bioRxiv (Cold Spring Harbor Laboratory), Jun 28, 2023
Brain pericytes maintain blood-brain barrier (BBB), secrete neurotrophic factors and clear toxic ... more Brain pericytes maintain blood-brain barrier (BBB), secrete neurotrophic factors and clear toxic proteins. Their loss in neurological disorders leads to BBB breakdown, neuronal dysfunction, and cognitive decline. Therefore, cell therapy to replace lost pericytes holds potential to restore impaired cerebrovascular and brain functions. Here, we show by a quantitative analysis of 8,344 proteins and 20,572 phosphopeptides that human iPSC-derived brain pericytes (iPSC-PC) share 96% of total proteins and 98% of protein phosphorylation sites with primary human brain pericytes. This includes cell adhesion and tight junction proteins, transcription factors, and different protein kinase families of the human kinome. In pericyte-deficient mice, iPSC-PC home to host brain capillaries to form hybrid human-mouse microvessels. They repair BBB leaks and protect against neuron loss, which we show requires PDGRFB and pleiotrophin. They also clear Alzheimer's amyloid-β and tau neurotoxins via lipoprotein receptor. Thus, iPSC-PC may offer a valuable replacement therapy for pericyte-deficient neurological disorders.
Resting-state functional connectivity (FC) is suggested to be cross-sectionally associated with b... more Resting-state functional connectivity (FC) is suggested to be cross-sectionally associated with both vascular burden and Alzheimer's disease (AD) pathology. For instance, studies in pre-clinical AD subjects have shown increases of cerebral spinal uid soluble platelet-derived growth factor receptor-β (CSF sPDGFRβ, a marker of BBB breakdown) but have not demonstrated if this vascular impairment affects neuronal dysfunction. It's possible that increased levels of sPDGFRβ in the CSF may correlate with impaired FC in metabolically demanding brain regions (i.e. Default Mode Network, DMN). Our study aimed to investigate the relationship between these two markers in older individuals that were cognitively normal and had cognitive impairment. Eighty-nine older adults without dementia from the University of Southern California were selected from a larger cohort. Region of interest (ROI) to ROI analyses were conducted using DMN seed regions. Linear regression models measured signi cant associations between BOLD FC strength among seed-target regions and sPDGFRβ values, while covarying for age and sex. Comparison of a composite ROI created by averaging FC values between seed and all target regions among cognitively normal and impaired individuals was also examined. Using CSF sPDGFRβ as a biomarker of BBB breakdown, we report that increased breakdown correlated with decreased functional connectivity in DMN areas, speci cally the PCC while the hippocampus exhibited an interaction effect using CDR score. We conclude that BBB breakdown as measured by CSF sPDGFRβ affects neural networks resulting in decreased functional connections that leads to cognitive dysfunction.
Pericytes play a key role in the development of cerebral microcirculation. The exact role of peri... more Pericytes play a key role in the development of cerebral microcirculation. The exact role of pericytes in the neurovascular unit in the adult brain and during brain aging remains, however, elusive. Using adult viable pericyte-deficient mice, we show that pericyte loss leads to brain vascular damage by two parallel pathways: (1) reduction in brain microcirculation causing diminished brain capillary perfusion, cerebral blood flow, and cerebral blood flow responses to brain activation that ultimately mediates chronic perfusion stress and hypoxia, and (2) blood-brain barrier breakdown associated with brain accumulation of serum proteins and several vasculotoxic and/or neurotoxic macromolecules ultimately leading to secondary neuronal degenerative changes. We show that age-dependent vascular damage in pericyte-deficient mice precedes neuronal degenerative changes, learning and memory impairment, and the neuroinflammatory response. Thus, pericytes control key neurovascular functions that are necessary for proper neuronal structure and function, and pericyte loss results in a progressive age-dependent vascular-mediated neurodegeneration.
