NHiN Rn TH6 GlOl
B E N H A L Z H E I M E R -
MOTSOHinrNCOrEUTRIMdl
Ndm 2006, tr6n toan the' gidi co 26,6 tri$u ngircrl mdc b$nh Alzheimer va d^ doan ty 1$
ngirori mdc b^nh nay se la 0,556% vao ndm 2030. Tmh \ii k\\\ b^nh Alzheimer ldn diu tien dugrc phat hi$n (each ddy horn 100 ndm) d6'n nay, cdc nha nghidn ci?u thuQc cac trirorng dgl hgc, trung tdm R&D cua cac cdng ty ducrc ph^m Id^n tr6n thd'gidi da co nhidu n6 Ig'c trong cac nghidn cufu vd^ cdn b$nh nay, nhung nhid'u ngiTorl Igi l(hdng dam nghT ring co thd' chu'a khdi b^nh. Tuy nhidn, cac nghidn cuTu gin ddy da d?t du^c nhffng tid'n bQ dang ki, md ra hy VQng cho cac b^nh nhdn Alzheimer...
N
ao bd Id mdt may tfnh hOu cd cue l<y phUc tgp, luu giO nhieu tfn hieu ve gidc quan, xD ly vd du trD thong tin, ghi nhd vd tong hpp mot cdch cd chpn Ipc vdo nhDng thdi diem chinh xac.Su pha huy do benh Alzheimer gay ra gid'ng nhu xda bd mdt 6 cUng, bat d^u vdi nhDng tai lieu gan nhat vd hoat dpng ngupc Igi.
Dau hifiu sdm cDa benh thudng Id "qufin gan, nhd xa". Theo To chDc Y tfi' the gidi, nam 2005 cd 0,379% ddn so the gidi mic bfinh Alzheimer vd Udc tinh ty lfi nay Id 0,441% vdo ndm 2015. 6,556%
vdo ndm 2030.
Bfinh Alzheimer khdng chf xoa di cdc thdng tin ma cdn huy hogi cdc t^ bdo th^n kinh (ndron) cung vdi 100 ty ty (10^°) lien ket giDa Chung. Hau hdt cdc thuoc hifin nay dung dl^u trj bfinh Alzheimer d^u di/a vdo hifin tupng nhieu ndron bj mat di (md cac ndron ndy Igi cd nhiem vu gidi phdng ra axetilcholin - chat ddn truyen th^n kinh). Cdc logi thudc dieu tn Alzheimer cd tdc dung Dc ch^ mdt loai enzym phan gidi axetilcholin, Idm tang nong dp cDa chat nay.
Ke't quk Id kich thfch cdc ndron vd suy nghT rd rdng hdn. Tuy nhifin, tdc dung cija thud'c chJ trong thdi gian tD 6 thdng tdi mdt ndm sD dung do chung khdng cdn khd ndng tifi'p tuc lam ngDng sp huy hoai cac ndron sau dd. Mdt logi thud'c khdc gpi la memantin cd the lam chdm sp sa sDt trf tug 6 cac benh nhdn Alzheimer th^
nang (hoac the trung binh) do kim ham hogt tfnh qua cao cua mOt chd't dan truyen thdn kinh khdc Id glutamat, tuy nhJen hifiu \gc cua thud'c ddi bao Idu thi chua khSng djnh dupc.
Hpn 10 ndm qua, It ai ddm nghT d^n vific cd t h i chDa dupc benh Alzheimer. Cdc nhd khoa hpc cdn bifi't r^t ft v^ sinh hpc, ddc biet Id ngudn gd'c vd tie'n triln cua benh. Tuy nhien, cdc nghifin cDu gan ddy da dgt dupc t i l n bp dang k l khi tim ra cdc qud trinh sinh bfinh hpc va trien khai mdt sd chiin lupc tham dd nhMm Idm cham hoac lam ngUng cdc qud trinh hijy hogi nay. NgUdi ta cung hy vpng rang, mdt trong cdc cdch dilu tri do hoac sU phd'i hpp cGa cdc phUdng phdp cd the ngdn chan su thodi hda cDa cdc ndron
dCi d l ch^m dUt b$nh Alzheimer.
