>> I'M FROM THE NATIONAL
INSTITUTE ON AGING AND TODAY
WITH ME IS DR. MOLLY WAXTER, WHO
IS HEART AND MIND BEHIND THE
WALS LECTURE.
IT IS OUR PLEASURE TO INTRODUCE
OUR SPEAKER FOR TODAY'S
WEDNESDAY AFTERNOON LECTURE, DR.
JONATHAN KIPNIS.
DR. KIPNIS IS ALANA. AND EDITH
L. WOLFF SH DISTINGUISHED
PROFESSOR OF PATHOLOGY AND
IMMUNOLOGY IN ST. LOUIS.
HE IS PROFESSOR OF NEUROLOGY AND
NEUROSCIENCE AND NEUROSURGERY
AND DIRECTOR FOR THE CENTER OF
BRAIN IMMUNOLOGY AND GLIA AT THE
WASHINGTON UNIVERSITY SCHOOL OF
MEDICINE.
BEFORE I TELL YOU MORE ABOUT
JONATHAN, IF YOU ARE ATTENDING
THE LECTURE FOR CME CREDITS, THE
CODE IS 57686.
57686.
IF YOU ARE WATCHING ONLINE AND
WOULD LIKE TO SUBMIT A QUESTION,
PLEASE USE THE SEND LIVE
FEEDBACK BUTTON AND YOUR
QUESTION WILL BE RELAID TO THE
SPEAKER AT THE END OF THE
LECTURE.
WE ARE DELIGHTED TO HAVE DR.
KIPNIS TO TALK ABOUT HIS STUDIES
ON INTERACTION BETWEEN IMMUNE
SYSTEM AND NERVOUS SYSTEM.
HIS LAB DISCOVERED LYMPHATIC
TISSUE SURROUNDING BRAIN THAT
BROUGHT NEW PERSPECTIVE ON
ALZHEIMER'S DISEASE, MULTIPLE
SCLEROSIS AND DR. KIPNIS' LAB
STUDIES THE COMPLEX RELATIONSHIP
BETWEEN LYMPHATIC SYSTEM,
GLYMPHATIC AND TRANSPORT BETWEEN
BLOOD/BRAIN BARRIER.
THEY HAVE RESEARCHED MAPPING THE
IMMUNE RECEPTORS, THE PART OF
THE BRAIN AND HE IS TRYING TO
UNDERSTAND HOW CYTOKINES IMPACT
BEHAVIOR.
HIS LAB STUDIES NEUROIMMUNE
INTERACTION IN THE CONTEXT OF
SPINAL CORD INJURY AND BY
UNRAVELLING THE CELLULAR
MOLECULAR MECHANISMS WE HOPE TO
MOVE FORWARD TO NOVEL
THERAPEUTICS THAT EMPLOYEE THE
HEALING POWER OF THE IMMUNE
SYSTEM.
DR. KIPNIS HAS BEEN A MEMBER OF
THE NATIONAL ACADEMY OF MEDICINE
SINCE 2022.
HE HAS RECEIVED MANY AWARDS.
HE HAS BEEN STUDYING INTERACTION
IN THE CONTEXT OF HEALTH AND
DISEASE SINCE HIS ELEMENTARY
SCHOOL, ALMOST.
SINCE HE GRADUATED SCHOOL WHEN
HE DISCOVERED THE ROLE OF
NATURALLY OCCURRING T-CELLS IN
THE IMMUNE RESPONSE TO CENTRAL
NERVOUS SYSTEM INJURIES.
FOR HIS DOCTORAL STUDIES HE
RECEIVED DISTINGUISHED PRIZE
FROM THE ISRAELLY PARLIAMENT.
HE RECEIVED A BACHELOR OF
SCIENCE FROM TEL-AVIV AND PH.D.
IN NEUROIMMUNOLOGY FROM THE --
INSTITUTE OF SCIENCE.
HE WAS A FACULTY OF MEMBER FOR
THE UNIVERSITY OF VIRGINIA FOR
13 YEARS BEFORE MOVING TO
WASHINGTON UNIVERSITY SCHOOL OF
MEDICINE UNIVERSITY IN ST. LOUIS
IN 2022.
PLEASE JOIN ME IN WELCOMING DR.
KIPNIS TO SPEAK ABOUT NAVIGATING
UNCHARTED NEUROIMMUNE WATERS.
>> THANK YOU.
THANK YOU MACK AND MOLLY FOR
INVITING ME.
IT IS REALLY FUN.
I DON'T SEE YOU AT ALL.
I HAVE THE FOUR SOURCES OF LIGHT
INTO MY EYES, AND IT IS NOT FUN
AT ALL, BUT I GUESS IT IS A
REQUIREMENT SO I HAVE TO GO WITH
IT.
I WAS TOLD THIS IS A BIG
LECTURE, SO I SHOULD DO MORE.
NORMALLY I PRESENT INTRODUCTION
AND ONE OR TWO STORIES THAT ARE
UNPUBLISHED.
TOODS WILL BE A BUNCH OF
DIFFERENT STORIES.
IF YOU LOSE YOURSELF AT ONE
POINT, DON'T WORRY, I PROBABLY
LOST MYSELF THERE AS WELL.
SO I WILL START THE LECTURE WITH
THIS QUOTE IT SAYS IT IS WHAT WE
KNOW ALREADY THAT OFTEN PREVENTS
US FROM LEARNING.
I THINK IT IS TRUE FOR EVERY
FIELD.
THINK ABOUT YOUR FIELD FOR A
SECOND AND YOU WILL AGREE WITH
ME, HOPEFULLY.
IT IS VERY, VERY TRUE FOR THE
FIELD OF NEUROIMMUNOLOGY,
ANATOMY OF THE BRAIN AND HEAND
FLOW OF CSF AND OLD CONCEPTS
PEOPLE THOUGHT THEY FIGURED OUT
WITH THE YUSZ OF EM AND NONE
WANTS TO THINK IT TO BE
DIFFERENT THAN WHAT THEY
PROPOSED.
THINGS MOVE FORWARD.
IF YOU WERE TO BUY A HOUSE AND
IT LOOKED LIKE THIS, YOU
PROBABLY WOULD NOT WANT THAT
PARTICULAR HOUSE.
YOU PROBABLY WANT YOUR PIPING TO
LOOK LIKE THIS.
I THINK IT IS TRUE FOR OUR
TISSUES.
ALL OF OUR TISSUES HAVE TWO
TYPES OF PIPES.
BLOOD VESSELS, I THINK EVERYONE
KNOWS.
THE LYMPHATIC VESSELS, THAT MANY
IN THE ROOM DON'T KNOW AND DON'T
CARE ABOUT.
BLOOD VESSELS ARE SIMILAR TO OUR
WATER PIPES AND LYMPHATIC
VESSELS ARE SIMILAR TO M SEWAGE
PIPES.
THE LYMPHATIC VESSELS REMOVE THE
WASTE FROM THE TISSUE OUT INTO
THE PERIPHERY.
BEFORE IT GETS DETOXIFIED, IT
GOES THROUGH THE LYMPH NODES.
JUST THINK OF YOUR NEIGHBOR
GOING THROUGH YOUR R TRASH CANS.
IN TWO OR THREE WEEKS THEY KNOW
EVERYTHING ABOUT YOU.
IF THEY SEE SOMEBODY WEIRD IN
YOUR TRASH CAN, BLOOD SOAKED
TOWELS, THEY PROBABLY WILL CALL
POLICE.
SAME IMMUNE SYSTEM, NORMAL COMES
WITH THE TISSUE, NOT COMING FROM
NORMAL HEALTHY TISSUE, THEY
WOULD GO AND EXPLORE WHAT IS
HAPPENING IN THAT TISSUE.
THAT IS VERY, VERY SIMPLISTIC
WAY TO EXPLAIN IMMUNE
SURVEILLANCE OF ORGANS WHAT THE
IMMUNE SYSTEM DOES.
THE NOTION WAS THE SECOND PART
OF THE LYMPHATIC SYSTEM DOES NOT
EXIST FOR THE BRAIN.
OUR MOST IMPORTANT ORGAN WAS
LEFT OUT OF IMMUNE SURVEILLANCE,
OUR MOST IMPORTANT SURVEILLANCE
AND TISSUE IN THE BODY.
BRAIN IS EXTREMELY BUSY AND MET
BOLICALLY PRODUCE WASTE.
HOW DOES THE BRAIN CLEANSE
ITSELF BECAUSE THERE ARE NO
LYMPHATIC TISSUES IN THE BRAIN
TISSUE.