Journal of Cerebral Blood Flow and Metabolism, Oct 8, 2008
Activated protein C (APC), a serine-protease with anticoagulant, anti-inflammatory, and cytoprote... more Activated protein C (APC), a serine-protease with anticoagulant, anti-inflammatory, and cytoprotective activities, is neuroprotective and holds potential to treat different neurological disorders. It is unknown whether APC crosses the blood-brain barrier (BBB) to reach its therapeutic targets in the brain. By using a brain vascular perfusion technique, we show that 125 I-labeled plasmaderived mouse APC enters the brain from cerebrovascular circulation by a concentration-dependent mechanism. The permeability surface area product of 125 I-APC (0.1 nM) in different forebrain regions ranged from 3.11 to 4.13μL/min-g brain. This was approximately 80-110-fold greater than for 14 C-inulin, a simultaneously infused reference-tracer. The Km value for APC BBB cortical transport was 1.6 ± 0.2 nM. Recombinant APC variants with reduced anticoagulant activity, 5A-APC and 3K3A-APC, but not protein C, exhibited high affinity for the APC BBB transport system. Blockade of APC binding site on endothelial protein C receptor (EPCR), but not blockade of its protease activated receptor-1 (PAR1) catalytic site, inhibited by > 85% APC entry into the brain. APC brain uptake was reduced by 64% in severely-deficient EPCR mice, but not in PAR1 null mice. These data suggest that APC and its variants with reduced anticoagulant activity cross the BBB via EPCR-mediated saturable transport.
Platelet-derived growth factor receptor-β (PDGFRβ) is expressed in the brain by vascular mural ce... more Platelet-derived growth factor receptor-β (PDGFRβ) is expressed in the brain by vascular mural cells -brain capillary pericytes and arterial vascular smooth muscle cells (VSMCs). Recent evidence shows that blood-brain barrier (BBB) disruption and increased permeability, especially in the hippocampus, positively correlates with elevated levels of soluble PDGFRβ (sPDGFRβ) in cerebrospinal fluid (CSF) in patients with mild dementia. To determine which vascular cell type(s) contributes to increased sPDGFRβ in CSF, we compared PDGFRβ expression and sPDGFRβ shedding in response to injury in early passage primary cultures of human brain pericytes, brain arterial VSMCs, and brain endothelial cells. PDGFRβ protein was undetectable in endothelial cells, but was found both in pericytes and VSMCs. PDGFRβ relative protein abundance was by 4.2-fold (p < 0.05) higher in pericytes compared to VSMCs. Hypoxia (1% O 2 ) or amyloid-β peptide (25 μM) compared to normoxia (21% O 2 ) both increased over 48 h shedding of sPDGFRβ and its levels in the culture medium from pericytes cultures, but not from VSMCs cultures, by 4.3fold and 4.6-fold, respectively, compared to the basal sPDGFRβ levels in the medium (1.43 ± 0.15 ng/ml). This was associated with the corresponding loss of cell-associated PDGFRβ from pericytes and no change in cellular levels of PDGFRβ in VSMCs. Thus, sPDGFRβ is a biomarker of pericyte injury, and elevated sPDGFRβ levels in biofluids in patients with dementia and/or other neurodegenerative disorders likely reflects pericyte injury, which supports the potential for sPDGFRβ to be developed and validated as a biomarker of brain pericyte injury and BBB dysfunction.
Pericytes are cells in the blood-brain barrier (BBB) that degenerate in Alzheimer's disease (AD),... more Pericytes are cells in the blood-brain barrier (BBB) that degenerate in Alzheimer's disease (AD), a neurodegenerative disorder characterized by early neurovascular dysfunction, elevation of amyloid β-peptide (Aβ), tau pathology and neuronal loss, leading to progressive cognitive decline and dementia. Pericytes are uniquely positioned within the neurovascular unit between endothelial cells of brain capillaries, astrocytes and neurons. Recent studies have shown that pericytes regulate key neurovascular functions including BBB formation and maintenance, vascular stability and angioarchitecture, regulation of capillary blood flow, and clearance of toxic cellular by-products necessary for normal functioning of the central nervous system (CNS). Here, we review the concept of the neurovascular unit and neurovascular functions of CNS pericytes. Next, we discuss vascular contributions to AD and review new roles of pericytes in the pathogenesis of AD such as vascular-mediated Aβ-independent neurodegeneration, regulation of Aβ clearance and contributions to tau pathology, neuronal loss and cognitive decline. We conclude that future studies should focus on molecular mechanisms and pathways underlying aberrant signal transduction between pericytes and its neighboring cells within the neurovascular unit, that is, endothelial cells, astrocytes and neurons, which could represent potential therapeutic targets to control pericyte degeneration in AD and the resulting secondary vascular and neuronal degeneration.
