Systemic immunity protects the mind: Can immune checkpoint blockade combat Alzheimer’s disease?

Systemic immunity protects the mind: Can immune checkpoint blockade combat Alzheimer’s disease?



>> GOOD AFTERNOON I'M DANIEL REICH IT'S MY HONOR TO INTRODUCE TODAY'S WALS SPEAKER. THIS TALK IS JOINTLY ORGANIZED WITH THE INFLAMMATORY DISEASES INTEREST GROUP SO IF YOU WILL INDULGE ME FOR A MOMENT I WANT TO TELL BUT THAT. THIS GROUP WAS ESTABLISHED IN 2015 FOLLOWING THE INTRAMURAL PROGRAM'S LONG TERM PLANNING PROCESS TO TRY TO BRING TOGETHER THE LARGE NUMBER OF LABOS CAMP US THAT STUDY INFLAMMATION AS A UNIFYING THEME IN DISEASE. IT CURRENTLY HAS SUPPORT FROM SEVEN ICs AS WELL AS THE DEPUTY DIRECTOR FOR INTRAMURAL RESEARCH. MOSTLY IT'S A SPEAKER SERIES BUT HAS A STEERING COMMITTEE FROM MULTIPLE ICs AND THERE IS A LIST SERVE. SO IF ANY OF YOU WANT INFORMATION ABOUT THE TALKS THAT ARE BEING ORGANIZED, PLEASE SIGN UP ON THE LIST.NIH.GOV WEBSITE. THIS IS OUR LINE UP FOR THE REST OF THE 2017-2018 SEASON. WE HAVE A LOT OF GREAT SPEAKERS AS YOU CAN SEE, BOTH FROM NIH AND FROM AROUND THE COUNTRY AND AS YOU'LL SEE TODAY, FROM AROUND THE WORLD AS WELL AND WE HAVE ALREADY STARTED PLANNING NEXT YEAR'S SEASON AS WELL. JUST A REMINDER THAT THIS IS THE MIDDLE TALK OF THREE SOMEWHAT RELATED FORETUE TUS TALKS TODAY. THERE WILL BE AN IIG SEMINAR AT 4:15 IN LIPSETT. DAN IS SPEAKING THERE. AND AS WELL RIGHT AFTER THIS TALK, THERE WILL BE A RECEPTION IN THE LIBRARY. SO, ON TO PROFESSOR SCHWARTZ WHO STUDIED CHEMISTRY AT THE HEBREW UNIVERSITY OF JERUSALEM AND WENT ON TO DO HER GRADUATE STUDIES UNDER MICHAEL SELAH AND MOSES AT THE INSTITUTE. AFTER A POSTDOC AT THE UNIVERSITY OF MICHIGAN, SHE RETURNED WHERE SHE HAS BEEN SINCE 1987. A PROFESSOR OF IN OR ABOUTO IMMUNOLOGY. OVER THE YEARS, SHE HAS WON NUMEROUS AWARDS FOR HER WORK IN OPTHALMOLOGY, SPINAL CORD INJURY, NEUROSCIENCE, NEUROIMMUNOLOGY, INCLUDING 2015 LUMBERING PRIZE FOR EXCELLENCE IN MEDICAL RESEARCH IN THE 2017 RAPOPORT PRIZE FOR EXCELLENCE IN BIOMEDICAL RESEARCH. SHE IS IS THE PRESIDENT OF THE INTERNATIONAL SOCIETY OF NEUROIMMUNOLOGY AND HER OWN SCIENTIFIC JOURNEY AND IDEAS ARE SUMMARIZED IN HER 2016 BOOK, NEUROIMMUNITY. PROFESSOR SCHWARTZ IS ONE OF THOSE PEOPLE WHO LOOKS AT THINGS DIFFERENTLY FROM THE WAY OTHER PEOPLE DO AND OF COURSE THAT IS THE BEST WAY TO DO SCIENCE. HER WORK HAS LONG BEEN FOCUSED ON THE INTERFACE BETWEEN THE BRAIN AND THE IMMUNE SYSTEM AS WELL AS NORMAL AGING. AND THAT WORK HAS REALLY SHIFTED THE PARADIGM IN THIS SPACE. IN A SERIES OF GROUNDBREAKING STUDIES, SHE AND HER TEAM SHOWED THAT BOTH THE ADAPTIVE AND THE INNATE ARMS OF THE IMMUNE SYSTEM CAN CONTRIBUTE NOT ONLY TO DISEASE PATHOGENESIS, BUT ALSO CRUCIALLY TO REPAIR PLASTICITY, A CONCEPT SHE CALLED PROTECTIVE AUTO IMMUNITY I. AS PART OF THIS WORK, SHE RECENTLY DEMONSTRATED THAT THE GATEWAY FOR THE IMMUNE SYSTEM TO INTERACT WITH THE BRAIN IS NOT THE MEN IN GEES AS COMMONLY THOUGHT BUT RATHER THE HIS PEE PLEXUS DEEP WITHIN THE VENTRICULAR SYSTEM OF THE BRAIN AND THAT DYSFUNCTION OF THIS GATEWAY PLAYS A MAJOR ROLE IN ALZHEIMER'S AND IT'S THIS WORK THAT IS THE TOPIC OF HER TALK TODAY SISS STEMMATIC IMMUNITY PROTECTS THE MIND. SO WELCOME PROFESSOR SCHWARTZ. [ APPLAUSE ] >> THANK YOU FOR THE INTRODUCTION. — [ LOW AUDIO ] WHAT I'M GOING TO DOE FOR YOU IS SUMMARIZE BRIEFLY 20 YEARS OF WORKING WHICH WE CALL PARADIGM SHIFT AND DEVOTE BIG PART OF MY TALK TO ISSUE OF IMMUNE SYSTEM BY IMMUNE CHECKPOINT BLOCKADE CAN COMBAT ALZHEIMER'S DISEASE. SO FOR THE LAST 20 YEARS HAD RELATIONSHIP BETWEEN THE BRAIN AND THE IMMUNE SYSTEM AND THIS WAS SUMMARIZED — WHERE IS THE POINTER? SO THIS WAS SUMMARIZED LATELY IN AN ARTICLE, WHICH WE ASKED, CAN IMMUNE THERAPY TREATMENT OR DEGENERATIVE DISEASES SUPPORT THE TRANSIENT BOOSTING ADAPTIVE IMMUNITY CAN FIGHT ADVANCD ALZHEIMER'S? SO WE KNOW THAT ALMOST ALL NEURODEGENERATED CONDITIONS, WHETHER THERE IS ACUTE INJURY, BRAIN OR SPINAL CORD OR MORE DEGENERATED DISEASES, ALZHEIMER'S, PARKINSON, ALS, ANY DEPRESSION OR JUST AGING DEMENTIA, THERE IS LOCAL INFLAMMATION. FOR DECADES IT WAS BELIEVED THAT IT IS VERY MUCH SIMILAR TO THE INFLAMMATION THAT WE SEE IN MULTIPLE SCLEROSIS AND THEREFORE ATTEMPTS HAVE BEEN MADE TO FIGHT AGAINST THIS LOCAL NEW INFLAMMATION WITH ANTI-INFLAMMATORY DRUGS. IN 20008 THERE WAS A HUGE CLINICAL TRIAL USING NON STEROIDAL ANTI-INFLAMMATORY DRUG IN ALZHEIMER'S WHICH FAILED AND THE QUESTION WAS, WHAT HAVE WE MISSED? ACCORDING TO OUR UNDERSTANDING, THE BRAIN IS NOT — [ LOW AUDIO ] WE HAND IT NEURODEGENERATED DISEASE INVOLVES NOT ONLY THE BRAIN BUT ALSO DYSFUNCTION OF SYSTEMIC IMMUNE SYSTEM AND WE HAVE TO BE CAPER TO DISTINGUISH BETWEEN THIS NEURODEGENERATED DISEASE AND NEW INFLAMMATION ASSOCIATED WITH AUTOIMMUNE DISEASE. SO WE KNOW THE — [ INAUDIBLE ] MAJOR ROLE IS TO RECOGNIZE AND DESTROY MICROORGANISM AND MALIGNANCY. IT WAS BELIEVED FOR DECADES THAT THEY KNEW THE BRAIN ESCAPE IMMUNE SURVEILLANCE. THIS WAS BASED MAINLY — BLOOD BRAIN BARRIER — COVERED BY BLOOD BRAIN BARRIER BASICALLY — [ LOW AUDIO ] DEFINITELY BLOOD BRAIN BARRIER SHOULD BE SEEN UNDER ALL CIRCUMSTANCES. — [ LOW AUDIO ] NOW WE KNOW ALSO