THERE IS ONE VERY POORLY DONE
PAPER FROM NIH, MAYBE I
SHOULDN'T MENTION IT, BUT IS
WRONG, BUT THERE IS NO LYMPHATIC
VESSELS IN THE BRAIN THAT IS
AGREEABLE ON EVERYBODY.
BUT THE BRAIN, AGAIN, LIKE I
SAID, IT IS HIGHLY METABOLIC.
SEVERAL YEARS AGO -- SHE CAME
OUT WITH HOW IT SERVES, THE
LYMPHATIC FUNCTION BEING ABLE TO
GO THROUGH THE BRAIN TISSUE.
OUR BRAINS ARE SWIMMING IN
CEREBRAL SPINAL FLUID.
CSF, WE HAVE A SPACE, PER
PERIARTERAL SPACE.
IT WILL GO THROUGH THE BRAIN
TISSUE AND COLLECT THE
METABOLITES AND COME OUT, HERE
WE MADE A FANCY MOVIE AND I CAN
SHOW IT TO YOU.
WE PAID A LOT OF MONEY FOR IT.
CSF GOES IN, WASHES THE SPACE.
IT IS VERY SIMPLE UNDERSTANDING
OF THE GLYMPHATIC SYSTEM.
IT IS NOT VERY, VERY FAR AWAY
FROM THAT MOVIE IF WE ARE
LOOKING AT PARTICULAR BRAIN
REGION.
AND OF COURSE THE QUESTION IS
WHERE ALL THIS JUNK GOES THEN?
HOW DO YOU CLEAN THAT FROM NOT
COMING BACK INTO THE BRAIN AND
NOT CREATING A BRAIN SWAMP?
SO WE TOTALLY INDEPENDENT OF
THIS GLYMPHATIC STORY, WE WERE
VERY INTERESTED IN BRAIN
MNINGES, THREE LAYERS WITH THE P
ATTACHED TO THE BRAIN, DURA
ATTACHED TO THE SKULL, AND THE
SPINAL FLUID FLOWS IN BETWEEN.
THAT AREA IS VERY, VERY RICH IN
ALL KINDS OF IMMUNE CELLS.
MY LAB WAS STUDYING DIFFERENT
IMMUNE CELLS IN THE DURA AND
DERIVED CYTOKNES AND HOW THEY
AFFECT BRAIN FUNCTION WITH A
PARTICULAR INTEREST IN HOW
THINGS ARE CHANGING IN AGES AND
DISEASES LIKE ALZHEIMER'S AND
HOW THAT MAY PLAY A ROLE.
THAT WAS MY LAB.
THAT WAS MY FIRST RO1, WHICH IS
IN META PHASE THIS VERY
EXCITING.
WHICH IS HOW I GOT INTO IT IN
THE VERY, VERY BEGINNING.
I WILL NOT BE TALKING ABOUT THIS
TODAY.
I WILL MENTION IT AT THE END.
A NEW STORY JUST CAME OUT.
WE ARE VERY EXCITED ABOUT
MENINGEAL IMMUNITY.
HOW THE IMMUNE CELLS ARE COMING
AND GOING TO INTO THE MENINGES.
ANTWAN ESTABLISHED THIS WHOLE
MOUNT OF THE MOUSE DURA.
HE PEELS THE OUTMOST LAYER AND
2-D ON A SLIDE.
HERE THE LABELS THESE IN RED ARE
BLOOD VESSELS.
THIS IS THE SIGN, PEACE SIGN,
WHATEVER YOU PREFER, THEY ARE
VERY THICK STRUCTURES, THE SI
SINUSES.
THEY DRAIN THE CRANIAL, BRAIN
BLOOD OUT INTO THE PERIPHERY.
VERY IMPORTANT STRUCTURES.
AND SO ALONG THESE STRUCTURES
ANTWAN DID STAINS FOR MARKER FOR
LYMPHATIC CELLS.
IT IS A LONG STORY.
THERE IS SOME STAINING WHICH
LOOKED VASCULAR.
IN THE EYE WE HAVE A VESSEL THAT
DRAINS THE EYE, IT IS NOT MADE
OF LYMPHATIC MATERIAL.
HERE WE HAVE LYMPHATIC CELLS.
CAN IT FUNCTION AS -- WILL IT
DRAIN CSF?
HERE IS A LIVE MOUSE WITH WINDOW
IN SKULL.
WE INJECT WITH GREEN AND RED
INTO THE CSF.
WE SEE THERE IS A GREEN TRACER
FROM THE WLOOD IN THE SINUS AND
THE TRACER FROM CSF IS IN THIS
ONE VESSEL.
IF WE TURN THE MOUSE UPSIDE DOWN
AND THE CSF WILL CONTINUE TO
FLOW INTO THE DRAINING.
I LOVE THE MOUSE BECAUSE THEY
ONLY HAVE ONE LUMP NODE ON EACH
SIDE AND TWO ARE SUPERFICIAL.
IN HUMANS WE HAVE OVER 100 ON
EACH SIDE OF THE NECK.
IT MAKES IT MUCH LESS FUN, BUT
IT IS VERY IMPORTANT TO
UNDERSTAND HOW THINGS ARE
WORKING.
WE PUBLISHED OUR PAPER, THERE
WAS A SERIES OF LABS THAT WERE
SHOWING VERY SIMILAR RESULTS.
WE WERE TOLD WE WERE WRONG AND
IRRELEVANT.
IT DIDN'T LAST TOO LONG.
THERE WAS A PAPER PUBLISHED THAT
SHOWED WHAT WE SHOWED.
THREE PAPERS, THIS IS EUROPEAN,
THIS IS AMERICAN FROM NIH.
THERE WAS A PAPER FROM
AUSTRALIA.
ALL THREE SHOWED THE PRESENCE OF
THESE VESSELS IN FISH.
THIS WAS NOW PRESENT IN RATS.
AND AGAIN NIH HERE WITH A LITTLE
BIT OF SUPPORT FROM US, NOT
MUCH, EVEN THOUGH HE GAVE US
AUTHORSHIP ON THE PAPER, WHICH
WAS NICE OF HIM, SHOWED THE
VESSELS EXIST IN PRIMATES AND
HUMANS.
HE SAID IT TOOK THEM TWO DAYS TO
FIND THE VESSELS AND TWO YEARS
TO CONVINCE HIMSELF THEY WERE
REAL.
THEY EXIST IN HUMANS AND FISH.
THEY ARE PROBABLY REAL.
NOW WE CAN UNDERSTAND WHAT THEY
ARE DOING.
BEFORE THEN, I KNOW MANY OF YOU
MIGHT HAVE HEARD OF THIS.
I WOULD LIKE TO SHOW YOU A BRIEF
HISTORY OF CNS LYMPHATICS.
JOSEPH II BELIEVED IN -- THERE
WAS NO WAY TO PRESERVE ORGANS.
THEY WERE MAKING REPLICAS OF
HUMAN ORGANS AND PARTS OF HUMAN
BODY USING WAX.
THE PRECISION WAS INCREDIBLE.
THIS IS A HUMAN BRAIN AND A FULL
HUMAN HEAD.
ALL FROM THE WAX.
THEY WERE ABLE TO DO THIS FROM
MARBLE SO WAX WAS PROBABLY EASY
TO DO THESE AMAZING THINGS FROM.
ALL THIS COMING FROM THE BRAIN,
LYMPHATICS COMING FROM THE
BRAIN, BASED ON THE WORK THERE
IS LYMPHATICS, IT IS NOT AS
INTENTION AS THEY WERE CLAIMING.
HE GOT CRITICIZED SO REALLY
CONTEMPORARIES KILLED THAT WHOLE
THING AND HE DIED BASICALLY
INFAMOUS, NOBODY EVEN KNOWS
WHERE HE IS BURIED,
UNFORTUNATELY.
THERE WAS SOME TRUTH TO THAT.
HE WAS EXAGGERATING OR VERY
UNLUCKY OR LUCKY TO WORK WITH
REALLY ABNORMAL HYPERLYMPHATIC
PERSON.
THERE WAS A PAPER IN 2003 THAT
SAYS HERE TODAY THERE ARE 867
MODELS ON DISPLAY IN THE MUSEUM.
THE MUSEUM IN VIENNA, IF YOU
HAPPEN TO BE THERE, MUST VISIT.
COMPLEXITY OF MODELS REVEAL
THEIR CREATORS AND ANATOMY.
FOUR MODELS STAND OUT FOR
ANATOMICAL MISCONCEPTIONS.
LYMPHATIC ON BRAIN.
IN 2003, I'M TOWARD THE END OF
MY PH.D.
I'M LEARNING ON THAT
MISCONCEPTION.
NO LYMPHATICS IN THE BRAIN.