The G-protein coupled receptor (GPCR)-kinase interacting proteins 1 and 2 (GIT1 and GIT2) are sca... more The G-protein coupled receptor (GPCR)-kinase interacting proteins 1 and 2 (GIT1 and GIT2) are scaffold proteins with ADP-ribosylating factor GTPase activity. GIT1 and GIT2 control numerous cellular functions and are highly expressed in neurons, endothelial cells and vascular smooth muscle cells (VSMC). GIT1 promotes dendritic spine formation, growth and motility in cultured neurons, but its role in brain in vivo is unknown. By using global GIT1 knockout mice (GIT1 KO), we show that deletion of GIT1 results in markedly reduced dendritic length and spine density in the hippocampus by 36.7 % (p < 0.0106*) and 35.1% (p< 0.0028*) respectively compared to WT controls. This correlated with their poor adaptation to new environments as shown by impaired performance on tasks dependent on learning. We also studied the effect of GIT1 gene deletion on brain microcirculation. In contrast to findings in systemic circulation, GIT1 KO mice had an intact blood-brain barrier and normal regional cerebral blood flow as determined with radiotracers. Thus, our data suggest that GIT1 plays an important role in brain in vivo by regulating spine density involved in synaptic plasticity that is required for processes involved in learning.
Soluble circulating low density lipoprotein receptor-related protein-1 (sLRP) provides key plasma... more Soluble circulating low density lipoprotein receptor-related protein-1 (sLRP) provides key plasma binding activity for Alzheimer's disease (AD) amyloid β-peptide (Aβ). sLRP normally binds 70-90% of plasma Aβ preventing free Aβ access to the brain. In AD, Aβ binding to sLRP is compromised by increased levels of oxidized sLRP which does not bind Aβ. Here, we determined plasma oxidized sLRP and Aβ40/42 sLRP-bound, other proteins-bound and free plasma fractions, cerebrospinal fluid (CSF) tau/Aβ42 ratios and mini-mental state examination (MMSE) scores in patients with mild cognitive impairment (MCI) who progressed to AD (MCI-AD, n=14), AD (n=14) and neurologically healthy controls (n=14) recruited from the Göteborg MCI study. In MCI-AD patients prior to conversion to AD and AD patients, the respective increases in oxidized sLRP and free plasma Aβ40 and Aβ42 levels were 4.9 and 3.7-fold, 1.8 and 1.7-fold and 4.3 and 3.3-fold (P < 0.05, ANOVA with Tuckey post-hoc test). In MCI-AD and AD patients increases in oxidized sLRP and free plasma Aβ40 and Aβ42 correlated with increases in CSF tau/Aβ42 ratios and reductions in MMSE scores (P < 0.05, Pearson analysis). A heterogenous group of 'stable' MCI patients that was followed over 2-4 years (n=24) had normal CSF tau/Aβ42 ratios but increased oxidized sLRP levels (P < 0.05, Student's t test). Data suggests that a deficient sLRP-Aβ binding might precede and correlate later in disease with an increase in the tau/Aβ42 CSF ratio and global cognitive decline in MCI individuals converting into AD, and therefore is an early biomarker for AD-type dementia.
Low-density lipoprotein receptor-related protein-1 (LRP1), a member of the LDL receptor family, h... more Low-density lipoprotein receptor-related protein-1 (LRP1), a member of the LDL receptor family, has major roles in the cellular transport of cholesterol, endocytosis of forty structurally diverse ligands, transcytosis of ligands across the blood-brain barrier, and transmembrane and nuclear signaling. Recent evidence indicates that LRP1 regulates brain and systemic clearance of Alzheimer's disease (AD) amyloid β-peptide (Aβ). According to the two hit vascular hypothesis for AD, vascular damage precedes cerebrovascular and brain Aβ accumulation (hit 1) which then further amplifies neurovascular dysfunction (hit 2) preceding neurodegeneration. In this study, we discuss the roles of LRP1 during the hit 1 and hit 2 stage of AD pathogenesis and describe a threelevel serial LRP1-dependent homeostatic control of Aβ clearance including (i) cell-surface LRP1 at the BBB and cerebrovascular cells mediating brain-to-blood Aβ clearance (ii) circulating LRP1 providing a key endogenous peripheral 'sink' activity for plasma Aβ which prevents free Aβ access to the brain, and (iii) LRP1 in the liver mediating systemic Aβ clearance. Pitfalls in experimental Aβ brain clearance measurements with the concurrent use of peptides/proteins such as receptor-associated protein and aprotinin are also discussed. We suggest that LRP1 has a critical role in AD pathogenesis and is an important therapeutic target in AD.