WITHIN THE BRAIN THERE ARE RESIDENT CELLS, THE MICROGLIA. FOR YEARS IF YOU OPEN ANY TEXT BOOK OF ANY PAPER FOR 10 OR EVEN 5 YEARS AGO, YOU WOULD SEE THERE IS INFLAMMATION MICROGLIAL FLESH INFILTRATING MICROPHAGES. WE KNOW THE MICROGLIA HAVE NOT IDENTIFIED TO MACROPHAGES, MICROGLIA, THE ONLY RESIDENT IS IN THE BRAIN. — SLOW PROLIFERATION AND MACROPHAGES DON'T REPLACE MICROGLIA. BUT IT IS VERY IMPORTANT TO NOTE MICROGLIA, THE BRAIN CELLS NEVERTHELESS THEY ARE UNDER TIGHT CONTROL TO ENSURE THAT THEY — ACTIVITY WITHOUT ENDANGERING ANY NEIGHBORING CELLS AND THEREFORE THEY ARE CONTROLLED BY THE MILIEU OF THE CNS, WHICH IS ENRICHED WITH TGF-BETA AND THERE IS ALSO VERY TIGHT CELL SETTING INTRODUCTION, THE MICROGLIAL EXPRESS RECEPTORS AND WHICH VERY MUCH SUPPRESSED BY THE LIGAND WHICH IS EXPRESSED BY NEURON AND THERE IS ALSO — SO OVER ALL MICROGLIA HAVE TIGHT CONTROL WHICH ENSURE TIGHT ACTIVITY BUT UNDER VERY STRICT REGULATION. SO SPECIFICALLY, WHAT WAS BELIEVED FOR MANY YEARS THAT THE BRAIN DOES NOT REQUIRE CIRCULATING IMMUNE CELLS. IT RELIES ONLY ON THE MYELOID CELLS. IT WAS BELIEVED THAT MICROGLIA AND INFILTRATING CELLS ARE REDUNDANT CELLS. WE KNOW NOW THEY ARE NOT. IMMUNE CELLS ENTRY THE CNS WAS BELIEVED FOR DEC DECADES THAT IT IS ONLY PATHOLOGY AND IT IS BAD. WE WILL DISCUSS THAT'S NOT THE SITUATION. AND WE KNOW NOW THAT ENTRIFUL IMMUNE CELLS FROM THE CIRCULATION REQUIRE BREAKDOWN OF THE BLOOD BRAIN BARRIER WHICH WAS COMMONLY BELIEVED. SO WHAT I'M GOING TO SHOW YOU TODAY, VERY BRIEFLY THE PAST AND MAINLY TO THE PRESENT. SO IN 1998-1999, WE SHOWED FOR THE FIRST TIME T-CELL AND MACROPHAGES SUPPORT REPAIR. WE FOUND THAT T-CELLS SUPPORT NORMAL BRAIN PLASTICITY AND EXCLUDED FROM THE BRAIN AND SINCE 2017 WHERE WE DISCOVERED THE PLEXUS SUPPORT ENTRY OF IMMUNE CELLS TO CNS WITHOUT THE NEED FOR BREACHING OF THE BLOOD BRAIN BARRIER AND THEN WE FOUND IN AGING AND IN ALL NEW DEGENERATED CONDITION, THIS BARRIER DYSFUNCTION AND WE CAN OVERCOME DYSFUNCTION BY IMMUNE CHECKPOINT BLOCKADE. SO BRIEFLY, AS I SAID, WE FOUND IN 1998 THAT MACROPHAGES SUPPORT REPAIR. THAT THE TIME IT WAS ACCEPTED WITH A LOT OF SKEPTICISM AND IT WAS CITED ONLY IN THE NEGATIVE WAY. HOW COME MACROPHAGES SUPPORT REPAIR IF THE BRAIN IS FULL OF RESIDENT MICROGLIA? WE CLAIM THAT THEY ARE NOT REDUNDANT CELLS. SUBSEQUENTLY, MANY OTHER WORK INCLUDING ALZHEIMER'S, DEMONSTRATED RECRUITMENT OF BLOOD-BORN MACROPHAGES OR MONOCYTES DERIVED MACROPHAGES AS WE CALL THEM, ARE NEEDED TO FIGHT AGAINST MANY OTHER PATHOLOGIES. WE BELIEVE THAT BLOOD BORN MACROPHAGES ARE NEEDED TO BE RECORDED IN PATHOLOGICAL CONDITIONS. WE KNOW NOW THAT BLOOD BORN MACROPHAGES CAN DISPLAY INSIDE THE BRAIN MANY ACTIVITIES. INFLAMMATORY TO INFLAMMATORY. THEY CAN BE SOURCE OF DEGRADING ENZYME. THEY CAN BE ACTING INFLAMMATORY TO DISPLAY ACTIVITY. SUBSEQUENT TO THE MACROPHAGES, WE DEMONSTRATED AN INDEPENDENT PAPER THE T-CELL ALSO SUPPORT BRAIN REPAIR AND SPECIFICALLY T-CELLS THAT RECOGNIZE CNS ANTIGEN AND WE COINED THE IDEA OF PROTECTIVE AUTOIMMUNITY. AT THAT TIME WE DIDN'T KNOW WHAT THE RELATIONSHIP BETWEEN THE T-CELL, THE MICROGLIA AND MACROPHAGES. THESE WERE TWO INDEPENDENT OBSERVATIONS. SUBSEQUENTLY, WE OBSERVED IN MODEL OF SPINAL CORD AND I JUST TOUCH IT VERY BRIEFLY. WE FOUND T-CELLS SUPPORT RECRUITMENT OF MONOCYTES DERIVED MACROPHAGES STILL. AND THE MAJOR ROLE OF MONOCYTES DERIVED MACROPHAGES, AT SITE OF THE INJURY IS TO SUPPRESS THE MICROGLIAL RESPONSE AND MONOCYTES DERIVED FROM IL10 DEFICIENT MICE FAIL TO SUPPORT REPAIR. SO OVER ALL WE HAD AN IDEA THAT T-CELL CAN SUPPORT RECRUITMENT OF MACROPHAGES AND THE LOCAL MACROPHAGES ARE NEEDED TO RESOLVE THE INFLAMMATION SUBSEQUENTLY WE FOUND NEEDED TO RESOLVE THIS TISSUE. INDEPENDENT WORK AT THAT TIME, GRADUATE STUDENTS WERE IN MY LAB. ONE IS A PROFESSOR NOW AND ONE AT THE WEIZMANN INSTITUTE, THEY WERE SPENDING WITH ME HOURS AND ASKING ME IF T-CELL ARE NEEDED TO SUPPORT REPAIR WHY WE NEVER HAVE FULL REPAIR? AND MAYBE T-CELL MUCH MORE FUNDAMENTAL FLOW BRAIN PLASTICITY. AND WE THOUGHT IF THERE IS THE CASE, IT IS VERY EASY TO CHECK. WE TOOK ANIMAL AND PLACED THEM IN RICH ENVIRONMENT, A CAGE THAT WAS DEVELOPED BY ANOTHER LAB, AND WE PLACED THE ANIMAL AND UNDER THIS CONDITION YOU CAN SEE INCREASING IN OR ABOUTOGENESIS. WHEN PLACED IMMUNE COMPROMISED ANIMAL IN THE SAME CAGE LIKE SKID MICE OR MICE THAT ARE DEFICIENT IN CNS T-CELL, WE FOUND THERE IS DRAMATIC REDUCTION IN NEUROGENESIS. IN OTHER WORDS, WE FOUND THAT ONE OF THE MECHANISM BY WHICH NEUROGENESIS IS BOOSTED IN THE RICH ENVIRONMENT INVOLVE T-CELL. YOU CAN SEE VERY NICELY HERE ARE NEWLY-FORMED IN THE HIPPOCAMPUS OF THE WILDTYPE ANIMAL AND VERY FEW IN IMMUNE COMPROMISED ANIMAL. WE CHECK COGNITION OF THESE MICE AND FOUND THE SAME THAT COGNITIVE ABILITY IS DOWN REGULATED IN IMMUNE COMPROMISED ANIMAL AND THIS WAS THE DEPLETED BY NUMEROUS WORKS THEREAFTER. SO WE SUGGESTED THAT T-CELLS SUPPORT BRAIN PLASTICITY, INCLUDING NEUROGENESIS. HIPPOCAMPAL ACTIVITY AND LATELY IT WAS SHOWN ALSO SOCIAL BEHAVIOR. SO OVER ALL WE ARE LEFT WITH KEY ISSUE. HOW CAN LEUCOCYTE ENTER TRAFFIC TO CNS WITHOUT BREACHING THE BLOOD-BRAIN BARRIER? BASICALLY OUR MACROPHAGES