HERE IT SAYS LYMPHATIC SYSTEM
WAS SO IMPRESSED THAT HE SAW
LYMPH VESSELS EVEN WHERE THEY
DIDN'T EXIST, IN THE BRAIN.
IT WAS DESCRIBED IN DETAIL IN
19th CENTURY.
HOW DO YOU DESCRIBE SOMETHING
THAT DOES NOT EXIST IN DETAIL.
WE LIVE IN THAT MISCONCEPTION.
ANYWAY, FUNNY ENOUGH, WE
PUBLISHED COMMENTARY SAYING HE
WAS RIGHT, BUT WE STILL HAVE NO
CLUE WHERE HE IS BURIED.
HE IS THE RIGHT PERSON TO BECOME
INFAMOUS, STUDYING LYMPHATICS.
IT WAS A JOKE.
I GUESS IT IS NOT FUNNY.
THE ONE THAT IS VERY CLOSE TO
OUR HEARTS IS THE
NEUROINFLAMMATION, THE MODEL FOR
MULTIPLE SCLEROSIS.
WE JUST MADE A DISCOVERY OF
LYMPHATICS I WAS INTERVIEWED BY
NPR.
WHAT DO YOU DREAM ABOUT THESE
VESSELS?
JUST A BLOB OF VESSELS.
THAT DREAM CAME TRUE.
A BUNCH OF LABS ARE WORKING ON
LYMPHATICS.
THIS IS A RECENT PAPER ON THE
ROLE OF PCR SIGNALLING ON
HEADACHES, WORK ON PARKINSON'S
IN PATIENTS.
A PAPER ON BRAIN INJURY AND
HEMMORATIC STROKE, AND THE
DIFFERENT SEXES IN MICE, THE
WORK ON BRAIN TUMORS AND HOW
THEY GUIDE IMMUNE RESPONSE
AGAINST BRAIN TUMORS.
THERE WERE A COUPLE OF PAPERED
ASSOCIATED WITH -- BECAUSE OF
THE LINK TO DYSFUNCTION BECAUSE
OF THE ABNORMAL SKULL FORMATION.
THIS IS A HANDFUL OF PAPERS I
HAD ON MY COMPUTER AND I'M JUST
LAZY TO PUT, I COULD PROBABLY A
HUNDRED DIFFERENT PAPERS OF THE
ROLE OF THESE VESSELS IN
DIFFERENT DISEASES.
I PAID A LOT OF MONEY FOR THIS
MOVIE, SO I WILL BE PLAYING IT
IS LOT.
TO JUSTIFY CAN COST.
I WILL SHOW YOU WHERE THE JUNK
GOES OUT AND IT WILL GO INTO THE
LYMPHATIC SYSTEM.
I WILL SHOW YOU INTERESTING
MECHANISMS THAT GOVERN THE FLOW
ALONG THE VEINS AND THROUGH THE
BRAIN AND WHY WE THINK IT IS
IMPORTANT AND WHY I CARE ABOUT
THIS.
THAT WOULD BE THE STORY.
IF YOU THOUGHT I'M SPEAKING FAST
UNTIL NOW BECAUSE NOW I WILL
START REALLY SPEAKING FAST.
I HAVE A BUNCH OF SLIDES TO
COVER.
AFTER THIS DIRTY CSF GETS OUT OF
THE BRAIN IT HAS TO REACH THE
LYMPHATIC VESSELS, THE BRAIN'S
SINK OR BRAIN'S TOILET.
HOW DO YOU REACH THE TOILET, IF
CSF IS HERE, IT GOES THROUGH THE
BRAIN, HOW DO YOU GET TO THAT
LAYER WHERE YOU HAVE TO CROSS
ARACHNOID.
IT IS PLACED THERE TO PREVENT
CSF EXIT TO THE DURA.
ARACHNOID SHOULD NOT ALLOW CSF
TO ENTER THE DURA.
IT HAPPENS IN HUMANS.
THIS PAPER FROM NORWEGIAN, THEY
INJECT PATIENTS AND SEE THE
TRACE THAT APPEARED IN THE DURA.
REMEMBER THAT IF YOU GO INTO
TEXTBOOKS AND THERE ARE
CLINICIANS IN THE ROOM THAT WILL
THROW AT ME ROTTEN TOMATOES,
WHICH IS FINE.
I'M USED TO IT.
THE TEXTBOOK SAYS THE ARACHNOID
HAS THE UNIQUE STRUCTURES CALLED
VILLI.
THEY HAVE HOLES AND STICKING
INTO THE SINUSES, INTO THE
VENOUS STRUCTURES AND PUSHING
CSF RIGHT THERE.
I SEE YOU IN THE WHITE COAT,
THAT IS HOW CLINICIANS ARE
LEARNING IT, CORRECT?
I WAS BOTHERED BY THIS IDEA
BECAUSE MANY ANIMALS DON'T HAVE
ARACHNOID RELATIONS AND CSF IS
BEING PRODUCED.
HOW IS CLEANING THERE?
OUR BABIES DON'T HAVE
GRANULATIONS UNTIL THEY BECOME
MUCH OLDER.
HOW DO YOU SEAL THE INTERFACE TO
PREVENT THE BLOOD FROM FLOWING?
IT MAKES NO SENSE.
IF YOU REALLY LOOK CAREFULLY
INTO THE ANATOMY, WHERE RICE
UNIVERSITY DID AND SHOWED THEY
ARE NOT GOING ALL THE WAY INTO
THE SINUS, THEY ARE COMING INTO
THE DURA WHICH SUPPORTS OUR
FINDING IN MICE AND NOR WIE JOHN
FINDINGS IN HUMANS.
WE THINK THEY ARE BEING TAKEN BY
THE LYMPHATIC VESSELS.
HOW DOES CSF GET INTO THE DURA?
BECAUSE IT HAS TO CROSS A
BARRIER THAT IS SUPPOSED TO BE
UNPERMEABLE.
LEON IS HIS LAST DAY.
THIS IS OUR OWN EM OF THE
ARACHNOID BARRIER CELL.
THEY CREATE THIS PERFECT BARRIER
SO HOW DO YOU CROSS IT?
THEY ARE VERY, VERY POOR IN
TRANSCYTOSIS.
WE INJECT AND THEY ALL ARRIVE IN
THE DURA AT THE SAME TIME.
SOMETHING ELSE IS HAPPENING.
SOME PASSENGERS ARE MOVING CSF
INTO THE BRAIN.
I'M NOW DABBLING INTO MORE
ANATOMY THAN ANY OF YOU WANT TO
HEAR.
I HAVE TO EXPLAIN IT.
THIS IS UGLY WHOLE HEAD
CLEARANCE.
IT IS UGLY BECAUSE THE SCALA DID
NOT SHRINK AS MUCH AS THE BRAIN
DID.
SO IT CREATED A SUB ARACHNOID
SPACE.
IT IS NICE FOR DEMONSTRATION
BECAUSE YOU CAN SEE THESE
VESSELS HERE, THESE ARE VEINS,
BRIDGING VEINS OR CORTICAL
BRAINS.
BRINGING THE BLOOD FROM THE
BRAIN INTO THE SINUSES.
THEY GOW THERE THE ARACHNOID
SPACE THROUGH THE MENINGES AND
DURA.
I WILL DO IT IN CARTOON FIRST.
IT BRINGS THE BLOOD.
AS IT GOES THROUGH THE
ARACHNOID, THERE IS A OPENING
AND TEAR.
IF YOU LOOK AT THE ARACHNOID
FROM THE ON THE, YOU SEE HOLES
THAT ARE COMING.
AS YOU SEE HERE, WE CALL THEM
CUFFS.
LIKE A CUFF ON A SHIRT.
SO THE CSF, WHILE THE BLOOD
FLOWS WITHIN, LET'S SAY, MY
HAND, THE CSF WILL FLOW WITHIN
MY SLEEVE.
CSF FLOWS IN THE SLEEVE AND ENDS
UP IN THE DUR AND CAN BE UPTAKEN
BY IMMUNE CELLS.
THE LYMPHATIC SYSTEM IS THERE
AND WHATEVER IS LEFT WILL GET
OUT OF THE LYMPHATIC SYSTEM.
THE GREEN HERE IS THE ARACHNOID
CUFF, ARACHNOID STRUCTURE THAT
GOES ALONG THE VEIN.
WITHIN THAT, THAT IS WHERE CSF
FLOWS.
IT GOES THERE BOTH WAYS FROM THE
DURA TO THE BRAIN AND THE BRAIN
TO THE DURA.
THE COOL THINGS ABOUT THE
STRUCTURE, THIS IS WHERE THE
BLOOD/BRAIN BARRIERS ENDS OR
STARTS, DEPENDING HOW YOU CALL
IT.
