NatureVolve

Q & A - Oliver Bracko & Nancy Ruiz

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To un­der­stand neu­rode­gen­er­a­tive dis­eases, why is it im­por­tant to in­ves­ti­gate brain blood flow? Is there a link be­tween brain blood flow and de­men­tia? [Oliver] In your pub­lished Na­ture Neu­ro­science study, how did your team at Cor­nell Univer­sity use mice to study the role of brain blood flow in Alzheimer’s dis­eases? [Oliver]

We have known for decades that blood flow to the brain is re­duced up to one-third in pa­tients with Alzheimer ’s disease. This is a large re­duc­tion in blood flow, sim­i­lar in size to the brain blood flow de­crease that causes the tran­sient dizzi­ness some­times ex­pe­ri­enced when stand­ing up too quickly af­ter ly­ing down. In Alzheimer ’s, large brain blood flow re­duc­tions are likely con­tribut­ing to the mem­ory and cog­ni­tive prob­lems, but we don’t yet fully un­der­stand the mech­a­nis­tic con­nec­tion and stud­ies aim­ing to un­der­stand the mech­a­nism be­hind these re­duc­tions are just beginning. Most likely sev­eral mech­a­nisms are in play, and life­style fac­tors such as car­dio­vas­cu­lar risk fac­tors, like obe­sity or Type2-di­a­betes, have an im­pact. Fur­ther­more, ge­netic risk fac­tors such as APOE4, the largest ge­netic risk fac­tor known to be as­so­ci­ated with Alzheimer ’s, are di­rectly or in­di­rectly con­tribut­ing to the over­all brain blood flow re­duc­tion seen in pa­tients. Re­cently sev­eral clin­i­cal tri­als have failed, which aimed to re­duce the patho­log­i­cal hall­marks of Alzheimer ’s amy­loid­beta plaques as well as hy­per­phos­pho­ry­lated tau. It be­comes more ev­i­dent that al­ter­na­tives to such treat­ments are in great need. Un­der­stand­ing brain blood flow re­duc­tions and their con­tri­bu­tions to Alzheimer ’s disease is an im­por­tant pre­req­ui­site to de­velop novel treat­ment strate­gies.

We are an en­gi­neer­ing lab and de­velop mi­cro­scopes. Our tech­nol­ogy en­abled us to study cap­il­lary blood flow in mice ge­net­i­cally en­gi­neered to de­velop Alzheimer ’s. Al­though it is pos­si­ble to study over­all blood flow in hu­man pa­tients with meth­ods like MRI, it is im­pos­si­ble to re­solve the blood flow of the small­est ves­sels (cap­il­lar­ies) of the brain. In mice, we iden­ti­fied that brain blood flow de­crease is caused by white blood cells (leu­co­cytes) stuck to the in­side of the cap­il­lar­ies in the brain. Be­cause blood cells flow in a sin­gle file in cap­il­lar­ies, the ad­hered white blood cells tran­siently block blood flow in these ves­sels. While only a cou­ple per­cent of cap­il­lar­ies have stalled blood flow due to these block­ages, each stalled ves­sel leads to de­creased blood flow in mul­ti­ple down­stream ves­sels, mag­ni­fy­ing the im­pact on over­all brain blood flow. When we used an an­ti­body that blocks leu­co­cytes’ ad­he­sion, the stalled cap­il­lar­ies started flow­ing again, and brain blood flow speed quickly in­creased by about 20%. When we tested the im­pact of im­proved brain blood flow on mice per­for­mance on mem­ory tasks, we found that mem­ory func­tion was im­proved within hours of giv­ing the an­ti­body that in­ter­fered with white blood cell ad­he­sion.

Di­rectly be­low: Oliver at a two-pho­ton mi­cro­scope.

Be­low, left: Vas­cu­lar in­flam­ma­tion imag­ing blood is red in­flam­ma­tion blue and green. Both im­ages: © Oliver Bracko. All rights re­served.

With your cit­i­zen sci­ence project Stall Catch­ers, how are you speed­ing up Alzheimer’s re­search? Have the par­tic­i­pants shared their ex­pe­ri­ences tak­ing part? [Nancy]

Stall catch­ers has been a great tool for us be­cause we have been able to en­gage a lot of peo­ple (sci­en­tists and non-sci­en­tists) with the re­search that we do in the lab and they also help us an­a­lyze our data, which takes a long time for us to do just by our­selves.

“...ex­er­cise is ben­e­fi­cial­for cog­ni­tive func­tion, and should play an ac­tive role in ther­a­pies against Alzheimer’s disease.”

I have seen a lot of en­thu­si­asm from par­tic­i­pants, es­pe­cially el­der peo­ple who like to help with speed­ing up Alzheimer ’s re­search, be­cause it feels per­sonal to them. Play­ing the game also rep­re­sents a way in which they can stim­u­late their brain by us­ing their phones or per­sonal lap­tops.

Which in­sights from your re­search aid the fu­ture de­vel­op­ment of Alzheimer’s ther­a­pies? Why may ex­er­cise be ben­e­fi­cial for pa­tients, ac­cord­ing to your re­cently pub­lished PLOS One pi­lot study? [Nancy]

In our pi­lot study, even though we did not find any changes in cere­bral blood flow or cap­il­lary stalls, we found an in­crease in neu­ro­ge­n­e­sis in the den­tate gyrus (new neu­rons be­ing formed in a re­gion in the hip­pocam­pus that is cru­cial for mem­ory) and an im­prove­ment in cog­ni­tive func­tion, specif­i­cally in short term mem­ory tasks, af­ter only three months of vol­un­tary run­ning in mouse mod­els of the disease.

This, along with many other stud­ies of ex­er­cise and its ef­fect on Alzheimer ’s disease, proves that ex­er­cise is ben­e­fi­cial for cog­ni­tive func­tion, and that ex­er­cise should play an ac­tive role in ther­a­pies against the disease.

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 ??  ?? Top right: Vas­cu­lar in­flam­ma­tion imag­ing blood is red in­flam­ma­tion blue and green. © Oliver Bracko. All rights re­served.
Top right: Vas­cu­lar in­flam­ma­tion imag­ing blood is red in­flam­ma­tion blue and green. © Oliver Bracko. All rights re­served.
 ??  ?? Di­rectly right: “Nancy” at a two-pho­ton mi­cro­scope. © Nancy Ruiz.
All rights re­served.
Di­rectly right: “Nancy” at a two-pho­ton mi­cro­scope. © Nancy Ruiz. All rights re­served.

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