CONNECTED TO CNS AND MORE IMPORTANTLY, HOW CAN T-CELL SUPPORT BRAIN PLASTICITY IF THEY ARE EXCLUDED? WE KNOW THERE ARE NO T-CELL IN BRAIN PARENCHYMA. STRUGGLING WITH THIS QUESTION FOR A WHILE, ONE OF MY GRADUATE STUDENTS, OUTSTANDING GRADUATE STUDENT, SHE WAS STRUGGLING WITH IT FOR FOUR YEARS. AND FINALLY, SHE DISCOVERED IN THE MODEL OF SPINAL CORD INJURY THAT MACROPHAGES SUPPORT REPAIR AND CAN ENTER INTO THE LEFT — BUT THE ONES DISPLAYING LOCALLY AND INFLAMMATORY ROLE ARE COMING BLOOD BARRIER WHICH IS IN THE FRONT VENTRICLES. THIS WAS A BIG SURPRISE BECAUSE THE SPINAL CORD INJURIES INFLICTED HERE, SHE FOUND THAT MONOCYTES IS DERIVED MACROPHAGE THAT IS LOCALLY DISPLAY ANTI-INFLAMMATORY ROLE ARE CRAWLING THROUGH THE BLOOD BARRIER. SO THE QUESTION WAS, WHAT REVEALED ACTIVATION OF THE BLOOD BARRIER? WE WENT FURTHER AND ISOLATED THE BLOOD BARRIER. THIS IS THE COREY PLEXUS EPITHELIUM AND WE FOUND THIS TISSUE, EVEN IF WE EXPENSIVELY PRO FUSED THE ANIMALS, WE FOUND T-CELL OUTSIDE THE BLOOD VESSEL IN STROMA. WE TOOK THIS T-CELL AND WILL WE DECIDED TO EXPLORE FURTHER HOW IT WORKS. WE ENVISIONED THAT MAYBE UNDER INJURIOUS CONDITION, WE KNOW THERE IS RELEASE OF IL6, TNF AND IL1 BETA. SO ENVISION THAT MAYBE THEVILLE I OF THE EPITHELIUM CELLS SENSES THE CYTOKINE MAYBE THERE ARE T-CELLS SITTING IN THE STROMA. WE ISOLATED THIS T-CELL FOUND THAT ALMOST 97% OF THESE T-CELL ARE CD4 POSITIVE T-CELL WHICH MEANS THEY ARE ENGAGED WITH THE COGNITIVE ANTIGEN AND WE FOUND IN THE STROMA T-CELL ENGAGED WITH ANTIGEN PRESENTING CELLS. WE FOUND THAT THIS T-CELL CAN LOCALLY REPRODUCE INTERFERON GAMMA AND IL4 AND IL10. WE DIDN'T FIND ANY T-CELL IN THIS STROMA. TO TEST OUR WORKING HYPOTHESIS, WE TESTED WHAT ARE THE T-CELL RECOGNIZING? AND TOGETHER WITH THE WEIZMANN INSTITUTE, WE DECIDED TO SEQUENCE THE T-CELL RECEPTOR OF THE T-CELLS WE ISOLATED FROM THE EPITHELIAL AND PLEX US AND WE FOUND T-CELLS, 70% OF THEM ARE RECOGNIZING CNS ANTIGEN. IN OTHER WORDS, THE GATEKEEPER OF THE BRAIN, THE COREY PLEXUS EPITHELIUM IS ENRICHED WITH T-CELL THAT RECOGNIZES TNF ANTIGEN. WE CREATED A MONOLAYER AND TESTED WHETHER INDEED THERE IS A CYTOKINE EPITHELIAL CELLS ARE SENSING SUCH AS TNF ALPHA UP REGULATED INTO IT AFFECTING EXPRESSION OF TRAFFICKING MOLECULES BY THE CHROID PLEXUS AND CHEMOKINE AND INTEGRIN. SO WE EXPOSED THE CELLS EITHER TO TNF ALPHA, OI6 OR IL1 BETA AND ALSO TO THE CYTOKINE THAT WE FOUND AT THE T-CELL ARE PRODUCING SUCH AS INTERFERON GAMMA, IL4 OR IL10. TO MAKE A LONG STORY SHORT, WE FOUND THAT THE ORANGEY CYTOKINE THAT COMES FROM THE T-CELL THAT ACTIVATES THE COREY PLEXUS IS INTERFERON GAMMA. CHROID PLEXUS. NONE OF THEM ARE ACTIVATING THE CHROID PLEXUS EPITHELIUM. THEY DIDN'T ACTIVATE ONLY INTERFERON GAMMA. AND THERE WAS ENERGY BETWEEN THE TNF ALPHA AND INTERFERON GAMMA TO ACTIVATE THE CHROID PLEXUS FOR TRAFFICKING MOLECULES, WHICH WAS VERY SATISFACTORY FOR US BECAUSE THAT IS WHAT WE ENVISIONED. THERE IS A SINGLE GENE BETWEEN WHAT EPITHELIAL CELLS SENSE WHEN IS THERE INFLAMMATION IN THE BRAIN AND CYTOKINE THAT PRODUCE T-CELL. WE FOUND THAT INTERFERON GAMMA KNOCK-OUT MICE OR INTERFERON GAMMA RECEPTOR KNOCK-OUT MICE, THERE IS A DRAMATIC REDUCTION IN THE NUMBER OF T-CELLS THAT WE FOUND IN THE CSF AND THERE IS DRAMATIC REDUCTION IN TRAFFICKING MOLECULES. WE TESTED WHETHER TNF ALPHA IS ACTIVATION OF THE CHROID PLEXUS EPITHELIUM AND WE FOUND YES, IT IS INDEED VERY MUCH DEPENDENT ON NF-kB/P65. SO WE FOUND INTERFERON GAMMA IS THE KEY CYTOKINE THAT IS NEAR THE ACTIVATED CHROID PLEXUS EPITHELIUM FOR TRAFFICKING. OUR KEY QUESTION CAME OUT, WHAT DOES THE FATE OF THE COMPARTMENT EFFECT THE BRAIN NEURODEGENERATED DISEASE? AND IF SO, CAN WE MANIPULATE THE CHROID PLEX US AND AFFECT THE DISEASE? WE STARTED IN AGING AND THEN WE MOVED TO ALZHEIMER'S. SO WE FIRST TESTED TOOK THE CHROID PLEXUS WITH AGING AND WE FOUND THAT THERE IS DRAMATIC REDUCTION IN THE AVAILABILITY OF INTERFERON GAMMA WITH AGING OF THE MOUSE AROUND 18 MONTHS THERE IS DRAMATIC DROP. WE TESTED WHETHER THE CHROID PLEXUS IN AGED MICE EXPRESS ANY OF THE COGNITIVE IMPAIRING MOLECULE THAT WE FOUND BY THE CREW. AND WE FOUND THERE IS A DRAMATIC INCREASE. WE FURTHER DECIDED TO GET MORE INSIGHT WHETHER AGING OF THE BRAIN REFLECTS AGING OF THIS CHROID PLEXUS EPITHELIUM OR AGING OF THE BLOOD OR AGING OF THE TISSUE. TO THIS END, WE COLLECTED 11 TISSUE FROM YOUNG ANIMAL AND 11 TISSUE FROM AGED ANIMAL AND DID OTHER SEQUENCING. TO OUR SURPRISE, WE FOUND IN AGING OF THE CHROID PLEXUS AS A VERY UNIQUE SIGNATURE THAT IS ELEVATION OF INTERFERON BETA WHICH WE DIDN'T FIND IN ANY OTHER AGED TISSUE AND WE DIDN'T FIND IN YOUNG TISSUE. SO THERE IS VAST ELEVATION OF INTERFERON BETA, TYPE I. AND DOWNREGULATION OF INTERFERON GAMMA WHICH WE FOUND BEFORE. INTERESTINGLY, SEVERAL MONTHS BEFORE OUR SCIENCE PAPER THERE WAS ANOTHER SCIENCE PAPER SHOWING THIS RELATIONSHIP BETWEEN INTERFERON BETA AND INTERFERON GAMMA. WE GOT HUMAN SECTION FROM UK AND WE ASKED EXPLICITLY TO GET TISSUE FROM AGED POPULATION, NEUROLOGICAL DISEASE AND WE FOUND IT IN AGED POPULATION THE SAME SIGNATURE OF THE CHROID PLEXUS AND ELEVATION OF SIGNATURE INTERFERON BETA. TOGETHER WITH OTHERS, WE