In humans, apolipoprotein E (apoE) has 3 isoforms: apoE2, apoE3, and apoE4. APOE4 is a major gene... more In humans, apolipoprotein E (apoE) has 3 isoforms: apoE2, apoE3, and apoE4. APOE4 is a major genetic risk factor for Alzheimer disease (AD). Apolipoprotein E4 has direct effects on the cerebrovascular system, resulting in microvascular lesions and blood-brain barrier (BBB) damage, as recently reviewed. 2 Neurovascular dysfunction is also present in cognitively normal APOE4 carriers and individuals with APOE4-associated disorders including AD. Moreover, postmortem brain tissue analysis has indicated that BBB breakdown in patients with AD is more pronounced in APOE4 carriers compared with APOE3 or APOE2. Our recent studies in transgenic mice have demonstrated that apoE4 leads to BBB breakdown by activating the proinflammatory cyclophilin A (CypA)-matrix metalloproteinase 9 (MMP-9) pathway in brain pericytes, which in turn results in degradation of the BBB tight junctions and basement membrane proteins. It has also been shown that apoE4-mediated BBB breakdown leads to secondary neuronal injury and cognitive decline in transgenic mice. Apolipoprotein E2 and apoE3 maintained normal BBB integrity in transgenic mice by suppressing the CypA-MMP-9 pathway. Here, we studied the cerebrospinal fluid (CSF)/plasma albumin quotient (Q Alb ), an established marker of BBB breakdown, 8 and CypA and active MMP-9 levels in the CSF of cognitively normal individuals with different APOE genotypes to determine whether apoE4dependent changes in BBB permeability and CypA-MMP-9 pathway as shown in APOE4, but not APOE3 and APOE2 transgenic mice, also occur in humans. Methods | Participants were volunteers who were recruited through advertisements or from the Memory Education and Research Initiative Program at the Nathan S. Kline Institute for
Amyloid beta (Aβ) homeostasis in the brain is governed by its production and clearance mechanisms... more Amyloid beta (Aβ) homeostasis in the brain is governed by its production and clearance mechanisms. An imbalance in this homeostasis results in pathological accumulations of cerebral Aβ, a characteristic of Alzheimer's disease (AD). While Aβ may be cleared by several physiological mechanisms, a major route of Aβ clearance is the vascularmediated removal of Aβ from the brain across the blood-brain barrier (BBB). Here, we discuss the role of the predominant Aβ clearance protein-low-density lipoprotein receptor-related protein 1 (LRP1)-in the efflux of Aβ from the brain. We also outline the multiple factors that influence the function of LRP1-mediated Aβ clearance, such as its expression, shedding, structural modification and transcriptional regulation by other genes. Finally, we summarize approaches aimed at restoring LRP1-mediated Aβ clearance from the brain.
Low-density lipoprotein receptor related protein-1 (LRP) is a member of the low-density lipoprote... more Low-density lipoprotein receptor related protein-1 (LRP) is a member of the low-density lipoprotein (LDL) receptor family which has been linked to Alzheimer's disease (AD) by biochemical and genetic evidence. Levels of neurotoxic amyloid -peptide (Aβ) in the brain are elevated in AD contributing to the disease process and neuropathology. Faulty A clearance from the brain appears to mediate focal Aβ accumulations in AD. Central and peripheral production of Aβ from Aβprecursor protein (APP), transport of peripheral Aβ into the brain across the blood-brain barrier (BBB) via receptor for advanced glycation end products (RAGE), enzymatic Aβ degradation, Aβ oligomerization and aggregation, neuroinflammatory changes and microglia activation, and Aβ elimination from brain across the BBB by cell surface LRP; all may control brain Aβ levels. Recently, we have shown that a soluble form of LRP (sLRP) binds 70 to 90 % of plasma Aβ, preventing its access to the brain. In AD individuals, the levels of LRP at the BBB are reduced, as are levels of Aβ binding to sLRP in plasma. This, in turn, may increase Aβ brain levels through a decreased efflux of brain Aβ at the BBB and/or reduced sequestration of plasma Aβ associated with re-entry of free Aβ into the brain via RAGE. Thus, therapies which increase LRP expression at the BBB and/or enhance the peripheral Aβ "sink" activity of sLRP, hold potential to control brain Aβ accumulations, neuroinflammation and cerebral blood flow reductions in AD.
