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Poster<br />

529. Treatments: Alzheimer's <strong>an</strong>d Neurodegeneration<br />

Location: South Hall A<br />

Time: Tuesday, October 20, <strong>2009</strong>, 8:00 am - 12:00 noon<br />

Program#/Poster#: 529.12/I36<br />

Topic: C.02.o. Therapies<br />

Support: NIH NRSA<br />

AHAF # A20009063<br />

Title: CNS PPARγ mediates rosiglitazone reversal of cognitive deficits in <strong>the</strong> Alzheimer’s<br />

disease mouse model, Tg2576<br />

Authors: *J. RODRIGUEZ-RIVERA 1 , K. T. DINELEY 2 , L. DENNER 3 ;<br />

1 2 3<br />

Ctr. <strong>for</strong> Addiction Res., Univ. Texas Med. Br., Galveston, TX; Neurol., Univ. of Texas Med.<br />

Br., Galveston, TX<br />

Abstract: Clinical studies have provided evidence to suggest that treatment with rosiglitazone<br />

(RTZ), a peroxiosome proliferator-activated receptor gamma (PPARγ) agonist, may improve<br />

cognition in Alzheimer's disease (AD) patients. The mech<strong>an</strong>isms by which RTZ achieves <strong>the</strong>se<br />

effects are unknown. Our recent studies in <strong>the</strong> AD mouse model (Tg2576) have shown that RTZ<br />

reverses <strong>the</strong> associative learning deficit exhibited by <strong>the</strong>se <strong>an</strong>imals at 9 months of age, when<br />

Tg2576 first exhibit gluco-regulatory abnormalities. Intracerebroventricular (i.c.v.) injections<br />

with a selective irreversible <strong>an</strong>tagonist of PPAR γ (GW9662) blocked <strong>the</strong> cognitive-enh<strong>an</strong>cing<br />

effects of RTZ in Tg2576 mice, providing evidence that central PPAR γ contributes to cognition<br />

in Tg2576. As such, cognitive rescue by PPAR γ agonism <strong>an</strong>d its reversal with PPAR γ<br />

<strong>an</strong>tagonism provide a special opportunity to identify <strong>the</strong> connectivity between <strong>the</strong> biochemical<br />

<strong>an</strong>d behavioral events by distinguishing those associated with cognitive per<strong>for</strong>m<strong>an</strong>ce <strong>from</strong> those<br />

that are causally related. Thus, while m<strong>an</strong>y ch<strong>an</strong>ges have been described to occur after cognitive<br />

impairment, it has been extremely challenging, if not impossible, to determine which ch<strong>an</strong>ges are<br />

really import<strong>an</strong>t, but only correlative. In our studies, only a subset of molecular <strong>an</strong>d<br />

electrophysiological ch<strong>an</strong>ges affected by subsequent cognitive rescue will be c<strong>an</strong>didates <strong>for</strong><br />

playing a causal role. We c<strong>an</strong> fur<strong>the</strong>r focus this subset because only some will be subsequently<br />

affected by inhibition with PPAR γ <strong>an</strong>tagonism. Our approach is to take <strong>the</strong> entire set of<br />

biochemical <strong>an</strong>d electrophysiological mech<strong>an</strong>isms implicated in cognitive decline, focusing only<br />

on those affected by RTZ rescue, <strong>an</strong>d <strong>the</strong>n fur<strong>the</strong>r focusing to those affected by GW <strong>an</strong>tagonism.<br />

In order to underst<strong>an</strong>d how PPAR γ agonism reverses cognitive deficits in Tg2576, we have<br />

initiated studies in which we measure functional readouts of CNS PPAR γ activity including

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