DECIDED TO EXPLORE WHETHER THE ELEVATION OF INTERFERON BETA AND THE DOWNREGULATION OF INTERFERON GAMMA IS CAUSED BY SIGNALING FROM THE BRAIN OR FROM THE CIRCULATION. SO WE CREATED THESE MICE AND WE FOUND THAT CONNECTING YOUNG ANIMAL TO AGED ANIMAL, AGE TO AGE, YOUNG TO YOUNG, IS CONTROLLED. TO MAKE A LONG STORY SHORT, WE FOUND THAT THE DOWNREGULATION OF INTERFERON GAMMA IS CONTROLLED BY THE CIRCULATION WHEREAS THE UP REGULATION OF INTERFERON BETA IS CONTROLLED BY SIGNALING COMING THROUGH THE CSF. THE NEXT QUESTION WE ASKED OURSELVES, CAN WE REJUVENATE THE CHROID PLEXUS AND RESTORE ABILITY? TO REJUVENATE THE CHROID PLEXUS, WE INJECTED INTO THE CS IS F ANTIBODY DIRECTED TO TYPE I INTERFERON BETA RECEPTOR. WE ENVISIONED INTERFERON BETA WHICH IS PRODUCED BY THE EPITHELIAL CELLS CAN DO REGULATION AND EFFECT EPITHELIAL CELLS AND CAN EFFECT THE BRAIN. SO TO NEUTRALIZE BOTH ACTIVITY, WE INJECTED ANTIBODY DIRECTLY INTO INTERFERON BETA RECEPTOR. WE FOUND THAT WE HAVE STORED ALL ACTIVITY OF THE CHROID PLEXUS BY NEUTRALIZING INTERFERON BETA RECEPTOR RELATIVE TO ISOTYPE IGG CONTROL AND WE REDUCED GLIOSIS IN THE AGED BRAIN. TO FURTHER TEST WHETHER IT HAS ANY EFFECT ON COGNITION, WE TOOK AGED MICE AND SCORED THE MICE FIRST TO FIND OUT THOSE AGED MICE THAT HAVE IMPAIRED COGNITION AS WAS REPORTED AND THE SAME IN HUMAN, 30% OF THE AGED MICE ARE STILL INTACT MEMORY. WE TOOK 70%, SPLIT INTO TWO GROUP, ONE RECEIVED IGG CONTROL AND THE OTHER RECEIVED THE ANTIBODY TO INTERFERON BETA RECEPTOR AND WE FOUND THAT THIS GROUP SHOWED IMPROVED COGNITION ALMOST TO THE LEVEL OF THE THOSE WITH INTACT MEMORY. SINCE WE PUBLISHED THIS PAPER, WE DECIDED TOO CHECK WHETHER THE SIGNALS OF THE INTERFERON BETA WHICH IS PRODUCED BY THE CHROID PLEXUS EFFECT THE MICROGLIA. WE SAW THE MICROGLIA FROM AGED BRAIN AND FROM YOUNG BRAIN AND THEN WE FOUND THE MAJORITY OF THE SIGNATURE OF THE MICROGLIA AGED MICE IS TYPE I INTERFERON. AND AMONG THE MOLECULE EXPRESSED BY THE AGED MICROGLIA IN WHICH EFFECTED THE NEUTRALIZING INTERFERON BETA RECEPTOR WHICH WAS PUBLISHED AS COGNITIVE IMPAIRING. AND ANOTHER PUBLISHED BY BETH STEVENS AND OTHERS, IMPAIRING COGNITION. SO OVERALL, WHAT WE FOUND IS THAT TYPE I IS A VERY PROMINENT SIGNATURE OF THE MICROGLIA. AND NEUTRALIZING TYPE I SIGNATURE CAN ALLEVIATE SOME OF THE SYMPTOMS OF AGING AND RESTORE MICROGLIA ACTIVITY. BASED ON THIS, WE DECIDED TO GO TO ALZHEIMER'S WITH THE IDEA THAT WE ALREADY KNEW IN ALZHEIMER'S WE NEED MACROPHAGES TO FIGHT AGAINST ALZHEIMER'S. WE ALREADY KNEW ENTRY OF MACROPHAGES TO THE CNS DEPEND ON THE CHROID PLEXUS EPITHELIUM AND WE ALREADY KNEW THAT WE NEEDED INTERFERON GAMMA IN ORDER TO SUBJECTIVATE THE CHROID PLEXUS AND INTERFERON GAMMA IS GOING DOWN WITH AGING. WE DECIDED TO SEE WHAT IS THE FATE OF THE CHROID PLEXUS IN AGING AND WHETHER WE CAN REVERSE IT. SO, AS YOU'RE FAMILIAR, THERE IDENTIFIED IN ALZHEIMER'S INCLUDING AMYLOID PLAQUES AND NEUROFIBERI LARRYITAGE ELSE AND THERE ARE ALREADY SEVERAL ANIMAL MODELS THAT MIMICS THE NEUROFIBRILLARY TANGLES. THERE IS A LOCAL NEUROINFLAMMATION AS I SAID AT THE BEGINNING OF MY TALK, TO TREAT THE NEW INFLAMMATION WITH SYSTEMIC ANTI-INFLAMMATORY DRUG. NEEDLESS TO SAY THAT ANY THERAPY THAT WAS DIRECTED TO A BETA PLUS WASN'T TURNED OUT TO BE DISEASE MODIFYING. IT'S NOT BECAUSE A BETA PLUS ARE NOT DESTRUCTIVE BUT BY THE TIME THAT THEY ARE PROMINENT AND THERE IS COGNITIVE DECLINE, IT MAY BE EFFICIENT BUT INSUFFICIENT. SO WE DECIDED TO FOCUS ON THIS IS JUST TO SUMMARIZE THE WORK THAT WAS PUBLISHED ALTHOUGH THE USE IS DEMONSTRATING THE RECRUITMENT OF MACROPHAGES TO THE SITE OF PATHOLOGY CAN BENEFIT THE DISEASE NOT ONLY FACILITATING REMOVAL OF BLOOD BUT ALSO CHANGING THE MILL YOU YOO OF THE CNS FROM ONE INFLAMMATORY TO LES INFLAMMATORY. SO WE DECIDED TO FOCUS ON TWO ANIMAL MODEL OF ALZHEIMER'S. ONE WHICH IS A ASSOCIATED WITH A BETA PATHOLOGY AND ONE IS ASSOCIATED WITH TAU PATHOLOGY. THE A BETA PATHOLOGY, THERE ARE SEVERAL MODELS. WE DECIDED TO FOCUS ON THE ONE WHICH WE CALL THE FIVE X5. THERE ARE FIVE HUMAN MUTATION AND THIS WAS DEVELOPED IN CHICAGO 2006. THIS IS THE ONLY MODEL THAT STIMULATE ALMOST ALL THE SYMPTOMS THAT ARE IN HUMAN WITH THE SENSE THERE IS A COGNITIVE LOSS, THERE IS A BAIT PATHOLOGY AND THERE IS ALSO NEURONAL LOSS AND LOCAL INFLAMMATION. SO WE STARTED WITH THIS MODEL AND THE FIRST THING THAT WE TESTED WHETHER THE CHROID PLEXUS EPITHELIUM EXPRESSED TRAFFICKING MOLECULES. AND WE TESTED ALL OF THE TRAFFICKING MOLECULES THAT WE KNEW ALREADY THAT ARE NEEDED FOR RECRUTMENT EVER MACROPHAGES. WE TESTED BY — AND THESE LINES SHOW YOU THE EXPRESSION OF TRAFFICKING MOLECULES BY AGED CONTROL, YOU CAN SEE FROM TWO MICE ONWARD, NOT ONLY THERE IS NO ELEVATION THAT YOU NEED TO FACILITATE MACROPHAGES BUT IT IS GOING DOWN. AND THE MOST STRIKING DOWNREGULATION CYCLE WAS INTERFERON GAMMA DEPENDENT. BASED ON THIS, WE WENT TO SEE IS WHETHER IN THIS MOUSE MODEL THERE IS REDUCTION IN THE AVAILABILITY OF INTERFERON GAMMA. AND WE FOUND BY FLOW CYTOMETRY AND INTERCELLULAR STEMMING INTERFERON GAMMA AND THERE IS A STRIKING DROP IN INTERFERON GAMMA IN THIS MOUSE MODEL. WE TESTED EXPRESSION OF — AND FOUND IN AC YOUNG