyloid angiopathy (CAA) are hallmark features of Alzheimer's disease (AD). Molecular damage to cerebrovessels in AD may result in alterations in vascular clearance mechanisms leading to amyloid deposition around ... ...

Abstract	Cerebrovascular dysfunction and cerebral amyloid angiopathy (CAA) are hallmark features of Alzheimer's disease (AD). Molecular damage to cerebrovessels in AD may result in alterations in vascular clearance mechanisms leading to amyloid deposition around blood vessels and diminished neurovascular-coupling. The sequelae of molecular events leading to these early pathogenic changes remains elusive. To address this, we conducted a comprehensive in-depth molecular characterization of the proteomic changes in enriched cerebrovessel fractions isolated from the inferior frontal gyrus of autopsy AD cases with low (85.5 ± 2.9 yrs) vs. high (81 ± 4.4 yrs) CAA score, aged-matched control (87.4 ± 1.5 yrs) and young healthy control (47 ± 3.3 yrs) cases. We employed a 10-plex tandem isobaric mass tag approach in combination with our ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method. Enriched cerebrovascular fractions showed very high expression levels of proteins specific to endothelial cells, mural cells (pericytes and smooth muscle cells), and astrocytes. We observed 150 significantly regulated proteins in young vs. aged control cerebrovessels. The top pathways significantly modulated with aging included chemokine, reelin, HIF1α and synaptogenesis signaling pathways. There were 213 proteins significantly regulated in aged-matched control vs. high CAA cerebrovessels. The top three pathways significantly altered from this comparison were oxidative phosphorylation, Sirtuin signaling pathway and TCA cycle II. Comparison between low vs. high CAA cerebrovessels identified 84 significantly regulated proteins. Top three pathways significantly altered between low vs. high CAA cerebrovessels included TCA Cycle II, Oxidative phosphorylation and mitochondrial dysfunction. Notably, high CAA cases included more advanced AD pathology thus cerebrovascular effects may be driven by the severity of amyloid and Tangle pathology. These descriptive proteomic changes provide novel insights to explain the age-related and AD-related cerebrovascular changes contributing to AD pathogenesis. Particularly, disturbances in energy bioenergetics and mitochondrial biology rank among the top AD pathways altered in cerebrovessels. Targeting these failed mechanisms in endothelia and mural cells may provide novel disease modifying targets for developing therapeutic strategies against cerebrovascular deterioration and promoting cerebral perfusion in AD. Our future work will focus on interrogating and validating these novel targets and pathways and their functional significance.
Language	English
Publishing date	2021-05-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2021.658605
Database	MEDical Literature Analysis and Retrieval System OnLINE

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