Mpt trong s6 cdc cdch dilu tn ndy dang dUpc thD nghidm Idm sdng vd cho cdc kfi't qud ban ddu c6 triln vpng. Ngdy cdng cd nhilu nhd nghifin cDu da cdm th^y "hy vpng" - m0t tU md trDdc kia khfing lifin tudng vdi b$nh Alzheimer.
Cia Urayet thac amyloid B^nh Alzheimer da dupc Alois Alzheimer - nha thSn kinh hpc ngudi ODc phdt hi$n l i n d i u tien cdch ddy hdn 100 ndm, vdi ddc tfnh chu yfi'u td x u i t hifin cdc mdng vd cdc bui protein d vd nao vd tgi h$ bifin (limbic) ddm nhi§m cdc ChDc ndng cao d p cua nao.
Cdc mdng ndy Id nhOng chit l^ng dpng d bfin ngodi cac ndron va dupc tgo thdnh bdi mOt protein nhd gpi Id amyloid - beta (A- beta). Cdc bui n^m d bfin trong cdc ndron vd cac mSu Hi phdn nhdnh (cdc axon, cdc dpt nhdnh) dupc tgo thdnh bdi cdc sdi cDa mdt logi protein gpi la Tau. Vi§c quan sat thd'y Tau md d i u cudc tranh cai kdo ddi trong sud't t h i k^ XX Id llfiu cdc mdng, cdc bui Id nguyfin nhdn gdy ra si; thodi hda
62 I K H " O A H S ' C S « * * " S " ° ' ^
NHlN Rfl TH€ GlCl
ci!ia cdc ndron thin kinh hay chl Id cdc d i u hifiu 6 ndi dien ra su chfit ci!la cdc ndron? Trong thgp kJ' qua, cdc chDng cd da Ong hp cho gid thuyet ddng thdc amyloid cho thd'y cd A-beta vd Tau d i u tham gia chu yeu vao bfinh Alzheimer, trong dd A-beta gdy hu hgi d i u tifin.
A-beta Id mpt peptit ng^n hodc mfit doan protein, dupc phdn ldp vd xdc dmh vao ndm 1984 bdi George G. Glenner vd Caine W.
Wong (flgi hpc California, My).
Peptit ndy b i t nguon tU mpt protein Idn hdn, gpi la protein tiln chat cija A-beta hodc APP (Amyloid precursor protein). Cac phdn tD APP gan qua mdng te bdo vdi mdt phin cilia protein bfin trong te' bdo va mdt phan khac 6 ben ngodi. Ly do tgi sao cdc te bdo tgo thanh A-beta cdn Id bf mat nhung chDng cd cho thd'y qud trinh ndy Id mdt phan cija con dudng truyen tin higu.
Mpt phan vung A-beta cua APP nim ben trong mdng, giDa ldp ngoai vd Idp trong. Vi mdng gom cdc lipit day nDdc nen cdc vung cua cdc protein qua mang cung ChDa cac axit amin day nudc. Khi A-beta bj c i t khdi APP bdi beta -secretaza vd gamma - secretaza, vd dupc gi&i phdng vdo mfii trudng nUdc ben ngodi mang, cdc vung d i y nudc cua cdc phdn tCr A-beta khac dfnh vdo nhau, tao thdnh cdc cpm nhd vd cum hda tan. Vdo dau nhOng nam 90 cua the ky XX, Peter T.
