The Estrogen Factor

The Miles researchers retracted their paper in March in Science, only a week after Kawabata, Higgins and Gordon retracted theirs. As Wirak and his co­authors noted, they had not examined enough normal C57 mice to become aware of the occurrence of the clusters. Because the clusters have a "nonspecific stickiness" for many antibodies, Walker explains, they bound antibodies against beta-amyloid and misled Wirak's group into identifying them as plaques of beta -amyloid.

doubt, but as Cordell acknowledges, it is too incomplete as a disease model to use in realistic tests of potential treat­ments. Many other transgenic mice are now being developed, Selkoe says, but none of them are known to produce much amyloid protein or to form it readily into plaques. "The whole expe­rience with transgenic mice so far indi­cates that it's very hard to get them to express the amyloid precursor protein and to slice it up in a way that makes plaques," he concludes.

hausted. Moreover, Walker believes all the transgenic mice, even those -of the retracted models, still hold promise. "Even if the mice don't develop frank Alzheimer's-like pathology in the nor­mal course of events, it might still be possible to perturb the system in some way to induce those changes," he ex­plains, adding, "It's a hot field, and I hope this setback won't throw too much cold water on it." Martin notes that researchers at the NIA are working on new transgenic models. "We're encour­aging them to be cautious," he says, with good reason. -John Rennie

The two retractions leave only the Cordell mouse. Its validity is not in

The quest for an animal model of Alzheimer's disease is by no means ex-

The Estrogen Factor

Estroge n's s p h e re of i nfl u e nce s e e m s to keep g row­i n g . The q u e e n of hormones o rc h e s trate s aspects of sexual d i ffe re ntiati o n in the deve l o p i n g b rai n , d i rects

fe m a l e re p rod u cti o n a n d can s l ow oste o p o ro s i s . Now i t appears that e stroge n m ay have a part to p lay i n the treat­m e n t of Al z h e i m e r's d i sease as we l l .

Re searc h e rs a t Co l u m b ia Unive r s i ty h ave fo u n d that re­ce ptors fo r e s trog e n and n e rve g rowth factor coe x i s t i n c e rta i n n e u ro n s i n an a rea o f the b ra i n ca l l ed the basal fo re b ra i n . Th i s fi n d i n g s u g g e sts that e s trog e n a n d n e rve g rowth facto r m ay act syne rg i st ica l ly or rec i p rocal ly to i n ­fl u e nce t h e s u rvival a n d h e a l th of t h e s e n e u ro n s . " I t i s a ve ry i m p o rtan t fi n d i n g , " c o m m e nts Patr i c i a G o l d man-Ra­k i c , p rofe s s o r of n e u ro s c i e n c e at Yal e Un ive rs i ty. The d i s ­cove ry of "th e i r i n te racti o n i s rea l l y nove l . "

T h e i m p l i cati o n s fo r Al z h e i m e r's d i sease are stra i g h tfo r­ward , G o l d m an-Rakic says. Alth o u g h the study, w h i c h was led by C. Dom i n iq u e Toran-Al l e ran d , was conducted in rats a n d m i c e , the basal fo re b ra i n of a l l m a m m a l s conta i n s c h o l i n e rg i c n e u ro n s . These n e rve ce l l s p roduce t h e n e u ro­tran s m i tte r acetyl c h o l i n e , w h i c h is v i ta l fo r m e m o ry. One c h a racte r i st ic of Al z h e i m e r's d i sease is that c h o l i n e rg i c n e u ro n s c a n n o l o n g e r p ro d u c e acety l c h o l i n e-h e n ce the loss of m e m o ry. Many s c i e n ti sts are exam i n i n g ways to treat c h o l i n e rg i c n e u ro n s w i th n e rve g rowth facto r, a com­pound that sti m u l ate s the g rowth of axo n s and d e n d rites a n d that keeps n e rve ce l l s a l ive. In the presence of n e rve g rowth facto r, c h o l i n e rg i c n e u ro n s do not d e g e n e rate.

Toran -Al l e rand's fi n d i n g s s u g g e s t that n e rve g rowth fac­to r a l o n e m ay not a l ways be s u ffi c i e nt. Some n e u ro n s i n the basal fo re b rai n a s we l l a s oth e r areas have rece ptors fo r n e rve g rowth facto r o r fo r e strogen a lone . But because rece ptors for estrog e n and n e rve g rowth factor are p resent i n some of the same n e u ro n s , both com pou n d s may i n fl u ­ence the same ce l l , she explai ns. I n add i ti o n , Toran-Al lerand says she has fo u n d oth e r pote ntial evi d e nce of such i n te r­action . The gene seque nce of n e rve g rowth factor conta i n s w h at i s cal led an estrogen re s po n s e e l e m e n t. "Eve rywh e re there i s n e rve g rowth facto r, it appears there is estrog e n , " To ran-Al l e rand notes . " I t m ay be a u n ive rsal p r i n c i p l e . "

