Hypercholesterolemia accelerates amyloid pathology in a transgenic mouse model of Alzheimer\'s amyloidosis

Oral Presentation:

Animal

Oral Presentation:

Models

(Beta Amyhid)

s125

Animal Models (Beta Amyloid)

AGE-DEPENDENT DEFICIT IN LATE-PHASE LTP IN THE HIPPOCAMPUS OF HUMAN APP69Sswl, X PSI,,,, DOUBLE TRANSGENIC MICE

TRANSFORMING ZHEIMER’S-TYPE HUMANS. Tmty

WywCorav.

Lisa Barc~llos, Lin.

Glud.~onr

Mu,liuh. MA:

AD is consldcred to he a causative agent in the neuronal dysfunction acsocmted wth AlLheimer.5 disease. To investigate the effects of elevated AP and plaques on cynaptic function we have generated a transgenic mouse line that expresses both the Swedish mutations in human APP, and the familial A246E mutation in human PSI. As part of a longitudinal study, mice were evaluated for changes in AP production. hrhaviour, neuropathology, and electrophysiology. The% mice showed accelerated AP accumulation at an earlier age (6 months) than single transgenic APPSWE mice 0, months). Using a conventional brain slice preparation we evaluated synaptic tunction in the CAI region of the hippocampus of these mice. All experiments were carried out blind to the genotype and comparironr were made with lsogenic age-matched controls. The extracellular field potentialb (fEPSP) in the CAI were unchanged between wild-type and double transgenic mice at 2,6,9 and I4 months of age. The maximum tEPSP slope decreased wth age, hut was preserved in older animals by incubating the slices in kynurenic acid during and 45 minutes after xxtmning, demonstrating that these mice have an age-dependent increase in ausceptlhility to excitotoxicity. Paired-pulse facilitation was normal at all of the ages studied (intentimulus intervals from 25 to 300 milliseconds). Similarly long-term potentiation (LTP) induced by a theta burst protocol (4 stimuli at IOOHz repeated IO times at 20Omq intervals) wah normal up to one hour after the high frequency stimulur at all age\. However, we observed a selectwe age-dependent deficit in saturation induced late-phase LTP. Late-phase LTP was induced by a repeated tetanus protocol (100 stimuli at IOOHz repeated 4 times at 5 minute intervals). Between 2 and Y month\ there was no significant deficit in LTP up to 3.5 hours after the last tetanus. At 14 Imonths the field EPSP slope in tranygenic slices decayed hack to 137% relative to the baseline slope whilst in wild type slices it remained at 196% of hawzline (p=O.O4, Fl,l7=4.95, n=7 and I2 slices from 4 and 6 animals respectively). Therefore exprewon of the human APPSWE x PSlA246E tranagenea in mice causes a wlectlvs age-related deficit in hippocampal late-phase LTP.

IMPAIRED SPATIAL LEARNING AND MEMORY IN APP,.,,,J PS2 DOUBLE TRANSGENIC MICE

Dominant mutations in the P-amylold precursor protein (APP) or prerendin (PS) genes are associated with familial Alzheimer’s Disease (FAD). To addras the relationship between FAD mutations and cognitive deficits, we examined double transgenic (Tg) nuce expressing mutant human APP and PS2 tranagenes. A novel line of Tg mice (TgCRNDX), expressing a compound mutant form of the human APP695KM670/67lN + V717F. wth very early-onset Alzhrimer Diseaw (AD) related pathology (elevated level of API-42 in the brain and AP plaque deposition from 3 months onwards) was used. These mice were crossed with Tg PS2(M239V)1379 mice, producing progeny co-expressing both transgenes. The cognitive characteristics of mice expressing both transgenes were compared to Tg mice expressmg only the PS2(M239V) gene (Tg(PS2)). Since It IF accepted that the hippocampal region i\ affected in the early stages of AD, we tested the mice longitudinally at age 2 and 5 months in the hidden platform (place discrimination task) version of the Morris water mue (WM). At 2 month\ of age Tg mice expressing the APP gene showed an impairment in the initial acquisition of the spatial information and significant impairment in the immediately followed reversal of learning wt. When retested at 5 months, the Tg mice were significantly impaired in the initial phase of learning acquition, and did not show any bias for the position of the platform during the probe trial. In the subsequent learning reversal test, re-learning of the new spatial position was significantly impaired. Tg(APPIPS2) mice did not differ from Tg(PS2) mice in their swim speed or the perfom~ance in the cued (visible) platform test at any age tested. We conclude that expression of mutated human APP in the presence of mutated PS2 gene confers impairment in spatial leaning and memory as early as 2 months of age, ab compared to the performance of smgle Tg PS2(M23YV)l379 mice. This impairment progresses with age and by age of 5 months the mice show constant deficiency in acquiring new spatial information.

Univ

Lmnrrrt

Gladstone Jorge

GROWTH FACTOR (TGF)-Bl MODIFIES ALPATHOLOGY IN TRANSGENIC MICE AND

Institute

OksenberR,

Ari

oj Neurological Green,

Univ

Disease.

San Francisco.

of CA, San Francisco.

CA;

CA; Carol

Institurr of Nam~logico/ Disrasr. Sun Fruncisco. CA: Elirzer of CA. La Jolla, CA; Strven M Grrenber~, Hurvurd Mrd Sch. Bo.mur.

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