Lansbury (Dgi hoc Y hoc Havard, My) da nhdn thiy: 6 ndng dd du cao cdc phdn tD A-beta trong dng nghifim cd t h i tap hpp tao thdnh cdc cau true dgng spi tUdng tu vdi cdc cau trDc gap trong cdc mdng cua Alzheimer. Cdc cum hoa tan cung nhD cdc sdi cua A-beta tdc dgng ddc doi vdi cac ndron nuoi
Nao cua ngUdi khong bi benh Alzheimer
trong dTa petri vd cdc cym hda tan cdn cd the dnh hudng den cac qud trinh quan trpng trong nhdn thDc vd trf nhd khi nghifin cDu b chupt.
K i t qud ndy da ijng hd cho gid thuylt thdc amyloid, tuy nhifin chUng cd chic chin nhat lgi xuat phat tU cdc nghien cDu tren cdc gia dinh cd nguy cP mac Alzheimer dac bifit cao. Cdc thanh vien cua cdc gia dinh ndy mang nhDng ddt biln di truyin dupc bilt trudc khd ndng mlc benh trudc 60 tuli. Nam 1991, John A.
Hardy thudc Vien Qudc gia v l lao hda cua My da phdt hifin nhDng ddt biln d i u tifin nhu vay trong gen dpc md cho APP dnh hDdng dac biet d i n cdc pham vi hoat dOng cCia protein bfin trong vd xung quanh vung A-beta. Ngay
Nao cua ngUdi mic benh Alzheimer
sau dd, mdt sd nhd khoa hpc ddc ldp vdi nghifin cDu nay cung da nhgn thay cdc dot biln ndy tdng CDdng SD tao thanh A-beta, hoac mpt logi dac bifit cua A-beta cd xu hDdng tgo thdnh cdc chit ling dpng. Tuy nhien, d nhDng ngudi cd hpi chUng Down mang 3 bdn sao cCia nhifim sic t h i 21 (thay cho 2 bdn sao binh thudng) cd ty le mlc bfinh Alzheimer cao hdn nhilu d IDa tuli trung nien. VI nhifim s i c t h i 21 chDa gen APP, nhDng ngudi bj hdi chUng Down tgo thdnh A-beta d mDc cao ngay tD khi mdi ra ddi va cdc amyloid lang ke't cd the gap d trong nao ngay d tuoi 12.
Cdc nha nghifin cDu sdm phdt hifin ra md'i lifin hfi khdc giDa bfinh nhdn Alzheimer va cdc gen dilu khiln tong hpp A-beta. Ndm
S6 thang 5.2012 j ^ j ^ Q ^ f ^ Q ( ^
NHlN Rfl TH^' Gldl
1995, Peter St. George - Hyslop (Dai hpc Toronto, Canada) da xdc djnh dupc cdc dOt biln trong 2 gen cd lifin quan gpi Id presenilin
1 va 2 6 nhDng ngDdi mang gen bfinh gdy ra cdc dgng rlt sdm (cd t h i xudt hi$n d tuli 30 ho^c 40).
NhDng nghifin cUu khdc cung chDng minh ring, cdc dfit bifin ndy lam tdng ty l§ cDa A-beta cd xu hudng vdn cyc. Hi$n nay cac nhd khoa hpc da bilt ring cdc protein do cdc gen presenilin dpc ma Id mOt phin cua enzym gamma - secretaza.
Nhu vdy, trong s6 3 gen gdy benh Alzheimer sdm d ngudi thi 1 dpc ma cho tien A-beta, cdn 2 dpc ma cho cdc thanh phin cua mdt proteaza tham gia tgo thanh peptit ddc. Hon nDa, cac nha khoa hpc cdn nhdn thd'y, nhDng ngudi mang mdt bien ddi ndo dd trong gen dpc ma cho apolipoprotein E (mdt protem giup lifin kfi't cdc peptit A-beta thdnh cpc va spi) cd nguy cd mlc Alzheimer rat cao vao cudi ddi.
Gay miin dich chu dong (hoac hi dong) de loai bo A-beta Midi nao
Nfi'u A-beta ddng vai trd quan trpng trong qud trinh phat triln cua benh thi rd rang cdc proteaza tao thanh peptit la myc tifiu cho cac logi thudc kim ham hoat tfnh cua Chung. Cac chd't kim ham proteaza td ra rd't cd hifiu qud trong viec dilu tri cdc chUng rd'i logn khdc nhD: suy gidm mifin djch AIDS vd tdng huyfi't dp.