PEOPLE, THE CHROID PLEXUS EXPRESS LEVEL OF ICON GOING DOWN WITH AGING AND FURTHER IN [ INAUDIBLE ] SO IN THIS MOUSE MODEL WE FOUND THERE IS REDUCTION OF TRAFFICKING MOLECULE AND REDUCTION INTERFERON GAMMA. SUBSEQUENT TO OUR WORK, THERE WAS ANOTHER WORK USING ANOTHER MOUSE MODEL OF ALD ALZHEIMER'S, THE J20, AND THEY FOUND EXACTLY THE SAME PHENOMENA THAT INTERFERON GAMMA IS GOING DOWN AND ICON IS GOING DOWN WITH THE DISEASE PROGRESSION. NOW IN PRINCIPLE, WE TESTED TO SEE WHETHER THERE IS ANY RELATIONSHIP BETWEEN EXPRESSION OF TRAFFICKING MOLECULES AND ENTRY OF IMMUNE CELLS TO THE CSF AND IN THE MODEL OF STRESS WHICH LEADS TO POST-TRAUMATIC STRESS DISORDER SYMPTOMS, WE FOUND A GREAT CORRELATION BETWEEN EXPRESSION OF TRAFFICKING MOLECULES AND OUR ABILITY TO DETECT IMMUNE CELLS MAINLY T-CELL INTO CSF. SO IN PRINCIPLE THERE ARE SEVERAL WAYS TO AUGMENT LEVEL OF AVAILABILITY OF INTERFERON GAMMA, WHICH I CALL THEM EITHER PRESS THE GAS OR LOOSEN THE BRAKES. SO EITHER YOU CAN ACTIVATE THE IMMUNE SYSTEM OR — TO ACTIVATE YOU NEED MOLECULES OR ANTI-VACCINATION. SO WE DECIDED TO TESTED WHETHER AUGMENTING AVAILABILITY FOR INTERFERON GAMMA COULD BE ACHIEVED BY BLOCKING SUPPRESSIVE MECHANISM. NOW SUPPRESSIVE MECHANISM CAN BE MYELOID SUPPRESSIVE CELLS OR IMMUNE CHECKPOINT INHIBITORY IMMUNE CHECKPOINT. WE DECIDED BECAUSE WE KNOW THAT WITH AGING THERE IS ELEVATION OF REGULATORY — [ INAUDIBLE ] WE KNOW WITH EXHAUSTION OF THE IMMUNE SYSTEM THERE IS ELEVATION OF INHIBITORY IMMUNE CHECKPOINT. 22 DECIDED TO FOCUS ON APPROACH OF LOOSENING THE BREAKS. SO WHAT WE DID THE FIRST THING WE DID IS BRED THE ALZHEIMER'S MICE WITH FOX P3R WHICH WE GOT FROM — AND WE CAN DEPLETE REGULATORY T-CELL. WE DEPLETED THEM AFTER TWO WEEKS THE LEVEL OF REGULATORY CELLS REBOUND. AND WE TESTED WHETHER A SINGLE SESSION OF REDUCING REGULATORY T-CELL WILL BE SUFFICIENT TO ACTIVATE THE CHROID PLEXUS AS A GATEWAY AND TO OVERCOME THE DISEASE PATHEDDOLOGY. SO WE FOUND THAT A WEEK AFTER THE DEPLETION OF REGULATORY T-CELL AT THE CHROID PLEXUS EPITHELIUM WAS ACTIVATED BOTH MY IMMUNOHISTOCHEMISTRY. WE FURTHER FOUND THAT MONTHS AFTER THE DEPLETION OF REGULATORY T-CELL WE SEE MYELOID CELLS AND REGULATORY T-CELL IN THE BRAIN PARENCHYMA AROUND THE PLEXUS. WHEN WE CHECK COGNITIVE ABILITY AND PATHOLOGY, WE WERE AMAZED TO SEE, THIS IS THE PATHOLOGY IN THIS MOUSE MODEL THE BETTER PLAQUES ARE HUMAN PLAQUES. SO VERY EASY TO DISTINGUISH. WE USE ANTIBODY DIRECTED TO HUMAN A BETA AND I'M NOT SURE THAT YOU CAN SEE WITH THIS SLIDE BUT YOU CAN SEE THE HIPPOCAMPUS OF THE MICE WITHOUT DEPLETION AND THIS IS THE DEPLETION ASSIST STEMMATIC OF REGULATORY T-CELL. THERE WAS A DRAMATIC REDUCTION BOTH IN THE CORTEX AND THE HIPPOCAMPUS. YOU CAN SEE QUANTIFICATION HERE. WE TESTED COGNITIVE ABILITY BY MOUSE MAZE WHICH MEASURE MAINLY SPECIAL LEARNING AND MEMORY. SO THIS MAZE INVOLVES THREE PHASES. A PHASE OF LEARNING ACQUISITION AND THE — TWO PHASES OF MEMORY. SO DURING FOUR DAYS OF MEMORY LEARNING ACQUISITION, THE ALZHEIMER'S MICE THAT WERE NOT DEPLETED OF REGULATORY T-CELL, DIDN'T LEARN THIS. THE BLACK SHOW YOU WILDTYPE AND BLUE SHOW MICE WITH DEPLETED REGULATORY T-CELLS. SO ALMOST BEHAVE AS NORMAL MICE. WHEN WE REMOVED THE PLATFORM FOR THE MAZE SO IN THE WATER POOL, THERE IS A PLATFORM WHICH IS VERY CLOSE TO THE SURFACE OF THE WATER. THE ANIMAL DON'T SEE THE PLATFORM BUT THERE ARE PICTURE AROUND THE WATER POOL. SO THEY CAN REMEMBER TO NAVIGATE THEMSELVES TO THE PLATFORM BASED ON THE PICTURE AROUND THE POOL. SO WHEN YOU REMOVE THE PLATFORM WE MEASUREED THE TIME THAT ANIMAL SPENT AROUND THE PLACE THAT THEY REMEMBERED THE PLATFORM. SO THE ANIMAL DEPLETED THE REGULATORY T-CELL REMEMBERED VERY SIMILAR TO THE WILDTYPE ANIMAL WHEREAS ANIMALS THAT WERE NOT DEPLETED OF REGULATORY T-CELL DIDN'T REMEMBER AND FOUND ALSO DRAMATIC REDUCTION IN THE GLIOSIS. BASED ON THIS IDEA WE REALIZED THAT WE NEED TO RECORD TOTALS ALZHEIMER'S BRAIN REGULATORY T-CELL AND IN ORDER TO ACHIEVE THESE, WE INDIVIDUAL TO REDUCE THE REGULATORY T-CELL TO ALLOW AVAILABILITY OF INTERFERON GAMMA PRODUCING CELLS AT THE CHROID PLEXUS. THIS WAS FOR US VERY MUCH REMINISCENT OF WHAT WE KNOW IN CANCER AND WE DECIDED TO CHECK WHETHER BLOCKING THE IMMUNE CHECKPOINT WE CAN ACHIEVE THE SAME. NOW WE DECIDED TO FOCUS ON PD-1/PD-L1 FOR A REASON. WE KNEW THE MEMORY WAS CD4 AND CD8 EXPRESSING PERMANENT D1 AND MORE IMPORTANTLY, THE LIGAND, THE PD-L1 CAN BE EXPRESSED BY EPITHELIAL CELLS REGULATORY T-CELLS AND ANTIGEN PRESENTING CELLS, ALL OF WHICH WE HAVE AT THE CHROID PLEXUS EPITHELIUM. SO WE ENVISION THAT SUPPRESSIVE T-CELL CAN OUT SUPPRESS EITHER BY REGULATORY T-CELL ANTIGEN PRESENTING CELLS AND ALSO DECIDES THE CHROID PLEXUS. SO WE DECIDED TO GIVE THE ANIMAL EITHER ANTI-PD-1 OR ANTI-PD-L1 AND THEREBY UNLEASH CD4 POSITIVE T-CELL IN ADDITION TO THE CD8 WHICH WILL UNLEASH FOR CANCER THERAPY. WE STARTED WITH ANTI-PD-1 BUT I'LL SHOW YOU UNPUBLISHED DATA WITH ANTI-PD-L1. SO, THE FIRST THING THAT WE DID, WE GAVE THEM — THIS WAS PUBLISHED A YEAR AGO IN NATURE MEDICINE. SO WE GAVE THE ANIMAL ANTI-PD-1 AND CHECK WHETHER THE CHROID PLEXUS WAS ACTIVATED INSIDE THE INTERFERON GAMMA-TYPE SIGNALING