IT IS A UNIQUE STRUCTURE IN THE
BRAIN.
EXACTLY AT THE END OF THAT CUFF
OF THE SLEEVE, THAT IS THE END
OF MARKERS IN A NORMAL VESSEL.
PERIPHERAL VESSEL STARTS.
WHICH TELLS YOU HOW IMPORTANT
THAT AREA IS TO CONTROL.
NOW MOLECULES CAN COME OUT AND
DIFFUSE THROUGH A SLEEVE INTO
THE BRAIN.
LOTS OF INTERESTING CONTROL
HAPPENING HERE AND SOME OF THE
NEW WORKS WE ARE WORKING ON.
IN MICE WE SHOWED BOTH WAYS, UP
AND DOWN, BUT IN COLLABORATION
WITH THE LAB, THEY SHOW THE
MOVEMENT OF THE TRACER FROM THE
DURA INTO THE CSF AGAIN THROUGH
THOSE BRIDGING VEINS.
I'M NOT OPPOSED TO WORK IN MICE
FOR THE SAKE OF A MOUSE.
IT IS VERY FUN WHEN OUR MOUSE
WORK TRANSLATES TO HUMAN ANATOMY
AND BIOLOGY.
WE HAVE AMAZING COLLABORATION
WITH DANNY HOPEFULLY WE WILL
CONTINUE IN THE FUTURE.
I'M NOT QUESTIONING -- IN THE
FIELD OF ALZHEIMER'S, THE
CURRENT STATE OF THE FIELD IS
THAT AMYLOID BETA IS BEING
REMOVED ACROSS THE BLOOD/BRAIN
BARRIER.
IT USED TO BE THE ONLY WAY, WE
ARE SAYING THERE ARE OTHER WAYS.
THE LYMPHATIC ROUTE IS A WAY TO
REMOVE AMYLOID FROM THE BRAIN.
A MOUSE, KILLING LYMPHATIC
VESSELS IN THAT MOUSE, WE SEE
AMYLOID IN THE DURA MATTER AND
INSIDE THE BRAIN, THE BLOCKS ARE
MORE OF THEM AND THEY ARE
LARGER.
IF YOU REMOVE THAT ROUTE OF
EXCISION OR WASTE REMOVAL, IT
BUILDS UP MORE AMYLOID WAIST IN
THE BRAIN.
IF WE ENHANCE THOSE ROUTES AND
COMBINE WITH ANTI-AMYLOID
THERAPY, WE GET SYNERGISTIC
EFFECT.
THERE WAS A GROUP FROM MAYO I
CLINIC SHOWED SOME ALZHEIMER'S
MARKERS WILL APPEAR IN THE
DRAINING LYMPH NODES, MUCH
HIGHER THAN IN PERIPHERAL BLOOD
AND MORE PREDICTIVE OF THE
DEVELOPMENTS.
AGAIN, SUPPORTING THIS LYMPHATIC
ROUTE OF REMOVAL IN ALZHEIMER'S
PATIENTS TO THE BLOOD VESSELS.
IF THAT IS TRUE OUR SLEEVES, OUR
POINTS WHICH WE BELIEVE ARE THE
EXIT POINT FROM THE BRAIN,
SHOULD SHOW SOME DEGREE OF
CLOGGING.
IN UNPUBLISHED DATA, WE ARE
SEEING THESE AREAS CLOGGED BY
AMYLOID.
WE COLLABORATED ON THIS AS WELL
BUT NOW WE HAVE FIRST IMAGING
FROM HUMANS IN COLLABORATION
WITH PAUL MARRA, THE ACE POINTS
ARE CLOGGED WITH AMYLOID IN
ALZHEIMER'S PATIENTS.
SOME OF WASTE REMOVAL IS
HAPPENING ACROSS THE ROUTE.
THIS IS THE WAY OUT.
WHAT ABOUT THE WAY IN?
WE SHOWED THAT VASCULAR
PULSATION IS IMPORTANT TO
PROPAGATE THE FLOW ALONG THE
VESSEL AND INSIDE THE VESSEL.
-- USED TO BE IN THE LAB, HE IS
NOW A PI IN PARIS, HE WAS REALLY
INTERESTED IN THIS FUNCTION OF
THE VESSELS.
AND MANY OF YOU HERE KNOW ABOUT
MICROGLIA.
YOU FIND THIS LABELING
THROUGHOUT THE WHOLE BRAIN.
THERE IS ANOTHER MYLOID CELL
THAT SITS INSIDE THE BRAIN, LESS
KNOWN TO NEUROSCIENTISTS.
PERIVASCULAR MACROPHAGES.
IT IS COVERED BY THE CELLS HERE
IN TEAL.
IF YOU LOOK AT THE BLOOD/BRAIN
BARRIER NICHE, SO FROM INSIDE,
OF COURSE, WE HAVE THE CELLS OF
THE BLOOD VESSELS, INSIDE WE
HAVE THE SMOOTH MUSCLE,
PERISITES AND MACROPHAGES IN THE
PUR
PURPLE.
MACROPHAAGES ARE CONSTANTLY
TRACING WHAT IS HAPPENING.
THEY ARE PHAGOCYTES AND IN TOUCH
WITH CSF AND IN THE BRAIN.
ANTWOINE HAD A COOL IDEA, THEY
TAKE UP SPACE.
IF WE REMOVE THOSE CELLS WE WILL
INCREASE THE SPACE AND MORE CSF
WILL BE ABLE TO GO THROUGH AND
IMPROVE CSF MOVEMENT.
ESPECIALLY IN OLD MICE.
IT IS A COOL IDEA.
LET'S DO IT.
HERE HE INJECTED THIS MICE WITH
BUBBLES OF FAT LOADED WITH TOXIC
MATERIAL, MACROPHAGES BECAUSE
THE UPTAKE IS IN THE CSF, THEY
WILL SWALLOW, THE MATERIAL WILL
BURST INSIDE AND KILL THE CELL.
60%, 70% OF CELLS WILL BE
ELIMINATED.
WHAT IS HAPPENING WITH CSF FLOW
IN THIS MICE?
IT WAS STUNNING BECAUSE WE FOUND
THE OPPOSITE.
THERE WAS LESS CSF GOING AROUND
THE BRAIN, GOING INTO THE BRAIN.
IT IS ALWAYS FUN TO GET RESULTS
OPPOSITE OF WHAT YOU EXPECTED
UNLESS YOU SWITCH THE GROUPS, IT
IS A COOL FINDING WHICH I DIDN'T
EXPECT WHICH IS PROBABLY TRUE.
LET'S TRY TO UNDERSTAND WHAT IS
HAPPENING HERE.
ANTWOINE DID -- WE REALIZED
THERE IS NO REAL GOOD METHOD TO
MEASURE CSF FLOW IN A LIVE
MOUSE.
HE DEVELOPED SUCH ASSAYS.
THIS IS A MEWS, THIS IS THE EYE
AND THE EAR, NOW YOU SEE THE
MOUSE ON THE SCREEN.
ANTWOINE LIFTS THAT PIECE OF
SKIN AND THE MUSCLE WHICH COVERS
THE BEGINNING OF MIDDLE
ARTERIES.
WE INJECT TRACERS, IT WILL GO
UNDER AND FOLLOW THE MCA AND DIE
INSIDE THE BRAIN.
WE ARE LOOKING AT THE BEGINNING
OF THE ARTERY AND YOU CAN
SEE.JEX THAT IS THE TREE OF MCA
IS BEING FILLED WITH THE TRACER.
NOW WE CAN COMPARE THE NORMAL
MICE AND MICE WITH NO
MACROPHAGES.
THE DIFFERENCE WAS ROBUST.
IT IS VERY FUN BECAUSE WHEN YOU
HAVE SUCH A BIG DIFFERENCE, YOU
CAN UNDERSTAND WHAT REALLY IS
HAPPENING THERE, AT LEAST
PARTIALLY.
LONG STORY SHORT, WHEN WE PUT
MICE IN A HIGH CO2 ENVIRONMENT
AND THEY NEED TO VASO DILATE
MORE, THOSE THAT DID NOT HAVE
MACROPHAGES COULD NOT DILATE.
THEY ARE CONSTANTLY EATING THE
DEBRIS THAT OTHER CELLS DEPOSIT.
IF YOU REMOVE MACROPHAGES YOU
START SEEING BUILD UP OF ECM
AROUND THE VESSELS.
F WE THINK THIS PREVENTS VESSELS
TO FULLY DILATE BECAUSE IT IS
BUILT UP WITH GUNK ALONG THE
VESSELS.
OLD MICE HAVE PROBLEMS WITH CSF
FLOW.
THIS IS LIVE IMAGING.