BDdc thD nhit trong vific tgo thdnh A-beta dUpc md d i u bdi beta - secretaza c i t di phin Idn APP ngay phfa ngodi mdng te bdo. Nam 1999, 5 nhdm nghifin cDu da ddc lap phdt hifin ra logi enzym nay dac biet phong phD d
trong cdc ndron t h i n kinh. M$c du g i n vdo mdng nhDng beta
secretaza giing vdi mOt s6 proteaza trong mfii trudng nUdc bfin trong vd bfin ngodi t l bdo.
Cdc proteaza ndy (trong dd cd proteaza tham gia sao chdp HIV- vi rut gdy bfinh AIDS) sCf dyng axit aspartic d l xuc tdc phdn Ung c i t protein. T i t cd proteaza d i u sis dgng nUdc d l c i t protein vd cdc enzym trong hp aspartyl proteaza sD dgng mOt cdp axit aspartic d l hogt hda phdn tis nUdc dung cho mgc dfch ndy. VI beta - secretaza thuOc hp ndy nfin cdc nhd nghifin cDu cd t h i khai thdc hilu bifi't v l cdc proteaza nfiu trfin nhim kim hdm beta secretaza. NhDng nghifin cDu v l di truyin cho thd'y kim ham hogt tfnh cDa enzym nay khfing dan de'n cdc tdc dyng phg cd hgi. Tuy nhifin, cdc chit kim ham beta - secretaza hifin v i n chua qua thD nghifim ldm sang vi chua tim ra cac chit cd hifiu lpc vdi kfch thudc du nhd d l xdm nhap vao nao. H i u hfi't cdc phdn tD Idn khdng t h i chpc thung hdng rdo mau - nao nay.
Gamma - secretaza thpc hifin budc thU hai trong viec tgo thdnh A-beta la cdt cudng cua APP con Igi sau sD chia tdch bdi beta - secretaza. Gamma - secretaza hoan thanh viec sis dyng nDdc d l c i t protein bfin trong mfii trDdng ky nudc cija mang t l bdo. Hai nghifin cDu quan trpng v l proteaza bao gom: 1- Ndm 1998, Bart De Strooper (Dgi hpc Cfing gido Louvain, BT) nhdn thd'y logi bd gen presenllinl b chupt ldm gidm sg c i t APP bdi gamma - secretaza;
dilu nay chDng td protein do gen doc ma Id can thifi't cho chUc ndng cua enzyme; 2- Michael S.
Wolfe (Dai hpc Tennessee, My) da chDng minh rang, cac chd't tUdng tg cdc chat kim ham co dien cua aspartyl proteaza cd t h i
kim ham sg chia c i t APP trong t l bdo bdi gamma - secretaza.
Kfi't qud nghifin cDu dd cho thiy, tUdng tu beta - secretaza, gammfe - secretaza cDng chUa mfit c$||, axit aspartic c i n cho phdn Dnfl";
xUc tdc c i t protein.
Sau dd, hai nhd khoa hpc n^y cdn xdc djnh dupc cdc chit kim ham gamma - secretaza lifin k i t trgc t i l p vdo presenilin vd 3 protein khdc n i m trong mdng phdi k i t hpp vdi presenilin cho phdp enzym ndy xuc tdc. Hifin nay, gamma secretaza dupc coi Id "thdnh vifin" cua mOt Idp proteaza mdi sD dgng nudc bfin trong mdng t l bdo d l thgc hi$n cdc ChDc ndng sinh hod. Cdc chfi kim ham gamma - secretaza \k nhDng phdn tD tUdng d l i nhd co t h i qua mdng vd tham nhap qua hdng rdo mdu - nao. Tuy nhifin, tilm ndng cija gamma - secretaza nhu mpt mgc tieu dilu tn bj cSn trd vi enzym ndy ddng vai tr6 quyet dmh trong sU thuin thgc cua cdc t i l n t l bdo chUa phdn hod b cdc bp phdn khdc nhau cua cP the (vf dg, cdc te bdo goc trong tuy xUdng phdt trien thdnh cdc te bdo hong c l u va bgch clu). Ddc biet, gamma - secretaza c i t mfit protein be m^t te bdo gpi la thg t h i Notch; dogn Notch tdch khii mdng bfin trong t l bdo, sau do truyin tfn hifiu vao nhdn va nhdn k i l m sodt te bdo.
