let's pivot and talk about the brain a little bit this is an area where your own knowledge has grown rapidly Tom this is clearly an area of immense curiosity for you for me um because you know cholesterol plays an important role in the brain I think to to put it mildly um and people have many questions about the role of cholesterol lowering therapy and brain health so um what let's just start with a basic question which is what role does cholesterol play in the brain um and what do we know about the different pools of

cholesterol we have cholesterol outside of the central nervous system cholesterol inside the central nervous system can they move back and forth can lipoproteins go back and forth is LDL taking cholesterol into the brain and back to tell us about how that whole system works so important I'm glad we're going to chat about this a little bit and it's obviously so complex really I'll almost give you credit you're the guy who got me interested in lipids in the brain year probably 15 years ago when you introduced me to Richard Isaacson at the Cornell dementia clinic and

he was very interested in lipids cuz he just knew lipids are part of what's going on in the brain and I better learn more about lipids and you were good buddies and I got dra pulled into that Circle so that's I like how you said dragged initially I mean uh I mean I mean pull pulled slowly yes now you're a strong Guy Peter you uh you motived me to study a lot of things that maybe I wouldn't have tripped into and that uh I don't know I would have ever met a Richard Isaacson had it

not been for you but thank God you did and so we've been trying to learn about brain and the lipids so often the last thing I'll say you did that great podcast with Dan Raider on hdl's and it's a podcast everybody should listen to but at the end you sort of turned to Dan you said where are we going with lipids Dan we've sort of solved the APLE B we're learning a lot about HDL and Dan said it's lipids in the brain is the next Frontier and why has that not been studied very much until

now because you can't stick a needle you have to go into the get cerebral spinal fluid to analyze what's going on in the brain and uh most people are amenable to a vena puncture in their elbow not a spinal tap so here's what's going on cholesterol is almost certainly the most important molecule in the brain the brain is by far the most cholesterol carrying organ in the body the brain actually makes more cholesterol than any other organ per se way more than the liver even so if I gave you a dumb question hey I'm a

I got this body here and I want to find out where all the cholesterol is where should I go open his skull and take out the brain that's where you're going to find the most cholesterol wow so obviously cholesterol is crucial to the brain and that's because the brain is made up of a lot of cells all of which have important functions especially those neurons that shoot off all the action potentials that make our body function and everything and what's on the surface of a neuron free cholesterol and phospholipids so Evolution I guess figured out

a long time ago that the brain needs cholesterol so we're not going to make the brain dependent on cholesterol that's floating around the plasma or what's in your liver or your intestine we're going to let the brain make all the cholesterol it needs so we're going to really drive the enzymes that uh synthesize cholesterol in the brain so the brain needs cholesterol to make a long story sure every cholesterol molecule that's in the brain got there by denovo synthesis in the brain not a single molecule of cholesterol was delivered from the periphery meaning that floating

around our plasma leaves the plasma and enters the brain now by the way where is all the cholesterol our plasma well I've already told you it's got to be inside of a lipoprotein floating in plasma that's where we measure cholesterol that's where we measure lipids in the plasma but I can assure you there is no cholesterol carrying particle in the plasma be it a vldl and HDL uh or an LDL that crosses the bloodb brain barrier and says okay brain here's your cholesterol for today doesn't happen there is a rapid turnover of cholesterol in the

per periphery cells make it they get rid of what they don't need it's brought back to the liver uh for to for the liver to decide what to do with it the turnover time for cholesterol in the plasma is 2 to three days all right so if a cholesterol molecule is synthesized in the brain what is its halflife five years now halflife if a halflife is uh a given number the total sort of brain resonance time of that cholesterol molecues you multiply that by seven so uh some cholesterol molecules last up to 30 years once

they're synthesized in the brain and that's why cholesterol synthesis in the brain starts in utero early on Mom Supply in the little fetal brain with a lot of cholesterol but very rapidly second third trimester those brain cells start making their own cholesterol once a child is born there's a lot of cholesterol synthesis going on on by virtually every cell that exists in the brain there's only like three of them but at a certain point somewhere between the ages of 5 and 10 the brain May has made all the cholesterol it needs so then only two

cells continue to make cholesterol so lesson number two what are the cells in the brain that we're in this conversation with neurons I've mentioned in utero and in childhood neurons produce a lot of cholesterol but at a certain age the neurons got more work to do they don't want to make cholesterol why because every cholesterol molecule requires 27 molecules of ATP to produce it's a super energy gien process neurons need ATP for a lot of other functions those electrical charges they make all right so what are the other two cells in the brain alod dendrites

make the most cholesterol and where does the cholesterol they make become myelin which coats every nerve ending every axon and dendrite in your body so the those aliga dendrites are big time cholesterol producers but they make all their cholesterol go to myin they don't send any cholesterol over to neurons so what is the other cell and its asites in again in infancy and childhood and utero alod dendrites asites and neurons are making cholesterol that us know tomorrow once the neurons s making it asites are the soul maker of cholesterol that supplies the neurons but how

would an asite synthesize cholesterol and send it over to the neurons aha the brain has to have a lipoprotein system just like the periphery does now between astrocytes and neuren neurons is basically it's brain interstitial fluid sort of a loose connective tissue it's called the matome so if asites synthesize cholesterol they obviously have to package it inside of a brain lipoprotein secrete that lipoprotein which swims through the matome and goes over and guess what the neuron expresses LDL receptors LDL receptor related protein or something called the scavenger receptor all of which can bind to the

type of lipoprotein that an asite produces so the brain also has a lipoprotein deliver system but here's the difference what is the main structural protein in the periphery APO b or APO A1 what is the main structural protein in the brain APO e so when an asite makes an lipoprotein it's an APO e containing lipoprotein and by the way they're smaller much smaller than the particles the bra that we find in the periphery if we put them in a cuge they have the density of a high density lipoprotein that W floats around the periphery so

they're often called brain hdls but don't confuse brain hdls with peripheral hdls CU most of the brain hdls have apoe as their structural protein in the periphery they have apoa1 here's where the story gets a little more complicated as always what is the smallest apil protein the body can make it's actually apil protein A1 which is why an HDL needs four or five of them so if apoa1 can dissociate from an HDL and we do have free HDL in the plasma that's measurable it is small enough that it can cross the bloodb brain barrier and

once it joins the bloodb brain barrier what is the small APO A1 looking for an HDL buoyancy particle so it joins with the apoe particles so the brain lipoprotein are all apoe or they're all apoe plus apoa1 and you can have multiple copies of each of those on those particles so wow so now as long as they APO A1 by the way which can bind to an LDL receptor or the scavenger receptor same with the apoe the neuron can grab them and either internalize them or delipidated them and the neuron gets its cholesterol and the

neuron's happy and then the delipidated particles can go right back and fill up at the asite again so that's brain cholesterol transformation [Music]