THIS IS A NORMAL YOUNG MOUSE TWO
MONTHS AND THIS ONE IS 24
MONTHS.
IT IS NOT NEW AND WE ALSO
REALIZED THAT THE TYPES OF
PERIVASCULAR MACROPHAGES ARE
CHANGING IN OLD MICE.
WE GIVE THEM MCSF INFUSION, A
GROWTH FACTOR.
IN A COUPLE OF HOURS, SIX, SEVEN
HOURS, WE GET REDUCTION OF
PERIVASCULAR AND MORE CSF CAN GO
THROUGH THE VASCULARTURE.
IT ONLY LASTED 24 HOURS AND WENT
BACK TO NORMAL I GAVE US HOPE
AND WE HAVE SEVERAL
COLLABORATIONS GOING ON TO MAKE
THIS EFFECT GO MUCH LONGER AND
GET SUBSTANTIAL BENEFITS TO THE
BRAIN.
I TELL MY KIDS THE BEAUTY OF
BEING A SCIENTIST, YOU CAN STILL
DESTROY THINGS AND IT IS VALID
AND EXCITING.
IF WE CAN'T FIX THEM IN
PERPETUITY, WE CAN DESTROY THEM.
WE GO INTO OUR AMYLOID MOUSE
MODEL, WE SEE AGAIN
ACCUMULATION, MORE ACCUMULATION
OF AMYLOID PLAQUES INSIDE THE
BRAIN.
WE ARE PREVENTING CSF FLOW IN
THE BRAIN WHICH LEADS TO PLAQUES
IN THE BRAIN.
WHAT ALLOWS THE FLOW OF CSF?
YOU SEE THERE IS A LOT OF BLANK
SPACE.
SOMETIMES YOU LOOK AT
COMMERCIALS FROM COMPANIES HOW
DRUGS WORK, EMPTY SPACE, ONE
NEURON, THE MOLECULE ARRIVES AND
ANOTHER ONE ARRIVES.
NO.
THIS IS NOT HOW A BRAIN LOOKS
LIKE.
IT HAS LOTS OF CELLS, EXTRA
CELLULAR DENSE TISSUE.
THAT IS SOMETHING WE FOUND -- IN
THE LAB.
HE CAME FROM SLEEP LAB.
HE OPENED HIS LAB AT YOU PEN.
WHAT PROPAGATES THE FLOW FROM
THE DENSE --.
HE SAID, NO, AS A SLEEP
BIOLOGIST.
I'M AN IMMUNEOLOGIST.
THE SLEEP WORLD IS WHY DO WE
SLEEP?
ONE OF THE NEW EXCITING THEORYS
IS WHEN WE SLEEP, WE CLEANSE OUR
BRAIN MORE EFFICIENTLY.
WE KNOW THAT SOME OF THE, FOR
EXAMPLE, OUR TRACER EXPERIMENTS
ARE WORKING WAY MORE EFFICIENTLY
IN A SLEEPING MOUSE THAN A
WAKEFUL MOUSE.
NO QUESTION ABOUT IT.
I WILL GO THROUGH THIS.
THIS IS A VERY COMPLICATED PAPER
AND IT IS PUBLISHED LAST YEAR.
I WILL DO IT VERY, VERY QUICKLY.
I WILL SUMMARIZE THE WHOLE THING
BECAUSE THE CONCEPT IS EXCITING.
WHEN WE SLEEP WE EMIT WAVES.
YOU CAN RECORD WAVES.
BY THE TYPE OF WAVES YOU EMIT,
I'M SURE YOU HAVE THE OURA RING,
DEEP LEAP OR REM SLEEP?
SO IT WAS SUGGESTED WHEN NEURONS
ARE FIRING, DURING SLEEP NEURONS
ARE FIRING TOGETHER,
SYNCHRONIZED ACTIVITY.
WE GENERATE SUBSTANTIAL SURGES
OF FLOW THIS IS THE WAY WE ARE
RECORDING.
IN DEEP SLEEP WE HAVE VE SLOW
WAVES WITH VERY HIGH MAGNITUDE.
HE SUGGEST MAYBE THIS POWER OF
PUSHING THIS INTO THE
INTERSTITIAL SPACE WILL BE
SUFFICIENT TO CARRY THE WATER
MOLECULES WITH THEM, WHICH WILL
CARRY THE METABOLITES AGAIN.
HE DID RECORDING.
THIS IS A 32-CHANNEL RECORDING.
WE RECORD THE MUSCLES IN THE
NECK AND 28 CHANNELS IN THE
HIPPO CAMPUS.
YOU SEE APPEARANCE OF THIS
MACROWAVES AND SYNCHRONIZED
ACTIVITY DURING SLEEP.
WE CAN SILENCE NEURAL ACTIVITY
USING CHEMOGENETIC APPROACH.
EXPRESS MODIFIED RECEPTOR.
SO WE GIVE THE MICE LIGANDS, WE
INTERFERE WITH ACTIVITY.
ALL THE WAVES ARE BEING
SUPPRESSED IN THE HIPPOCAMPUS.
IF YOU LOOK AT GLOBAL BRAIN,
THERE IS NO EFFECT.
WE ARE AFFECTING A SMALL AREA OF
THE HIP POECAMPUS.
WILL THIS BE SUFFICIENT TO
AFFECT THE CSF FLOW FROM THAT
BRAIN REGION?
HERE IS AN EXPERIMENT,
EXPRESSING THE P SUMS ON THE ONE
SIDE OF THE HIP POECAMPUS,
CONTROL OR GFP.
THEN AFTER THREE WEEKS WE INJECT
THEM WITH A DRUG, WITHIN A
COUPLE OF HOURS WILL SILENCE
ACTIVI
ACTIVITY.
WE INJECT WITH TRACER AND DURING
THE DAYTIME THE MICE WILL FALL
ASLEEP AND WE WILL BOTHER THEM.
THERE IS SOMETHING THAT GOES
THROUGH THE CAGE AND MAKE SURE
THE MOUSE IS GENTLY BOTHERED AND
NOT SLEEP.
WE TAKE THE BRAIN OUT.
HOW MUCH FLOW, HOW MUCH CSF
ENTERS, GOES THROUGH THE
PARTICULAR AREA OF THE BRAIN
WITH OR WITHOUT NEURAL ACTIVITY.
WHEN WE SUPPRESS NEURAL
ACTIVITY, IN SLEEPING MOUSE MORE
FLOW GOES THROUGH THAT AREA FOR
THE WHOLE BRAIN, BUT HIP
POECAMPUS.
WHEN MOUSE IS SLEEPING THERE IS
MORE TRAFFIC AND WE REDUCE CSF
GOING THROUGH THE AREA WITHOUT
AFFECTING OTHER THING GOING
AROUND.
40 HERTZ, FAST WAVES, AFFECTED
AMYLOID REMOVAL IN THE BRAIN.
WE CAN INCREASE THE FLOW.
IT IS A COMPLICATED PAPER, BUT
IT IS QUITE EXCITING.
WE ARE PROPOSED IS DURING
DAYTIME WE IN THE NIGHT TIME
WHEN OUR BRAIN IS FULL OF JUNK,
THEY FIRE TOGETHER AND IT
CREATES WAVES WHICH ALLOWS
REMOVAL OF THE WASTE OR
MOVEMENT.
NEURONS THAT FIRE TOGETHER WIRE
TOGETHER.
SO THEN SUGGESTED NEURONS THAT
FIRE TOGETHER SHOWER TOGETHER.
THAT IS THE IDEA.
IMPLICATIONS ARE EXCITING.
ONE OF THE PHENO TYPES OF OLD
MICE IS THEY DON'T SLEEP WELL.
SO IMPROVEMENT OF SLEEP.
THAT IS SUPER EXCITING.
IF I HAVE ONE GOAL, REDUCE MY
SLEEP TO ONE HOUR.
CAN YOU MAKE YOUR CLEANING AT
NIGHT IN A SHORT TIME AND WAKE
UP AND GO BACK TO YOUR STUFF.
THAT IS A VERY EXCITING STUFF.
IF I'M INVITED FOR A SMALLER
TALK AND I WILL BRING ALL THE
UNPUBLISHED RESULTS.
ANYWAY, WHY DO WE CARE?
WHAT HAPPENS IN THE BRAIN WHEN
LYMPHATICS ARE IMPAIRED?
THIS IS THE WORK OK.D.
JUST GOT PUBLISHED AND I'M NOT
GOING TO ELAP RATE.
KD FOUND IF YOU TAKE YOUNG MICE
AND INTERFERE WITH THEIR
LYMPHATIC VESSELS WE HAVE
COGNITIVE DYSFUNCTIONS.
WE DIDN'T UNDERSTAND HOW THIS IS
ALL HAPPENS.