AND THIS WAS THE CASE. AS CONTROL WE USE IGG CONTROL. ANTIBODIESED TO — WE CHECKED TO SEE WHETHER THE CHROID PLEXUS WAS ACTIVATED TO EXPRESS TRAFFICKING MOLECULES AND SAW IT ACTIVATED. AND INTERESTINGLY, WHEN WE GAVE THE ANIMAL PRIOR TO THE ANTI-PERMANENT D1 A DAY BEFORE THE ANTI-PD-1 INTERFERON GAMMA, WE BLOCKED THE INDUCED ACTIVITY OF THE ANTI-PD-1 WHICH WAS VERY FINE FOR US BUT INDEED IT WAS INTERFERON GAMMA DEPENDENT. WE NEXT TESTED WHETHER AS A RESULTED OF THE TREATMENT THERE IS INCREASED RECRUITMENT OF MONOCYTES DERIVED MACROPHAGES, AND WE FOUNDED THAT TWO WEEKS AFTER THE TREATMENT THERE WAS ABOUT TWO FOLD INCREASE IN THE NUMBER OF MONOCYTES DIVIDE MACROPHAGES AND AGAIN, WHEN WE GAVE THE ANIMAL ANTI-INTERFERON GAMMA PRIOR TO THE ANTI-PD-1, WE BLOCKED THIS ELEVATION. BESIDES THIS, WE DECIDED TO MOVE TO TEST COGNITIVE ABILITY AND IN THIS CASE, WE INTENTIONALLY USED VERY ADVANCED STAGE OF THE DISEASE. IN THIS ANIMAL, THERE IS A COMPLETE LOSS OF COGNITION BASED ON THE PEOPLE THAT DEVELOPED THIS MODEL AND BASED ON OUR EXPERIENCE AT SIX MONTHS OR MORE. SO WE STARTED AT 10 MONTHS OLD AND TREATED THE ANIMAL 10 MONTHS OLD WITH ANTI-PD-1 AND TESTED THEM EIGHT MONTHS LATER. THIS IS SAY SINGLE INJECTION IN OUR RECORDINAL PAPER WE GAVE TWO DOSAGE — [ INAUDIBLE ] SUBSEQUENTLY WE REPEATED AND INJECTION WAS SUFFICIENT AND MICE LATER TO SEE COGNITIVE ABILITY. NOW IT WAS RECOMMENDED IN THIS MICE TO HUES THE TOOL MAZE SO AGAIN WATER POOL BUT THEY ARE 6 ARM IN THE WATER POOL AND IN ONE ARM THERE IS A PLATFORM AND WHAT YOU MEASURE THE LEARNING CURVE, THE ANIMAL BY THE NUMBER OF AIR ERRORS THEY MADE BEFORE THEY NAVIGATE THEMSELVES STRAIGHT TO THE ARM WITH THE PLATFORM. SO TO ADD SOME MICE SHOWN IN THEY REMEMBERED. THE BLACK SHOWS YOU WILDTYPE ANIMAL. GRAY SHOW YOU THE ONE SYSTEM TREATED WITH THE IGG WHICH WE CALL PLACEBO AND THE GREEN SHOW YOU ANIMALS THAT WERE TREATED WITH ANTI-PD-1 SO THERE WAS REVERSE OF COGNITIVE LOSS IN THIS MICE. WE TESTED THE PLAQUE BURDEN AND YOU CAN SEE HERE THIS ANIMAL RECEIVED TWO SESSION OF INJECTION AND ANALYZE TWO MONTHS AFTER WE STARTED TREATMENT. SO ANIMALS THAT RECEIVED 3 INJECTIONS WE TESTED TWO MICE AFTER WE STARTED, THERE WAS A VERY NICE PLAQUE REMOVAL AND THE GREEN SHOW YOU GLIOSIS AND THE RED SHOW YOU THE PLAQUE. WHEREAS ANIMALS THAT WERE TREATED WITH IGG YOU STILL SEE A VERY HIGH BURDEN OF PLAQUE AND GLIOSIS. SO THE EFFECT ON HIS STOL GEE WAS DRAMATIC. SINCE WE PUBLISHED THIS PAPER, WE DECIDED TO SEE WHETHER EVERY TREATMENT IN THIS MICE MODEL WILL PREVENT LOSS OF COGNITION OR DELAY LOSS OF KIG NITION. SO WE STARTED TO TREAT THE ANIMAL AT THREE MONTHS, FOUR MONTHS, AND FIVE MONTHS AND TESTED THEM AT FIVE AND SIX MONTHS. AND WHAT CAN YOU SEE AT FIVE MONTHS, THE ONES THAT — THE CONTROL MICE ARE STILL SHOWING SOME COGNITIVE ABILITY AT THE LAST TRIAL, THE LAST DAY. AT SIX MONTHS THEY ALREADY — SO IN THE CAUSE OF THIS EXPERIMENT, THE CONTROL ARM BECOMING WORSE WHEREAS THE ONES THAT TREATED WITH ANTI-PD-1 MAINTAINED 80 TO LEARN AND REMEMBER. SUBSEQUENTLY, WE TESTED TO SEE WHETHER THE TREATMENT IS ASSOCIATED WITH RESCUE OF NEURONS WHICH WE MEASURE BECAUSE THAT IS THE PLACE THAT WAS RECOMMENDED IN THIS MOUSE MODEL TO SEE NEURONAL SURVIVAL AND CASPASE 3 IS A MEASURE OF APOPTOSIS. YOU CAN SEE HERE THAT THE TREATMENT IS A VERY NICE NEW PROTECTION AND THERE IS DRAMATIC REDUCTION IN CASPASE 3 EXPRESSED BY THE NEURONS. WE DECIDED TO TEST WHETHER ANTI-PD-L1 WILL HAVE SIMILAR EFFECT AND YOU CAN SEE DOSE DEPENDENT RESPONSE. THE . 1 MILLIGRAM. NO EFFECT .5 AND 1.5. SO THE ANTI-PD-1 HAS SIMILAR EFFECT AND SHOW VERY NICE DOSE DEPENDENCY AND WE SHOW VERY NICE EFFECT ON THE INFLAMMATORY MILIEU IN FAVOR OF THE ELEVATION OF IL10 AND REDUCTION OF IL20. NOW IMPORTANTLY, BECAUSE THE TREATMENT IS GIVEN SYSTEMIC AND NOT TO THE BRAIN, WE ENVISIONED THAT IT IS NOT DEPENDENT ON THE TYPE OF PATHOLOGY OF THE BRAIN BUT WE ARE ACTIVATING A CASCADE OF IMMUNE EVENTS THAT STARTS AND CULMINATES IN THE BRAIN. SO WE DECIDED TO CHECK ANOTHER MOUSE MODEL OF ALZHEIMER'S WHICH IS NOT A BETA DRIVEN AND IT'S TAU PATHOLOGY. IN THIS MODEL, THE HUMAN MUTATION OF MICROTUBULAR REPORTING IS PHOSPHORYLATED. IN THIS MOUSE MODEL YOU TEST — RECOMMENDED TO TEST SHORT-TERM MEMORY. SO BASICALLY IT IS A ANIMALS FIRST LEARN TWO YAM ONE ARM IS CLOSED. AND AFTER THAT THEY ARE HABITUATED TO THE TWO ARM YOU OPEN THE THIRD ARM AND MEASURE THE TIME THE ANIMAL SPENT IN THE NOVEL ARM. IF THEY DON'T REMEMBER, YOU SPEND EQUALLY TIME IN THE SHORT ARM. IF REMEMBER, THEY WILL SPEND MORE TIME IN THE NOVEL THAN IN THE TWO OTHER ARM. SO, YOU CAN SEE IT VERY NICELY HERE. SO THE TAU PATHOLOGY TREATED WITH IGG AND THESE ARE TREATED WITH ANTI-PD-1 AND ANTI-PD-L1. SO THE WILDTYPE SPENT 60% OF THE TIME IN THE NOVEL ARM AND SIMILARLY THE TREATED ONE, AND WAS FOUND IN THIS MOUSE MODEL AGAIN, THE TREATMENT IS ASSOCIATED WITH RECRUITMENT OF MONOCYTES DERIVED MACROPHAGE SYSTEM INTO THE PARENCHYMA AND THERE IS REDUCTION OF PHOSPHORYLATION OF TAU. SO THE EFFECT OF THE DISEASE IS NOT DEPENDENT ON THE TYPE OF ETIOLOGY BUT OF THE IMMUNE SYSTEM AND THIS IS JUST TO SHOW YOU THAT IT WILL CAUSE A DRAMATIC REDUCTION IN