Cns & Neurological Disorders-drug Targets, Mar 1, 2009
The main receptors for amyloid-beta peptide (Aβ) transport across the blood-brain barrier (BBB) f... more The main receptors for amyloid-beta peptide (Aβ) transport across the blood-brain barrier (BBB) from brain to blood and blood to brain are low-density lipoprotein receptor related protein-1 (LRP1) and receptor for advanced glycation end products (RAGE), respectively. In normal human plasma a soluble form of LRP1 (sLRP1) is a major endogenous brain Aβ 'sinker' that sequesters some 70 to 90 % of plasma Aβ peptides. In Alzheimer's disease (AD), the levels of sLRP1 and its capacity to bind Aβ are reduced which increases free Aβ fraction in plasma. This in turn may increase brain Aβ burden through decreased Aβ efflux and/or increased Aβ influx across the BBB. In Aβ immunotherapy, anti-Aβ antibody sequestration of plasma Aβ enhances the peripheral Aβ 'sink action'. However, in contrast to endogenous sLRP1 which does not penetrate the BBB, some anti-Aβ antibodies may slowly enter the brain which reduces the effectiveness of their sink action and may contribute to neuroinflammation and intracerebral hemorrhage. Anti-Aβ antibody/Aβ immune complexes are rapidly cleared from brain to blood via FcRn (neonatal Fc receptor) across the BBB. In a mouse model of AD, restoring plasma sLRP1 with recombinant LRP-IV cluster reduces brain Aβ burden and improves functional changes in cerebral blood flow (CBF) and behavioral responses, without causing neuroinflammation and/or hemorrhage. The C-terminal sequence of Aβ is required for its direct interaction with sLRP and LRP-IV cluster which is completely blocked by the receptorassociated protein (RAP) that does not directly bind Aβ. Therapies to increase LRP1 expression or reduce RAGE activity at the BBB and/or restore the peripheral Aβ 'sink' action, hold potential to reduce brain Aβ and inflammation, and improve CBF and functional recovery in AD models, and by extension in AD patients.
Background PICALM is one of the most significant susceptibility factors for Alzheimer's disease (... more Background PICALM is one of the most significant susceptibility factors for Alzheimer's disease (AD). In humans and mice, PICALM is highly expressed in brain endothelium. PICALM endothelial levels are reduced in AD brains. PICALM controls several steps in Aβ transcytosis across the blood-brain barrier (BBB). Its loss from brain endothelium in mice diminishes Aβ clearance at the BBB, which worsens Aβ pathology, but is reversible by endothelial PICALM re-expression. Thus, increasing PICALM at the BBB holds potential to slow down development of Aβ pathology. To identify a drug that could increase PICALM expression, we screened a library of 2007 FDA-approved drugs in HEK293t cells expressing luciferase driven by a human PICALM promoter, followed by a secondary mRNA screen in human Eahy926 endothelial cell line. In vivo studies with the lead hit were carried out in Picalm-deficient (Picalm +/-) mice, Picalm +/-; 5XFAD mice and Picalm lox/lox ; Cdh5-Cre; 5XFAD mice with endothelial-specific Picalm knockout. We studied PICALM expression at the BBB, Aβ pathology and clearance from brain to blood, cerebral blood flow (CBF) responses, BBB integrity and behavior. Our screen identified anti-malaria drug artesunate as the lead hit. Artesunate elevated PICALM mRNA and protein levels in Eahy926 endothelial cells and in vivo in brain capillaries of Picalm +/-mice by 2-3-fold. Artesunate treatment (32 mg/kg/day for 2 months) of 3-month old Picalm +/-; 5XFAD mice compared to vehicle increased brain capillary PICALM levels by 2-fold, and reduced Aβ42 and Aβ40 levels and Aβ and thioflavin S-load in the cortex and hippocampus, and vascular Aβ load by 34-51%. Artesunate also increased circulating Aβ42 and Aβ40 levels by 2-fold confirming accelerated Aβ clearance from brain to blood. Consistent with reduced Aβ pathology, treatment of Picalm +/-; 5XFAD mice with artesunate improved CBF responses, BBB integrity and behavior on novel object location and recognition, burrowing and nesting. Endothelial-specific knockout of PICALM abolished all beneficial effects of artesunate in 5XFAD mice indicating that endothelial PICALM is required for its therapeutic effects. Conclusions Artesunate increases PICALM levels and Aβ clearance at the BBB which prevents development of Aβ pathology and functional deficits in mice and holds potential for translation to human AD.