HE SAID LET ME CHECK FOR MYSELF.
HE DID SEVERAL ESSAYS, YOU
INTRODUCE THE MOUSE IN THE WATER
AND OPEN A SECOND ARM.
IN NORMAL, HEALTHY MOUSE WILL GO
INTO THE NEW ARM THAN THE OLD
ARM.
THEY ARE CURIOUS.
THEY REMEMBER THE OLD ARM AND
ARE PREFERRING THE NEW ARM.
MICE THAT HAVE LYMPHATIC
DYSFUNCTION, WE DID TWO WAYS OF
LYMPHATIC DYSFUNCTION IN THIS
PAPER, THEY DON'T HAVE A
PREFERENCE.
THEY ARE IMPAIRED IN NOVEL
EXPLORATION BEHAVIOR AS WELL AS
OTHER BEHAVIORS.
KD WAS RECORDING AND WHILE THERE
WAS NO AFFECT ON EXCITATORY
INPUTS.
THE NUMBER OF NEURONS IS NOT A
PROBLEM.
THE INPUTS WERE REDUCED WE
THOUGHT MICROGLIA, FIRE MICE
PROMOTER OF CSF RECEPTOR.
THE MOUSE IS BORN WITH
MACROPHAGES BUT NOT MICROGLIA.
WE DON'T GET THE INHIBITORY
SYNAPSE DYSFUNCTION.
THEY ARE PLAYING A KEY ROLE.
THEY ARE PROBABLY EATING THOSE
SYNAPSES.
WE DID NOT SEE THAT.
WE SEE THE EATING, BUT THERE WAS
NO CHANGE IN THE AMOUNT OF
EATING.
WHAT WE DID DETECT IS UP
REGULATION IN AISLE 6 PRODUCED
BY MICROGLIA.
I'M SUMMARIZING FOUR YEARS OF
WORK IN ONE SLIDE.
I'M DOING A DISSERVICE TO K.D.,
BUT IT IS PUBLISHED SO IT WILL
BE EVI TO FOLLOW.
THESE ARE MICE THAT HAVE NO ISLE
6 RECEPTOR.
IT IS PRODUCED BY MICRODPLEEA
AND SIGNAL ON TO NEURONS.
WE MICROGLIALIL-6.
ABOUT WHAT IS HAPPENING WITHIN
THE CELL.
SO AGED MICE, IT IS A PATTERN
YOU HAVE PROBABLY SEEN.
STUDYING BASIC PHYSIOLOGY AND
APPLYING IT TO AGES AND LOOK AT
WHAT IS GOING WRONG WHERE
MODELS.
WE ARE STUDYING WHAT IS
HAPPENING IN YOUNG MICE AND HOW
THESE THINGS ARE GOING WRONG IN
AGING.
IN AGING WE SEE REDUCTION OF
INHIBITORY INPUTS IN THE SAME
REGION.
LYMPHATIC VESSELS ARE SEVERELY
DETERIORATED IN AGED MICE.
THAT IS NOT NEW.
WE SHOWED THIS BEFORE.
WE DON'T KNOW HOW TO IMPROVE
SYNAPSES, BUT WE KNOW HOW TO
IMPROVE LYMPHATIC VESSELS.
WE INFECT MICE WITH VIRUS THAT
WILL SHOW VEGFC.
AND LYMPHATIC VESSELS ARE
EXPANDING SUBSTANTIALLY AND NO
DIFFERENT FROM YOUNG MICE.
WE SEE INCREASE IN INHIBITORY
SYNAPSE.
EXCITE SYNAPSES WERE NOT
AFFECTED.
SUPER EXCITING WORK, GIVES US A
GLIMPSE OF MOLECULAR.
WHAT SIGNALS MICROGLIA RECEIVE
TO PRODUCE NEED YEA TOR AND HOW
THE MEDIATORS ARE AFFECTING THE
SYNAPTIC INPUT INTO NEURONS.
FINALLY, IF YOU WILL ALLOW ME
FIVE MORE MINUTES.
WHY DO I CARE?
I'M AN IMMUNOLOGIST, WHAT I CARE
IS UNDERSTANDING HOW THE IMMUNE
SYSTEM SEES WHAT IS HAPPENING IN
THE BRAIN AND HOW THIS PROCESS
IS IMPAIRED IN DIFFERENT
DISEASES AND, OF COURSE, IN
AGING.
WE MAKE CLEAN CSF.
IT IS GOING THROUGH THE BRAIN
TISSUE AND COMES OUT OF DIRTY
CSF, CARRY METABOLITES AND
PROTEINS AND PEPTIDES FROM THE
BRAIN.
IT GOES INTO THE DURA AND
BECOMES THE CSF LYMPH.
THE MOLECULES ARE COMING INTO
THE DURA, THEY ARE BEING UPTAKEN
BY A LOT OF IMMUNE CELLS.
IT WILL BE UPTAKING BY APCs AND
PRESENTED TO PATROLING CELLS.
THEY LEAVE BY NEARBY LYMPHATIC
VESSEL.
THIS IS PRESENTATION OF THE
BRAIN IMMUNE CODE.
WE THOUGHT, OKAY, FROEBL THERE
IS A PROBLEM IN THE BRAIN, THEN
THIS IMMUNE CODE WILL CHANGE
BECAUSE YOU WILL START
EXPRESSING NEW PROTEINS.
THIS BAR CODE HERE PROBABLY WILL
CHANGE WAY WAY BEFORE DISEASE
REALLY STARTS.
SO WE WERE VERY EXCITED TO
UNDERSTAND WHAT IS BEING
PRESENTED IN THE BORDERS OF THE
BRAIN AND HOW THIS IS RELEVANT.
REALLY BRILLIANT PH.D. STUDENT
IN THE LAB.
IN COLLABORATION WITH -- WHO
PASSED AWAY TWO YEARS AGO, WE
TOOK ALL THESE BODER CELLS THAT
PRESENT THE PEPTIDES AND LOOKED
AT WHAT IS BEING PRESENTED.
I'M DOING IT VERY QUICKLY.
IT WAS JUST PUBLISHED A COUPLE
OF MONT AGO.
IT IS ONLINE.
MITCH SAW LOTS OF INTERESTING
CELL PROTEINS.
ONE IS MIRKS YLINE.
PEPTIDES WERE FOUND THAT WERE
NOT PREDICTED.
THESE PEPTIDES WE FOUND THEM IN
THIS STRAIN AND IN DIFFERENT
STRAINS OF MICE AND ALSO IN
HUMANS.
THEY WERE PRESENT IN HUMAN
SUBJECTS.
WHAT ARE THE PEPTIDES DOING?
THEY MAY HAVE YOU YEEK
REGULATORY ROLE.
IF THIS IS INDUCTION OF DISEASE
IN THE MOUSE WHEN WE IMMUNE
NICE, CELLS WITH GO INTO THE
BRAIN AND CAUSE PARALYSIS.
MULTIPLE SLER ROW SIS.
WE SEE SUBSTANTIAL REDUCTION AND
SEVERITY OF THE DISEASE.
IF WE MODIFY THE PEPTIDE IT
LOSES ITS EFFECT.
THIS PEPTIDE IS DRIVING
SOMETHING VERY, VERY SPECIFIC.
I WILL NOT BOTHER YOU WITH
DETAILS.
THIS PEPTIDE INDUCES AN DODGE
NOUS CELLS, THE SUPPRESSER
CELLS.
THEY SUPPRESS INDOGENO SURKS
RESPONSES IN THE BRAIN.
IN DISEASE CONDITIONS WHAT
HAPPENS IS THE PROTECTIVE
PEPTIDES ARE DISAPPEARING.
I THOUGHT THEY WOULD GO UP, BUT
THEY ARE GOING DOWN.
AND THAT IS POTENTIALLY ANOTHER
LAYER THAT ALLOWS MORE SEVERE
INFLAMMATION TO GO ON.
CAN WE REPLENISH.
IF YOU THINK OF A BAR CODE
AGAIN, LOSING SOME OF THE BARS
GETTING WIPED OUT.
CAN WE REINSTATE THEM?
CAN WE BRING THEM BACK?
WE PACKAGED OUR PEPTIDE IN THE
EXTRA CELLULAR VESICLES SO
INJECT IN THE CSF AND UPTAKEN
AND PRESENTED IN THE BORDERS
THAT SUPPRESSES THE DISEASE
VERY, VERY NICELY.
BASICALLY WHAT WE ARE SUGGESTING
IS THE BRAIN IS CONSTANTLY BEING
WASHED.
THE BRAIN'S SIGNATURE IS BEING
BROUGHT OUT INTO THE DURA AND
PRESENTED THERE AND SURVEYED BY
THE IMMUNE CELLS.