THE PHOSPHORYLATION OF TAU MUTATION. NOW, WE REPEATED THIS EXPERIMENT IN A DOSE DEPENDENT MANNER AND THIS SHOWS YOU VERY NICELY THIS IS WILDTYPE ANIMAL. THE TIME INDIVIDUALS SPENT IN THE NOVEL ARM. THIS IS IGG CONTROL IN ALL ARM AT THE SAME TIME. THIS IS LOW DOSE IN ALL ARM THE SAME TIME AND IF YOU GO IL, YOU SEE ANIMALS SPENT MORE IN THE NOVEL ARM BOTH IN.5 AND 1.5. SO BASED ON ALL OF THIS, WE ASKED OURSELVES WHY DO WE NEED TO RECRUIT MACROPHAGES? WHY MICROGLIA CANNOT DO THE JOB? SO I FINISH WITH A VERY BRIEF STORY ABOUT THE MICROGLIA. WE DECIDED TO CHECK WHAT IS THE FATE OF THE MICROGLIA IN THIS DISEASE? THEY WILL SUPPORT ON MICROGLIA ALZHEIMER'S CLAIMING THEY ARE NOT EFFECTIVE, SOME CLAIMS THEY ARE INFLAMMATORY. SO A LOT OF — AND WE FOUND THAT LACK OF CONSENSUS IS REFLECTION OF NOT HAVING GOOD MARKERS FOR MICROGLIA. SO TOGETHER WITH THE WEIZMANN INSTITUTE, WE DECIDED TO GO FOR SINGLE-CELL RNA-SEQ OF THE MICROGLIA. I KNOW SOME OF YOU — [ INAUDIBLE ] MICROGLIA WE DID COLLABORATION AND WE DECIDED TO COLLECT SINGLE-CELL RNA AND SINGLE CELL MICROGLIA INTO THE SEQUENCE. WHAT WE FOUND IS THAT IN THE ALZHEIMER'S THERE IS SAY SMALL SUB POPULATION OF MICROGLIA THAT BEHAVE DISTINCTIVELY FROM THE REST, ABOUT 5-10%. WE COULDN'T DETECT THEM IF YOU DO YOUR BEST RNA SEQUENCING OF MICROGLIA ONLY BY SINGLE CELL COULD WE DETECT THEM. WE FOUND THAT BASED ON THE MARKERS THEY EXPRESSED, THEY ARE LOSING SOME OF THE STRAINING ACTIVITY OF MICROGLIA SUCH AS CXCL1 AND THEY ARE UP REGULATED MANY GENES THAT HAVE ALREADY REPORTED BY GWAS THAT ARE ASSOCIATED WITH THE DISEASE PATHOLOGY SUCH AS [ INAUDIBLE ] SO BASED ON THE PROFILE, WE FELT CONFIDENT THIS MICROGLIA ASSOCIATED WITH ACTIVITY WHEN WE FOUND THEY ARE ADJACENT TO THE PLUS IN MICE AND IN HUMAN. WE FOLLOWED THE DEVELOPMENT OF THIS MICROGLIA AND WE FOUND THAT THEY ARE DEVELOPING WITH THE DISEASE PROGRESSION. AND THEN WE COLLABORATED WITH MARCO BECAUSE WE FOUND THAT THEY ARE ELEVATEING TRENCHING 2 AND IT'S — TREMENDOUS 2. WE FIRST SAW DOWNREGULATION OF THE MANY GENES THAT ARE ASSOCIATED WITH HOME STAYSIS AND THEN WE FOUND FRESHMEN 2 AND THEN FOUND MANY OTHER. SO WE WANTED TO SEE WHETHER TREM2 IS KEY REGULATED IN DEVELOPMENT. SO WE HAVE SINGLE CELL MICROGLIA FOR WILDTYPE ANIMAL, 22 POSITIVE
— TREM2
POSITIVE AND NEGATIVE MOUSE. TO MAKE A LONG STORY SHORT, WHAT WE FOUND THAT THE FIRST STAGE OF MICROGLIA ACTIVATION IN THIS MOUSE MODEL IS TREM2 INDEPENDENT AND THE LAST STAGE IS TREM2 DEPENDENT. THE DISEASE IS WORSE IN T. RM2 KNOCK-OUT MICE AND WHAT WE ARE SEEING IN TREM2 KNOCK OUT ALZHEIMER'S MICE WE DON'T SEE THE MICROGLIA. ALL OF THEM ARE STUCK IN THE INTERRING PHASE. SO IT MEANS THEY ARE TREM2 NEGATIVE AND ELEVATION WITH MICROGLIA ORCHESTRATE THE DEVELOPMENT OF THIS DISEASE ASSOCIATE MICROGLIA AND WE ARE CURRENTLY FOCUSING TO SEE TO WHAT EXTENT THEY ARE BENEFICIAL AND WHETHER THE TREATMENT IS BY RECRUITING MACROPHAGES OR CHANGE PROFILE. BUT WE HAVE ONLY PRELIMINARY DATA. SO OVERALL, IED LIKE TO SUMMARIZE MY TAKE HOME MESSAGE TODAY. SO WHAT WE ARE SHOWING THIS WELL CONTROLLED IMMUNE ACTIVATION OUTSIDE OF THE CNS RATHER THAN SUPPRESSION IS NEEDED TO COMBAT NEURODEGENERATED DISEASE REGARDLESS OF THE DISEASE ETIOLOGY. WE FOUND IN A BETA AND FOUND IT IN THE TAU. SINCE IMMUNE ACTIVATION IS NOT DISEASE SPECIFIC, IT CAN POTENTIALLY BE APPLICABLE TO A WIDE SPECTRUM OF DISEASE. THE CHOICES OF ACTIVATION MODE, WHETHER STEPPING ON THE GAS PEDAL OR RELEASING THE BREAKS IS VERY MUCH DEPEND ENT ON THE DISEASE STAGE AND THE TYPE OF DEFICIENCY. WE HAVE OTHER DISEASE MODELS SUCH AS ALS WHEN WE FOUND THIS CHROID PLEXUS DYSFUNCTION NEVERTHELESS THE CHECKPOINT INHIBITORY CHECK POINT ARE NOT SUFFICIENT. WE SEEING THAT ACTIVATION OF THE SYSTEMIC IMMUNE SYSTEM FACILITATES RECRUITMENT OF MACROPHAGES TO PARENCHYMA BUT WE DON'T KNOW WHETHER ACTIVITY SAID TOTALLY DEPENDENT ON MACROPHAGES OR THE MACROPHAGES INDUCE OTHER CELLS TO BE MORE BENEFICIAL. THE TREATMENT IS MECHANISM-DRIVEN AND MICROGLIA ARE POTENTIALLY BENEFICIAL BUT THEIR ACTIVATION REQUIRES RELEASE SOME OF THE MICROGLEIAL OFF SIGNALING WE ARE FURTHERING STUDY. THIS IS A CARTOON PRODUCED FOR ME — >> WHEN YOUR ENTERTAIN UNDER THREAT, IT SENDS A DISTRESS SIGNAL TO THE IMMUNE SYSTEM TO COME TO THE RESCUE. BUT IMMUNE CELLS ARE TOO BIG TO GET INTO THE BRAIN THE NORMAL WAY. SO THEY HAVE TO USE A BACKDOOR. AS WE AGE, THAT BACKDOOR ENTRY GETS HARDER. BUT WHAT IF WE JUST GIVE THE IMMUNE CELLS A BIT OF HELP? A BOOSTER? WELL, RESEARCHERS ARE FINDING THAT CAN HAVE A POSITIVE EFFECT ON ALZHEIMER'S MEMORY LOSS. AT LEAST TO MICE ANYWAY. COULD IT WORK IN HUMANS TOO? >> SO I GOT THIS CARTOON FROM THE EU FOR GETTING THE ADVANCED — ERC FOR THE SECOND TIME AND I THOUGHT IS NICE ILLUSTRATION. SO BEFORE I FINALIZE BECAUSE I TALKED A LOT ABOUT IMMUNE CHECKPOINT BLOCKADE AND YOU KNOW A LOTTED IN COUNSELING CHECKPOINT, I WOULD LIKE TO EMPHASIZE THAT BASED ON THE MECHANISMS OF ACTION, WE DON'T NEED TO KEEP EXPOSED ANIMAL OF THE PATIENT FOR CONTINUOUSLY FOR THE IMMUNE CHECKPOINT. IT SHOULD BE TREATMENT. WE FOUND THAT THE SINGLE TREATMENT WE STILL SEE EFFECT. AND THE INTERVAL IS NEEDED IN ORDER TO ALLOW THE ENTIRE