The role of blood-brain barrier (BBB) transport in clearance of amyloid -peptide (A) by A immu... more The role of blood-brain barrier (BBB) transport in clearance of amyloid -peptide (A) by A immunotherapy is not fully understood. To address this issue, we studied the effects of peripherally and centrally administered A-specific IgG on BBB influx of circulating A and efflux of brain-derived A in APPsw ϩ/Ϫ mice, a model that develops Alzheimer's disease-like amyloid pathology, and wild-type mice. APPsw ϩ/Ϫ mice and penetrates into the brain to sequester brain A. In young mice, A-anti-A complexes were cleared from brain to blood by transcytosis across the BBB via the neonatal Fc receptor (FcRn) and the low-density lipoprotein receptor-related protein (LRP), whereas in older mice, there was an age-dependent increase in FcRn-mediated IgG-assisted A BBB efflux and a decrease in LRP-mediated clearance of A-anti-A complexes. Inhibition of the FcRn pathway in older APPsw ϩ/Ϫ mice blocked clearance of endogenous A40/42 by centrally administered A immunotherapy. Moreover, deletion of the FcRn gene in wild-type mice inhibited clearance of endogenous mouse A40/42 by systemically administered anti-A. Our data suggest that the FcRn pathway at the BBB plays a crucial role in IgG-assisted A removal from the aging brain.
Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4 1 . APOE4 is a major genetic ri... more Human apolipoprotein E has three isoforms: APOE2, APOE3 and APOE4 1 . APOE4 is a major genetic risk factor for Alzheimer's disease 2, 3 and is associated with Down's syndrome dementia and poor neurological outcome after traumatic brain injury and haemorrhage 3 . Neurovascular dysfunction is present in normal APOE4 carriers and individuals withAPOE4-associated disorders . In mice, lack of Apoe leads to blood-brain barrier (BBB) breakdown , whereas APOE4 increases BBB susceptibility to injury 13 . How APOE genotype affects brain microcirculation remains elusive. Using different APOE transgenic mice, including mice with ablation and/or inhibition of cyclophilin A (CypA), here we show that expression of APOE4 and lack of murine Apoe, but not APOE2 and APOE3, leads to BBB breakdown by activating a proinflammatory CypA-nuclear factor-κB-matrix-metalloproteinase-9 pathway in pericytes. This, in turn, leads to neuronal uptake of multiple blood-derived neurotoxic proteins, and microvascular and cerebral blood flow reductions. We show that the vascular defects in Apoe-deficient and APOE4-expressing mice precede neuronal dysfunction and can initiate neurodegenerative changes. Astrocyte-secreted APOE3, but not APOE4, suppressed the CypA-nuclear factor-κBmatrix-metalloproteinase-9 pathway in pericytes through a lipoprotein receptor. Our data suggest
The original article [1] contained an obsolete version of Additional File 5: Fig. which has since... more The original article [1] contained an obsolete version of Additional File 5: Fig. which has since been amended.
A “multi-omics” analysis of blood–brain barrier and synaptic dysfunction in APOE4 mice
Journal of Experimental Medicine
Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer’s disease, leads to blood–b... more Apolipoprotein E4 (APOE4), the main susceptibility gene for Alzheimer’s disease, leads to blood–brain barrier (BBB) breakdown in humans and mice. Remarkably, BBB dysfunction predicts cognitive decline and precedes synaptic deficits in APOE4 human carriers. How APOE4 affects BBB and synaptic function at a molecular level, however, remains elusive. Using single-nucleus RNA-sequencing and phosphoproteome and proteome analysis, we show that APOE4 compared with APOE3 leads to an early disruption of the BBB transcriptome in 2–3-mo-old APOE4 knock-in mice, followed by dysregulation in protein signaling networks controlling cell junctions, cytoskeleton, clathrin-mediated transport, and translation in brain endothelium, as well as transcription and RNA splicing suggestive of DNA damage in pericytes. Changes in BBB signaling mechanisms paralleled an early, progressive BBB breakdown and loss of pericytes, which preceded postsynaptic interactome disruption and behavioral deficits that developed...
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Papers by Abhay Sagare