Zhen Zhao, PhD

Research Directions

i) To search for the genetic causes of vascular cognitive impairment and dementia
50 million people worldwide are now suffering from dementia; however, the exact causes remain elusive. Vascular Cognitive Impairment and Dementia (VCID) due to cerebrovascular diseases and pathologies represents 20~40% of the dementia cases, and largely overlaps with AD in terms of pathologies and pathogenic factors. Recently, we have been working with two groups of genetic risk factors that are vascular residents but can either predispose individual to cerebrovascular diseases or strongly modify the course of AD and VCID, such as platelet-derived growth factor receptor beta (PDGFRß), LRP1 and PICALM. Although this is just the first peek through the looking glass, yet our finding has brought new insight into the genetic causes of VCID and AD, suggesting that a better understanding the etiology and pathogenesis of AD and VICD, especially decoding the common genetic causes may help us redefining a subset of cases, and land more effective therapeutics for them in the near future.

ii) To study the molecular mechanism of the receptor-mediated transport at the blood-brain barrier
Receptor-mediated transcytosis (RMT) provides a major clearance pathway for Aß at the BBB, by flushing Aß out from brain to circulation. However, the understanding of this unique system remains limited, particularly regarding the molecular machinery which drives the cargos through multiple transcytosis events, including receptor-mediated endocytosis, intracellular trafficking, and exocytosis, as well as avoids the degradation pathway through late endosomes and lysosomes. Impaired vascular Aß clearance leads to elevated brain Aß level and exacerbates AD pathology. Piling evidence indicates that the alteration in the RMT system, particularly abnormal expression of AD vascular risk genes in the cerebral vasculature, contributes to pathogenesis. By studying the PICALM-dependent transvascular RMT machinery, we also hope to identify new key molecular targets of the BBB, which can be or manipulated pharmacologically or by adeno-associated virus (AAV)-mediated gene delivery, for more effective CNS drug delivery across the BBB.

iii) To examine the crosstalk between the cells within the neurovascular unit
Structural and functional brain connectivity, synaptic activity and information processing require highly coordinated signal transduction between different cell types within the neurovascular unit (NVU). The cells of the NVU are not just adjacently located and structurally connected; they communicated with each other vigorously via different signaling modules in order to function in orchestration. Such crosstalk is achieved by various cellular mechanisms, including but not limited to signaling receptors and channels, microRNA-containing exosomal vehicles (EVs) and gap junction-mediated direct exchange of small molecules. Neurovascular congruency is essential for the proper patterning of the CNS during development and neurovascular interaction is critical for normal brain functions, while its dysfunctions contribute to the pathogenesis of CNS injuries and neurodegenerative diseases, such as stroke and Alzheimer’s disease. We expect to provide evidence of functional pericyte–neuron crosstalk for brain health and functions, as well as pericyte contribution to brain’s innate immunity during CNS diseases or viral infections.

• NIH/NIA: R01AG061288, 2019-2024
• BrightFocus Foundation: BrightFocus Foundation, 2019-2022
• NIH/NIA: R21AG063287, 2019-2021
• NIH/NINDS: R01NS110687, 2019-2014
• L.K. Whittier Foundation: L.K. Whittier Foundation Translational Research Project, 2017-2018
• NIA/USC ADRC: ADRC Pilot, 2016-2017
• Cure Alzheimer’s Fund: Cure Alzheimer’s Fund, 2015-2019
• Alzheimer’s Association : NIRG-15-363387, 2015-2017