THE SIGNATURE WHEN IT CHANGES,
THAT IS WHEN IMMUNE RESPONSE IS
CHANGING.
WE HAVE THE NORMAL SCANNING OF
THE BRAIN LIKE A BAR CODE, IN
DISEASE CONDITIONS, IN THIS CASE
THE MOLECULES, ONE OF THE MAJOR
CELLS ARE MISSING.
SO THE IMMUNE RESPONSE BECOMES
ABNORMAL AND INSTEAD OF
SUPPRESSING THE RESPONSE BECOMES
MORE OF AN ACTIVATOR TYPE.
IF WE LOOK INTO THE AGED MICE,
AGAIN, THE SIGNATURE OF PROTEINS
IS COME LEADLY DIFFERENT.
IN A.D., THIS IS MY FAVORITE
SLIDE.
THIS IS ONLY THREE MONTHS OLD
MOUSE AND FOUR MONTHS OLD MOUSE.
IF YOU LOOK INSIDE THE CIRCLE,
THIS IS THE IN YELLOW IS THE
AMOUNT OF SUPPRESSIVE PEPTIDE,
IN FOUR MONTHS IT DISAPPEARS
COMPLETELY.
WE CANNOT FIND IT.
WHAT HAPPENS TO AD INSIDE THE
PEPTIDE AND HOW IMMUNE CELLS ARE
CHANGING?
MAYBE THE FLASH OF THE BRAIN IS
NOT GOOD AND WE DON'T GET THE
PEPTIDE COMING OUT.
LOTS OF EXCITING QUESTIONS.
CAN WE MAYBE DETECT THAT IMMUNE
BAR CODE, IMMUNE SIGNATURE OF
DISEASE IN PATIENTS.
THIS IS SMALL PREP.
FIVE AND FIVE.
WE HAVE A NICE AMOUNT OF
PARTIALS.
WE HAVE SAMPLES FOR OVER SIX
MONTHS.
WE JUST BOUGHT A NEW FANCY MASS
SPEC TO GIVE US BETTER READS ON
THE SAMPLE.
EVEN WITH A SMALL SAMPLE, WE
ALREADY SEE THERE ARE SOME
PEPTIDES ONLY APPEARING IN AD
AND OTHERS IN PD.
MY STUDENT TELLS ME IF I GET A
SAMPLE AD OR PD HE WILL BE ABLE
TO TELL WHICH ONE IT IS BECAUSE
SOME PEPTIDES ARE EITHER/OR.
THIS IS A DREAM THAT MAYBE ONE
DAY WE CAN DO THIS, I MEAN, IT
IS MORE INVASIVE THAN BLOOD
TEST, CSF TEST, IF WE GET ENOUGH
MATERIAL FROM CSF.
THIS IS ALL DONE FROM DURA.
POTENTIALLY WE COULD DEVELOP
REALLY EXCITING DIAGNOSTIC TOOLS
TO PREDICT DISEASES OF THE
BRAIN.
THIS IS WISHFUL THINKING.
I HOPE ONE DAY IT WILL BECOME
REALITY.
I SHOW THE DATA AND THANKED THEM
ALONG THE WAY.
MANY PEOPLE IN THE LAB, WHO I
WAS NOT ABLE TO PRESENT, MANY
COLLABORATORS.
AND MANY FUNDING SOURCES, I
WOULD LIKE TO EMPHASIZE NIA
BECAUSE THEY BELIEVED IN MY
THINGS VERY EARLY IN LIFE.
WHEN IMMUNOLOGY WAS NOT A FIANCE
THING AND NO ONE WANTED TO DEAL
WITH THE IMMUNE EFFECTS ON THE
BRAIN.
I WAS LUCKILY TO GET SUPPORT
FROM NIA, THE ALZHEIMER'S FUND.
AND MANY OTHER SOURCES.
AND I GUESS I WILL STOP HERE.
THANK YOU.
>> WE HAVE A FEW QUESTIONS BUT
THE MIC IS NOT WORKING.
CUP YOUR HANDS.
>> SO ONE QUESTION.
DID YOU CHECK THE MYELOID
COMPARTMENT AND THIS CHANGE IN
PEPTIDE CONCENTRATION COULD BE
RELATED TO TYPE OF -- THAT
PROCESSED IT?
>> BRILLIANT QUESTION.
IN A VERY SIMPLE EXPERIMENT,
FIRST OF ALL, IF YOU TAKE
MYELODAPC AND LOAD THEM, YOU SEE
WHAT HAS BEEN PRESENTED, WE
CANNOT FIND OUR SUPPRESSIVE
PEPTIDES PRESENTED BY B CELLS.
NEVER.
THAT IS WHY ANTI-B CELL THERAPY
IS WORKING IN ALS.
IT IS HYPOTHESIS, WHICH IS
EXCITING, BUT WE NEED TO PROVE
IT IS THE CASE.
WE ALSO KNOW WHEN YOU ACTIVATE
MICROFWLEEA OR MYELOID CELLS,
YOU ACTIVATE PRO TEASES.
WE DON'T KNOW IF THE CLEAVAGE
HAPPENS IN APC OR THE CELL OF
ORIGIN?
IS IT PREPACKED THAT WAY OR
CHOPPED BY APCs.
IF YOU TAKE CULTURES, IT IS
COMING FROM -- AND TREAT THEM
WITH DIFFERENT LPS AND CRAZY ACT
VASE, YOU SEE THE RELEASE OF
VESICLES WILL CONTAIN DIFFERENT
PEPTIDES.
THIS IS PROBABLY A COMBINATION.
>> GOING BACK TO THE LAST POINT,
WHEN CROWE HAVE AN INFECTION OR
MENINGEAL INFECTION, DO YOU SEE
THE SWITCH AND REDUCTION OF THE
SUPPRESSION MECHANISM?
>> YES.
SO WHAT WE THINK IS HAPPENING.
I WAS TALKING WITH KEN, I SAID,
KEN, OUR SUPPRESSER PEPTIDES IS
GOING UP.
YOU INTRODUCE SEVERE
INFLAMMATION.
THE BODILY TISSUE RESPONDS.
THERE IS A PROBLEM, WE NEED TO
ALLOW IMMUNE RESPONSE TO FIGHT
INFECTION.
IT IS BEING SENSED AROUND THE
BRAIN AND DON'T PRESENT ANY MORE
SUPPRESSIVE PEPTIDES.
>> IS IT TYPE 1?
>> YES.
IT IS.
>> LET'S GO OVER HERE.
>> HI.
IF YOU HAVE SHOWN THE PEPS THERE
TIDES ARE RESTRICTED --
>> I KIND OF GLANCED THROUGH IT.
I DIDN'T SHOW YOU.
T SO WHEN WE IMMUNIZE WITH OUR
PEPTIDE WE VIE DUCTION IN THE
RES.
THESE ARE CTLA POSITIVE.
IF THE YOU WISH LIKE TR1 TYPE OF
CELLS.
IF YOU INHIBIT THE BETA, YOU
LOSE THE INHIBITORY EFFECT.
IT IS NOT CLASSICAL T-RES.
YOU DO SEE THEM AS WELL.
YOU CAN DETECT THOSE ENDOGENOUS
CELLS.
IN NORMAL MOUSE, YOU SEE THEM IN
THE AROUND THE BRAIN AND NOWHERE
ELSE.
THEY ARE C T LA POSITIVE, YOU DO
SEE SOME.
>> DR. CASPE.
>> THAT WAS FANTASTIC.
MHC CONNECTION.
IF YOU POSTULATE THE TYPE OF
PROCESSING AND PRESENTATION THAT
OCCURS FOR THE PEPTIDES YOU SEE
THERE, HAS A MAJOR EFFECT ON
DISEASE AND PHYSIOLOGY.
YOU SHOULD SEE STRONG MHC
ASSOCIATIONS.
COULD YOU TALK ABOUT THAT?
>> WHICH YOU DO WITH ALZHEIMER'S
AND MS.
AD IS STRONG FOR SURE.
YEAH.
I DON'T KNOW IF I ANSWERED YOUR
QUESTION.
YOU KNOW, I'M NOT NECESSARILY
SAYING THAT THESE THINGS ARE THE
DRIVING FORCE OF THE DISEASE.
SO BUT IT'S VERY POSSIBLE THAT
THIS WILL JUST END UP MAYBE
BEING A DIAGNOSTIC TOOL.
YOU SEE CHANGES ARE HAPPENING.
MAYBE THE OUTCOME TO THE CHANGES
IS NOT AFFECTING PROGRESSION OF
BUNCH OF DIFFERENT DISEASES.