Lilu lupng cao cua cdc chit kim hdm gamma - secretaza tdc dgng rd't ddc b chupt do hdu quS cua vific phd vS tfn hieu Notch, gfli Ifin mdi quan tdm ddc biet ve cac dilu trj ndy. Cdng ty dUpc Eli Lilly (My) da budc d i u thD nghifim fl nhDng benh nhan Alzheimer tir|
nguy$n mdt logi thud'c cho thu 31^ an toan va cd the sD dung im trj cho cac benh nhan mdi xtm
bfinh. I
64 K H ^ A H S C Sfi *h^"9^ 2012
NHIN Rfl TH6 GIOI
Flurizan - mdt loai thudc da dupc nghien cDu cung co triln vpng dang ke dd'i vdi cdc benh nhdn Alzheimer giai dogn sdm va se dupc dua vao thD nghifim lam sdng mpt each rdng rai.
Mdt chifi'n lupc khdc chOa Alzheimer Id lam sgch ndo do cdc chat kfi't tg ddc cOa A-beta sau khi peptit dupe tgo thdnh. Cdc nhd khoa hpc da thpc hifin tifim A- beta vao de phat triln cac mSng amyloid dap Dng mien djch ngan can sg tao thdnh cdc mdng vdn trong ndo. TD kfi't qud thD nghifim dDdng tfnh 6 chupt (cdi thien sp hilu bifi't va tri nhd), vdo nam 1999, Cdng ty Elan (My) da thgc hifin thD nghifim b ngUdi. Vific tiem A-beta thD nghifim 6 ngudi ban d i u an todn, nhung d pha tie'p theo da xay ra mpt so trudng hpp bj vifim nao, khien cho vific nghien cDu phdi tgm dDng vdo nam 2002. Cdc nghifin cDu sau dd cho thd'y, cd the vific dieu trj da gdy ra viem do thuc day cdc te bao T cDa he mien djch tan cong qua mgnh vdo cdc A-beta kit lang. Tuy nhifin, viee nghien cDu cung cho k i t qua Id cd nhieu bfinh nhdn tgo thdnh khdng the khdng A-beta va bieu hifin cac dau hieu cija trf nhd, ddng thdi sU tdp trung dDpc cdi thifin...
Gdy mien djch ehCi ddng hoac b| ddng d l cd the logi bd A-beta khoi nao nhD thfi' ndo vdn cdn Id dilu bi mat vl viec cdc khdng the cd the qua dupc hdng rdo mdu - nao bang each nao vdn chDa dUdc lam ro. Mpt so nghifin cDu cho rang viec di vdo nao cd the khdng can thiet: thu hut A-beta trong phin cdn lgi cija cd the cd t h i dan den sg di ddi cua peptit khdi nao vi cac phan tCf cd xu hUdng chuyen dpng tD ndi cd nong dp cao tdi ndi cd nong dp tha'p. Mac du miin djch bj ddng hien dupc xem Id cd
triln vpng nhd't, nhUng mien djch chCi dpng cung dem Igi hieu qu^
khdng kem. NhDng nghifin cDu sd bp cua Cynthia Lemere (Dgi hpc Harvard, My) cho thiy, gay mien djch vdi nhUng phin chpn Ipc cua A-beta thay cho cd peptit nguyfin vgn cd the kfch thfch cdc t l bdo B tgo thanh khdng t h i ci!ia hfi mifin djch md khfing kfch thfch cdc te bdo T gdy ra vifim ndo.