• Acetylated tau: A missing link between head injury and dementia Med (N Y). 2021 06 11; 2(6):637-639. . View in PubMed
• Endothelial Tip Cell Finds Its Way with Piezo1 Neuron. 2020 10 14; 108(1):5-7. . View in PubMed
• Therapeutic TVs for Crossing Barriers in the Brain Cell. 2020 07 23; 182(2):267-269. . View in PubMed
• Experimental chronic cerebral hypoperfusion results in decreased pericyte coverage and increased blood-brain barrier permeability in the corpus callosum J Cereb Blood Flow Metab. 2019 02; 39(2):240-250. . View in PubMed
• Blood-Brain Barrier: From Physiology to Disease and Back Physiol Rev. 2019 01 01; 99(1):21-78. . View in PubMed
• Pericyte degeneration causes white matter dysfunction in the mouse central nervous system Nat Med. 2018 03; 24(3):326-337. . View in PubMed
• Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-ß42 by LRP1-dependent apolipoprotein E isoform-specific mechanism Mol Neurodegener. 2018 10 19; 13(1):57. . View in PubMed
• Neuropharmacology. 2018 05 15; 134(Pt B):293-301. . View in PubMed
• Alzheimer’s disease: A matter of blood-brain barrier dysfunction? J Exp Med. 2017 Nov 06; 214(11):3151-3169.. View in PubMed
• Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain Nat Neurosci. 2017 Mar; 20(3):406-416. . View in PubMed
• Remote control of BBB: A tale of exosomes and microRNA Cell Res. 2017 07; 27(7):849-850. . View in PubMed
• Regional early and progressive loss of brain pericytes but not vascular smooth muscle cells in adult mice with disrupted platelet-derived growth factor receptor-ß signaling PLoS One. 2017; 12(4):e0176225. . View in PubMed
• 3K3A-activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice Nat Med. 2016 09; 22(9):1050-5. . View in PubMed
• Accelerated pericyte degeneration and blood-brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease J Cereb Blood Flow Metab. 2016 Jan; 36(1):216-27. . View in PubMed
• Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy Cell Stem Cell. 2016 11 03; 19(5):663-671. . View in PubMed
• Establishment and Dysfunction of the Blood-Brain Barrier Cell. 2015 Nov 19; 163(5):1064-1078. . View in PubMed
• Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers Nat Commun. 2015 Aug 03; 6:7839. . View in PubMed
• Central role for PICALM in amyloid-ß blood-brain barrier transcytosis and clearance Nat Neurosci. 2015 Jul; 18(7):978-87. . View in PubMed
• GLUT1 reductions exacerbate Alzheimer’s disease vasculo-neuronal dysfunction and degeneration Nat Neurosci. 2015 Apr; 18(4):521-530. . View in PubMed
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• UVRAG is required for virus entry through combinatorial interaction with the class C-Vps complex and SNAREs Proc Natl Acad Sci U S A. 2014 Feb 18; 111(7):2716-21. . View in PubMed
• Activated protein C analog protects from ischemic stroke and extends the therapeutic window of tissue-type plasminogen activator in aged female mice and hypertensive rats Stroke. 2013 Dec; 44(12):3529-36. . View in PubMed
• PtdIns(3)P-bound UVRAG coordinates Golgi-ER retrograde and Atg9 transport by differential interactions with the ER tether and the beclin 1 complex Nat Cell Biol. 2013 Oct; 15(10):1206-1219. . View in PubMed
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• Activated protein C analog promotes neurogenesis and improves neurological outcome after focal ischemic stroke in mice via protease activated receptor 1 Brain Res. 2013 Apr 24; 1507:97-104. . View in PubMed
• An activated protein C analog stimulates neuronal production by human neural progenitor cells via a PAR1-PAR3-S1PR1-Akt pathway J Neurosci. 2013 Apr 03; 33(14):6181-90. . View in PubMed
• Pericyte loss influences Alzheimer-like neurodegeneration in mice Nat Commun. 2013; 4:2932. . View in PubMed
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• A dual role for UVRAG in maintaining chromosomal stability independent of autophagy Dev Cell. 2012 May 15; 22(5):1001-16. . View in PubMed
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• Regulation of axonal development by natriuretic peptide hormones Proc Natl Acad Sci U S A. 2009 Oct 20; 106(42):18016-21. . View in PubMed
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• Zlokovic, Berislav
• Sagare, Abhay
• Toga, Arthur
• Aisen, Paul
• Thompson, Paul
• Lieber, Michael
• Lyden, Patrick
• Wang, Danny