T h i s d i scove ry may ho ld particu lar re l evance for wom e n . More than h a l f of t h e est imated fou r m i l l ion Americans w h o have Alz h e i m e r's d i sease are women. But whereas t h e p rev­a lence rates for women are g reate r than those for m e n ­perhaps because women l ive longer-it h a s a lso b e e n sug­g ested that wo m e n acq u i re the d i sease m o re fre q u e ntly. I f estrogen i s neces sary fo r the deve l o p m e n t and s u rvival of

26 SCIENTIFIC AMERICAN June 1992

n e u ro n s in the basal fo re b rai n , then l o s i n g th e i r m aj o r s o u rce of estro g e n d u ri n g a n d afte r m e n o p a u s e o r afte r ovariectomy m ay put v u l n e rab le wo m e n at g reate r r i s k of Al z h e i m e r's d i sease, Toran-Al l e rand says. (Me n , in contrast, have an i n tri n s i c s o u rce of estrogen in testoste ro n e , w h i c h c a n be conve rted t o estrogen i n t h e b rai n.)

Alth o u g h they h ave b e e n few and far betwe e n , several stu d i e s s u p po rt th i s hypoth e s i s . D u r i n g the ear ly 1 9 80 s , Victor ia N . Lu i n e , now a t H u nte r Col l e g e , fo u n d that e s tro­g e n cou ld cause the p rod u ction of the e n zyme that synthe­s i ze s acetylch o l i n e in parts of the b rai n of ovariecto m ized fe male rats . Lu i n e's fi n d i n g s p ro m pted Howard Fi l l i t , now at the Mo u n t S i na i Med ica l Ce nter-a n d , l ate r, a tea m of Japa n e s e s c i e n ti s ts-to g ive estro g e n to a s m al l g ro u p of women w i th Al z h e i m e r's d i sease.

Both g ro u p s fo u n d that aspects of d e m e ntia d i m i n i s h e d i n ce rta i n pati e n ts afte r treatm e n t. B u t s o m e re searc h e rs were c rit ical of the stud ies . They q u e stioned the s m a l l sam­p l e s ize and arg u e d that estroge n had a l ready been s h ow n t o i m p rove mood i n postm e n o pausa l wo m e n . Th e refo re , they conte n d e d , m ood e n hance ment acc o u n ted for the ap­pare n t reve rsal of as pects of d e m e ntia.

N eve rth e l e s s , many re searc h e rs re m a i n i ntr i g u e d . Bar­bara B. S h e rw i n a n d S u sa n a Ph i l l i p s of McG i l l Un ive r s i ty, w h o study estro g e n re p l ace m e n t th e rapy i n wo m e n , have fo u n d that i t e n hances s h o rt-te rm m e m o ry. B u t S h e r w i n o b s e rves that " m o o d i n a n d of itse l f cannot acco u nt fo r the changes i n cog n i tive fu nct ion that we see. "

"A n u m be r of ve ry s m a rt, we l l -tra i n ed p e o p l e h ave sa id anecdota l l y that i n c l i n i cs w h e re e l d e r ly w o m e n a re treat­ed w i th estro g e n re p l ace m e n t the rapy, they don 't see Alz­h e i m e r's d i seas e , " observes Te resa Radebau g h , c h ief of the d e m e ntia and ag i n g branch at the Nati o n a l I n s titute on Ag i ng . " It c o u l d be a total m i rag e , but i t i s c e rta i n l y wo rth look i n g at, parti c u l ar ly g iven Toran-Al l e rand 's fi n d i n g s."

The i d e a that e stro g e n d e fi c i e n cy c o u l d contr i b u te to Al z h e i m e r's d i sease has oth e r s u p po rt. Mi r iam K. Aro n s o n of the Al b e rt Ei n s te i n Co l l ege of Med i c i n e fo u n d that wo m e n w i th myocard ia l i n farcti o n-h eart attac ks s o m e ­ti m e s assoc iated i n postm e n o pa u s a l w o m e n w i th p l u m ­m eti n g e s tro g e n l eve l s-w e re five ti m e s m o re p ro n e to deve l o p d e m e ntia than w e re those with o u t s u c h a h i s to ry.

Fu rth e r re search i s p l a n n e d , i n c l u d i n g look i n g at the re­lati o n , if any, betwee n e strogen re p l ace m e n t the rapy a n d d e m e ntia i n a l a rg e , o n g o i n g study. " A n u m be r of p e o p l e are starti ng t o tal k a b o u t it , " Rad e ba u g h says. " I t i s a fasc i ­n ati n g q ue s ti o n . " -Marguerite Holloway

© 1992 SCIENTIFIC AMERICAN, INC