Cdc nha nghifin cDu khdc da theo duoi chifi'n lupc phi mifin djch de ngdn chdn sp kfi't tg cua A-beta.
Ho nhdn thiy cdc hpp chit tUPng tdc true tiep vdi A-beta glD peptit hod tan trong djch ben ngoai cdc ndron than kinh, ngdn chdn sutao thdnh cdc phDc hpp cd hgi. Hang Neurochem (Canada) da tap trung phdt triln Alzhemed - mpt phdn tD nhd bat ehudc heparin la chat chdng dong tD nhifin. Trong mau, heparin ngdn chgn SD tap hpp thdnh cgc nhDng khi gan vdi A-beta, polisacarit ndy khifi'n dfi tao thdnh chd't kfi't Idng lifin ke't vdo cung vj trf tren A-beta. Vi Alzhemed kim ham hogt tfnh cua heparin, do dd cung lam giam sp ket vdn cDa peptit. Hdp chd't nay cd ddc tfnh thd'p hodc khong cd dpc tfnh (thdm chi ngay vdi lilu lupng rat cao) dUa vdo dilu trj se giup cdi thien phan nao nhgn thDc b ckc benh nhdn Alzheimer b the nhg. Cdc thD nghiem Idm sang b pha cull eung dang dDpc trien khai.
Van d l cdc spi tau gdy ra cdc bDi npron cung dUdc xem la mgc tifiu ed triln vpng d l ngan chan sU thoai hod cija cac ndron than kinh. Cdc nhd nghien cDu dang tap trung nghien cDu chat kim ham cdc enzym kinaza gan nhilu gdc photphat vdo Tau, budc quan trpng trong sg tgo thdnh spi. Hp hy vpng cdc chit kim ham nay sfi hoat ddng ddng bd vdi cac chd't
tan cdng A-beta.
Cae nhdm nghien cDu cung da xem xet SLf dgng thud'c lam gidm cholesterol (nhU statin) ddi vdi bfinh tim mgch d l dilu tri bfinh ndy vi nhilu k i t qud nghien cDu djch tfi hpc eho tha'y, nhDng ngUdi sD dyng statin cd nguy cd mac Alzheimer thip hdn. Cd t h i khi gidm nong dd cholesterol, statin cung sfi gidm sg tgo thdnh APP hode ed tdc dgng trUc tiep d i n viec tao thdnh A-beta do kim ham hogt tfnh cCia eac secretaza.
Gan day, phUdng phap dieu trj t l bdo cung dupe cdc nhd khoa hpe quan tam. Nha nghien cDu Mark Tuszynski (Dai hpc California, My) da lay sinh thie't da tD cac benh nhan bj Alzheimer b the nhg, sau dd lap gen dpc ma cho yfi'u to' sinh trudng than kinh (NGF) vdo cac t l bao nay. Tiep dd, cdc t l bao da edi bien di truyen nhd phdu thuat dupc dDa vao nao trDdc cua cdc bfinh nhan. Theo Mark Tuszynski, cdc te bao cay dudi da se sdn sinh vd tilt NGF, glDp ngdn chdn sU that thoat cac npron tgo thdnh axetilcholin vd cai thien trf nhd. Tri lieu dpa vdo t l bdo Id mpt phUdng phdp phu hpp de chuyen giao NGF - mpt protein Idn khdng the thdm nhap nao bang cdch khac va phuong phdp nay lam cham tinh trgng suy gidm nhdn thDc b bfinh nhdn Alzheimer. Mpt kfi't qua quan trpng nhD vdy la bDdc khdi dau cho ngdnh y hpc tdi sinh phgc hoi cdc ChDc ndng tdm than •
Nguyen Dinh Quyin (tong hdp)
So thSng 5.2012 t^- 65