I DO THINK IT AFFECTS
PROGRESSION OF AD AND
NEUROINFLAMMATORY CONDITIONS.
BUT STILL I DO BELIEVE WHEN
DISEASE STARTS IN THE BRAIN AND
YOU START MAKING OR PRODUCING
DIFFERENT PROTEINS, THE FLOW
THING IS REAL AND REALLY THE
BRAIN WASTE IS BEING WASHED INTO
THE CSF INTO THE DURA AND THE
CELLS ARE PRESENTING THESE
PEPTIDES YOU WILL START SEEING A
CHANGE IN THAT SIGNATURE.
WHICH IF YOU CAN DETECT EARLY
ENOUGH, THAT BY ITSELF COULD BE
VERY, VERY EXCITING THING.
>> OVER HERE, PLEASE.
>> VERY NICE TALK.
YOU SHOWED WHAT AGE THE CSF FLOW
DECREASES AND WHAT FIRES
TOGETHER SHOWERS TOGETHER.
DURING EARLY DEVELOPMENT, DO YOU
SEE UNIQUE PATTERNS OF CSF
NODES?
>> VERY, VERY INTERESTING
QUESTION.
ONE THING WE ARE NOT DOING IN
THE LAB
>> OKAY.
>> IS DEVELOPMENTAL ASPECTS OF
MS.
WE DON'T DO NEURODEVELOPMENT AT
ALL.
>> OKAY.
>> MENINGEAL LYMPHATICS, FOR
EXAMPLE, THEY DEVELOP AFTER
EVERY OTHER LYMPHATIC BED.
THE MOUSE IS BORN WITH ALL THE
LYMPHATICS, BUT DOES NOT HAVE
MENINGEAL LIMB FAT IGS.
THEY APPEAR AFTER THREE WEEKS.
>> OH, WOW.
>> THERE IS A LOT OF THEM AND
THERE IS A PRUNING AND THERE ARE
LESS OF THEM.
ONE OF MY POST DOCS IS STUDYING.
HIS PAPER MAY BE COMING OUT.
I DON'T KNOW WHAT IS HAPPENING
IN -- WITH CSF, PATTERNS OF CSF
FLOW IN EHLY DEVELOPMENT.
VERY INTERESTING QUESTION.
>> ESPECIALLY WITH SPONTANEOUS
ACTIVITY.
>> REMEMBER ALSO MICROGLIA
ARRIVE IN THE BRAIN, THE ARRIVAL
OF THE CELLS AND DISPERSAL
THROUGHOUT THE BRAIN, FIRST
ALONG THE ARTERIES AND THE BRAIN
TISSUE, FOLLOWS THE PATTERNS OF
THE FLOW.
SO IT IS PROBABLY THERE WAY
BEFORE -- IT PROBABLY
ESTABLISHES ITSELF.
I DON'T KNOW WHEN CSF STARTS
BEING PRODUCED IN MICE.
I DON'T KNOW.
I SHOULD KNOW THAT.
THAT PATTERN IS WHAT FLOW WILL
LOOK LIKE WITH APPEARANCE OF
CELLS IN THE BRAIN.
>> OKAY.
THANK YOU.
>> MAYBE TWO MORE QUESTIONS THEN
WE HAVE A RECEPTION.
OKAY.
>> HI.
I APPRECIATE THE MENTION OF
SLEEP AS WE START TO LEARN IT IS
MORE OF AN ACTIVE PROCESS.
AND I CAN IMAGINE IT BRINGS ITS
OWN CHALLENGES WHEN DEVELOPING
YOUR EXPERIMENTAL DESIGNS.
MY QUESTION IS HOW DO YOU
ANTICIPATE THE TIE OF AGING
IMMUNAL -- SYSTEMICALLY AND ROOT
MICROBIOTA.
>> IT IS A SUPER COMPLICATED
QUESTION.
MY NEIGHBOR THREE FLOORS ABOVE
ME IS JEFF GORDON.
EVERY TIME WE DO IT, WE TRY TO
MAKE SURE WE KNOW WHAT WE ARE
DOING.
WE JUST GOT IRB TO DO SOMETHING
THE ALZHEIMER'S PATIENTS.
I CANNOT TALK ABOUT IT RIGHT
NOW.
IT IS JUST THE BEGINNING OF THE
PROJECT.
DEFINITELY ALL SYSTEMS ARE
COOPERATING AND PLAYING TOGETHER
AND I CANNOT REALLY TELL YOU
EXACTLY WHAT IS HAPPENING WITH
THIS PARTICULAR PATHWAY.
MICROBIOTICS ARE CHANGING,
BARRIERS IN THE BRAIN ARE
CHANGING, LYMPHATIC VESSELS ARE
CHANGING.
THE AMOUNT OF LYMPHATIC VESSELS
IS CHANGING.
TOTALLY OFF TOPIC OF THE
QUESTION, BUT I DON'T KNOW IF
YOU HEARD OF THIS NEW SURGICAL
APPROACH IN CHINA ALL OVER THE
NEWS, THEY DO STENOSIS OF
LYMPHATIC VESSELS IN THE NECK OF
ALZHEIMER'S PATIENTS.
FROM WHAT IS BEING SHOWN IN THE
MEDIA AND WHAT THEY CAN REPORT
IN LECTURINGS, , I HOPE IT IS
TRUE.
REMEMBER ALSO WHILE I DO BELIEVE
IN SLEEP THE BRAIN CLEARANCE IS
AT ITS MAXIMUM CAPACITY, I AM
NOT SAYING THERE IS NO BRAIN
CLEARANCE DURING WAKEFULNESS.
THERE ARE A LOT OF ARGUMENTS
BETWEEN SOME GROUPS.
WE REMAIN NEUTRALITY BECAUSE IT
IS DEFINITELY HAPPENING IN
DAYTIME, BUT ENHANCED IN NIGHT
TIME.
DIFFERENT TYPES OF WASTE MAY
REQUIRE DIFFERENT APPROACHES TO
REMOVE IT.
SOME MAY BE MOVING DURING
DAYTIME AND SLEEP TIME.
NOT SURE IF I ANSWERED YOUR
QUESTION.
BUT I CERTAINLY ANSWERED
SOMEBODY'S QUESTION.
>> LAST QUESTION.
THANK YOU SO MUCH FOR THE
PHENOMENAL STORY.
BASED OND ALL YOU DISCOVERED,
WHAT IS YOUR -- GLYMPHATIC IN
ORDER TO IMPROVE AGING
DISORDERS.
>> I USED TO BE AT UNIVERSITY OF
VIRGINIA TWO HOURS ODOWN THE
ROAD.
I WAS INVITED TO GIVE A TALK
ABOUT BLACKSBURG, IT IS NOT AN
MD SCHOOL, THE OTHER.
SOMEBODY ASKED ME WHAT DO YOU
THINK A BRAIN MASSAGE WILL DO TO
LYMPHATICS.
I SAID, I HAVE NO CLUE, BUT SIGN
ME UP.
WE JUST RECENTLY PROPOSED TO
ARPAH, BRAIN MASSAGE, MANUAL
THERAPY FOR LYMPHATICS ALONG
WITH THE NECK TO IMPROVE THE
SUCTION.
IT DID NOT GO VERY WELL.
I DO BELIEVE THERE IS SOMETHING
THERE.
IF YOU TALK TO MANUAL THERAPISTS
THEY TELL YOU BEAUTIFUL AMAZING
STORIES.
THERE IS SOMETHING THERE.
>> THIS IS VERY PROMISING.
ALSO WE HAVE A COUPLE OF STUDIES
WE FOUND FOR SOUND BASED
MANIPULATIONS AND FOR MAYBE
ACUPUNCTURE.
>> ARE YOU ENA?
>> YES.
>> YOU KNOW OUR WORK.
>> VERY MUCH.
WHAT YOU ARE DOING.
>> I ALWAYS THOUGHT THAT
STANDING ON MY HEAD IS A GOOD
THING SO I BOUGHT THIS THING AND
STAND UP.
NOW THROUGH YOUR FUNDING, WE SAW
THAT WHEN YOU PUT THE MICE TILT
UP AND TILT DOWN, THE FLOW OF
CSF IS COMPLETELY DIFFERENT AND
I'M NOT SURE ANYMORE I WANT TO
STAND ON MY HEAD NOW.
NOT TO SAY YOU SHOULD DO IT.
I DON'T KNOW WHAT IT DOES TO
YOUR SF SF DRAINAGE OUT OF THE
HEAD.
>> THANK YOU SO MUCH.
-- CSF DRAINAGE OUT OF THE HEAD.
>> THANK YOU SO MUCH.
>> CME CODE 57686.
THERE IS A RECEPTION OUTSIDE.
SEE YOU OUT THERE.