ACTIVITY TO GET. SO THE TREATMENT WILL BE DISTINCTIVE FOR THE TREATMENT FOR CANCER AND THAT IS WHY I COMPETITIVE GRANTS BY THE EU, WHICH IS CALLED THE — ERC AND MANY OTHER EU AND MANY OTHER FOUNDATION, COMPETITIVE FOUNDATION IN ISRAEL AND OUTSIDE OF ISRAEL. THIS GRADUATE STUDENT DID CURRENTLY IN MY LAB THAT DID THE WORK, QUITE INTERNATIONAL. ALL THE SINGLE CELL WAS DONE IN COLLABORATION WITH OUTSTANDING YOUNG SCIENTISTS AT THE WEIZMANN INSTITUTE AND SOME OF THE WORK WAS DONE IN COLLABORATION WITH STANFORD AND OTHERS FROM ISRAEL AND FROM ITALY AND FROM SWEDEN. AND THESE ARE FORMER GRADUATE STUDENT MANY OF WHICH OR WHOM ARE NOW INDEPENDENT PROFESSOR EITHER IN THE STATES OR ISRAEL OR EUROPE AND WITHOUT THEM I COULDN'T BE ABLE TO DO THIS WORK. THANK YOU. [ APPLAUSE ] I AM HAPPY TO TAKE QUESTIONS. >> HI. SO, I'M USED TO SEEING LIKE A TYPE I INTERFERON SIGNATURE LEADING TO SOME SORT OF DAMAGE OF SOME KIND. I WAS WONDERING HOW YOU THINK THIS CHROID PLEXUS IS PREVENTING ANY SORT OF DAMAGE WHILE MAINTAINING. >> I THINK THERE IS MORE AND MORE DATA ACCUMULATING THAT EVEN IN MS AND TYPE I INTERFERON BY ITSELF IS NOT DAMAGING. IT MAY BE THAT OVERDOSEING CAN BE BAD EVEN IN ANIMAL MODEL. INTERFERON GAMMA BY ITSELF IS NOT SUFFICIENT TO DRIVE THE DISEASE. >> THAT WAS TOUR DE FORCE. THIS MIGHT BE A NAIVE QUESTION. BUT PD-1 PATHWAY BLOCKADE HAS NOW BEEN PERFORMED ON CANCER PATIENTS. IS THERE ANY EVIDENCE THAT THEY EXPERIENCE COGNITIVE CHANGES? >> YOU'RE ASKING A VERY GOOD QUESTION. WE CONTACT MANY CENTERS IN ISRAEL AND IN EUROPE AND IN THE STATES TREATING PATIENTS WITH ANTI-PD-1. OR ANTI-PD-L1. FIRST OF ALL THEY ARE TREATING IN A DIFFERENT REGIMEN. SECONDLY IT WAS NEVER RECOMMENDED BY THE FDA OF ANY CLINICAL DRIVE TO TEST COGNITIVE. SO THERE IS NO REPORT ON THESE. SO THE ANSWER IS ZERO. THE ONLY THING THEY TOLD ME THAT ELDERLY POPULATION RESPOND VERY WELL TO ANTI-PD-1 AND ANTI-PD-L1 FOR CANCER. SO IT MEANS A POTENTIAL. BUT COGNITIVE ABILITY, NO FURTHER. >> SO THE QUESTION IS, IS THIS SYSTEM OF IMMUNE PROTECTION EFFECTING THE FETAL STAGE? BECAUSE IT WAS SUGGESTED THAT INFECTION OF THE MOTHER MIGHT CAUSE — SO I WAS THINKING IN TERMS OF THE IMPLICATIONS OF YOUR OBSERVATIONS IN THE MICE. >> WE ARE CURRENTLY TESTING IT. THAT IS A VERY GOOD POINT. EXCELLENT POINT. I DON'T HAVE AN ANSWER. THE ONLY THING I HAVE CLEAR ANSWER, WE TESTED MENTAL DISABILITY AND WE FOUND THAT IN ANIMAL MODEL, THE CONES ARE DEPRESSION OR POST-TRAUMATIC STRESS DISORDER. THE GATE COMPLETELY SHUT OFF AND IF WE — SUPPRESSION, WE CAN REDUCE SOME OF THE SYMPTOMS OF DEPRESSION. BUT WITH RESPECT TO PREGNANCY, WE HAVE VERY PRELIMIARY DATA. IT'S THE COMMUNITY HAS MODEL OF BABIES DURING PREGNANCY — WE COULD NOT DETECT ANY EFFECT OF THE CHROID PLEXUS. >> THE CLINICAL TRIALS SOON? >> IT IS BEYOND MY CONTROL. BUT A START-UP COMPANY SIGNED AGREEMENT WITH A COMPANY FOR TRANSLATING INTO PATIENT. >> SO DO YOU HAVE AN IDEA OF HOW THIS IS GOING TO MOVE TO THE CLINICAL TRIALS? DO YOU THINK IT WILL STAY SYSTEMIC OR DO YOU HAVE ANY PLANS OF MAKING IT MORE SPECIFIC TO THE CHROID PLEX US? >> NO, WE CANNOT — YOU CAN NOT MONITOR INPATIENT, IN LIVING INDIVIDUAL THE CHROID PLEXUS. SO WE ARE USING BLOOD MARKERS TO MONITOR THE ACTIVITY AS MEASURE OF THE EFFECT ON THE CHROID. THERE IS NO WAY TO DETECT THE CHROID. YOU CAN SEE THE SIGNATURE BUT THE RESPONSE — NO WAY TO MEASURE CHEMOKINE. >> HI. FANTASTIC TALK. >> THANK YOU. >> I WAS WONDERING IF THE T-CELLS THAT AFFORDED PROTECTION, DID THEY GET TURNED INTO TISSUE RESIDENT T-CELLS ORD DID THEY STAY IN THE PERIPHERY? >> THAT'S A GOOD POINT BUT I DON'T HAVE ANSWER. WE HAVE T-CELL THAT SIT ALL THE TIME IN THE CHROID PLEXUS WE KNOW THAT THEY ARE NATIVE FOR ACTIVATION. WE SEE IN SEVERAL PARADIGMS ENTRY OF T-CELL INTO THE PARENCHYMA. BUT THERE IS NO WAY TO TELL YOU THE — IS THE ONE THAT IS IN THE PARENCHYMA. ALSO WE SEE WITH ALL THE PATHOLOGY WE SEE FACTOR CELLS AND THEN T-CELL AND WE DON'T KNOW WHETHER IT IS LOCAL CONVERSION OR SEPARATE RECRUITMENT. SO THERE ARE MANY THINGS THAT IS WE STILL DON'T KNOW AND WE DON'T HAVE THE TOOLS TO FOLLOW THE SOURCE. >> AND THEN JUST ONE MORE FOLLOW-UP ISSUE. I WAS GOING TO ASK IF THIS PROTECTION IS TRANSPLANTABLE? CAN YOU TAKE THE T-CELLS FROM A PROTECTED MOUSE AND TRANSFER THEM? >> WE DID IT LONG AGO. YOU CAN TAKE T-CELL AND TAKE ANY EFFECT OF T-CELL — THERE IS NOTHING. THEY SHOULD BE MEMORY T-CELL THAT COGNITIVE ANTIGEN IS BEING PRESENTED IN THE CHROID PLEXUS. WE STILL DON'T KNOW WHETHER THE T-CELL WE SEE IN THE PARENCHYMA THE SAME. THERE IS NO — WE DON'T KNOW. >> WHAT DO YOU THINK IS THE MECHANISM BY WHICH CELLULAR ENTRY IS RESTRICTED TO THE CHROID PLEXUS AS DISTINGUISHED FROM ALL THE OTHER TYPE JUNCTIONS IN THE NERVOUS SYSTEM? AND ASKED A FINNESTRA PLAY ANY ROLE IN THIS PROCESS? >> SO, THE DIFFERENCE BETWEEN THE CHROID PLEXUS IS BECAUSE THE ONLY PLACE WHERE IT IS NOT ENDOTHELIAL [ INAUDIBLE ] IT'S EPITHELIAL CELLS CONNECTED. WHERE IT IS NOT CONNECTED OF THE CHROID PLEXUS WHERE MADE BY EPITHELIAL CELLS AND EPITHELIAL CELLS SAYS ONCE IT IS ACTIVATED, CAN PASS THROUGH. >> THANK YOU. [ APPLAUSE ]

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