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Environmental Enrichment Reduces A



Levelsand Amyloid Deposition in Transgenic Mice

Orly Lazarov,

John Robinson,

Ya-Ping Tang,

loss and severe cognitive decline. These clinical fea-tures are associated with deposition of

-amyloid (A

)

Ilana S. Hairston,

Zeljka Korade-Mirnics,

Virginia M.-Y. Lee,

Louis B. Hersh,

peptides and neuronal loss in the cerebral cortex andhippocampal formation. A

peptides are liberated from

Robert M. Sapolsky,

Karoly Mirnics,

*and Sangram S. Sisodia

the larger transmembrane amyloid precursor protein(APP) by the action of BACE 1 and

-secretase. Early-

Department of Neurobiology, Pharmacology,and Physiology and onset, familial forms of the disease (FAD) are causedby expression of mutant variants of APP, presenilin 1

Department of PsychiatryUniversity of Chicago (PS1) or presenilin 2 (PS2)(Price and Sisodia, 1998 ). Expression of these mutant genes leads to the overpro-Chicago, Illinois 60637

Departments of Biological Sciences and of duction of highly fibrillogenic A

peptides, and coex-pression of FAD-linked PS1 and APP leads to ac-Neurology and Neurological SciencesStanford University celerated amyloid deposition in the hippocampus andcerebral cortices of transgenic mice(Price and Si-Stanford, California 94305

Department of Pathology and Laboratory Medicinesodia, 1998 ). In view of compelling evidence that has emerged toCenter for Neurodegenerative Disease ResearchUniversity of Pennsylvania School of Medicine suggest that the brain, and the hippocampus and cor-tex in particular, exhibit environment-induced plasticityPhiladelphia, Pennsylvania 19104

Department of Molecular and Cellular Biochemistry throughout adult life, and the demonstration that APPprocessing andA

production can be modulated byCollege of Medicinesynaptic activity(Kamenetz et al., 2003; Nitsch et al.,University of Kentucky1993 ), we tested the hypothesis that A

amyloidogen-Lexington, Kentucky 40536esis could be modulated by environmental “experi-

Department of Psychiatryence.” The classical paradigm that has been employedDepartment of Neurobiologyto assess environment-induced plasticity is termed

Department of Pediatrics“environmental enrichment” and involves placing ani-University of Pittsburghmals in large cages that contain running wheels, color-Pittsburgh, Pennsylvania 15261ful tunnels, and assorted toys. Indeed, it is well estab-lished that animals placed in such environments exhibitenhanced memory function(Fordyce and Wehner,

Summary

1993 ), increased survival of newborn cells in the den-tate gyrus(Kempermann et al., 1997 ), and enhanced

Cerebral deposition of



-amyloid (A



) peptides is an

recovery from lesion-induced memory deficits(Rampon

invariant pathological hallmark in brains of patients

et al., 2000 ). Morphologically, exposure to environmen-

with Alzheimer’s disease (AD) and transgenic mice co-

tal enrichment is manifested in an increase in numbers

expressing familial AD-linked APP and PS1 variants.

of dendritic spines, extent of branching, and number of

We now report that exposure of transgenic mice to an

synapses per neuron (for review, seevan Praag et al.

“enriched environment” results in pronounced reduc-

[2000] ), implying that neural outcomes are a function of

tions in cerebral A



levels and amyloid deposits,

the degree and nature of environmental experience.

compared to animals raised under “standard hous-

We employed a well-established mouse model in

ing” conditions. The enzymatic activity of an A



which coexpression of familial AD (FAD)-linked APP

degrading endopeptidase, neprilysin, is elevated in

“Swedish” (APPswe) and PS1



E9 polypeptide variants

the brains of “enriched” mice and inversely corre-

leads to A

deposition throughout the hippocampus

lated with amyloid burden. Moreover, DNA microarray

and cortex(Lazarov et al., 2002 ). A cohort of newly

analysis revealed selective upregulation in levels of

weaned, male APPswe X PS1



E9 mice were exposed

transcripts encoded by genes associated with learn-

to an enriched environment conditions for 5 months,

ing and memory, vasculogenesis, neurogenesis, cell

after which time the brains of these animals were exam-

survival pathways, A



sequestration, and prostaglan-

ined using biochemical and histological approaches.

din synthesis. These studies provide evidence that

We now show that environmental enrichment leads to

environmental enrichment leads to reductions in

marked reductions in both the steady-state levels of A

steady-state levels of cerebral A



peptides and amy-

peptides and A

deposition in brains of enriched mice

loid deposition and selective upregulation in levels of

compared to mice in standard housing conditions. In

specific transcripts in brains of transgenic mice.

parallel, we observe a significant elevation in the activ-ity of an A

-degrading protease, neprilysin (NEP) in

Introduction

brain extracts from enriched mice compared to stan-dard-housed animals. Using high-density Affymetrix Alzheimer’s disease (AD), the major cause of adult-GeneChips microarray technologies, we show that, inonset dementia, is associated with progressive memoryhippocampi of younger mice, the majority of transcriptsthat were significantly upregulated in enriched mice

*Correspondence: ssisodia@drugs.bsd.uchicago.edu (S.S.S.);karoly+@pitt.edu (K.M.)

corresponded to immediate early genes (IEG), but tran-

Cell702Figure 1. Reduced Amyloid Deposition in theHippocampus and Cortex of Enriched versusStandard Housing Mice(A) Immunohistochemical analysis of brainsections of standard housing (SH, [Aa]–[Ad],hippocampus; [Ai]–[Al], cortex) and enrichedmice (Enr, [Ae]–[Ah], hippocampus; [Am]–[Ap], cortex) immunolabeled with anti-A

3D6 antibodies. Pictures were taken fromfour enriched and four standard housingmice. Scale bar, 250



m.(B) Quantitative analysis of volume of amy-loid burden in brains of standard housingand enriched mice. Volume is in arbitraryunits (mean cubic pixels ± SE, ANOVA, p

0.0374).(C) Reduced number and size of thioflavineS-stained amyloid deposits in the hippocam-pus and cortex of enriched versus standardhousing mice. Thioflavine S-positive amyloiddeposits in brain sections of enriched (Enr;Ca, Cb, Ce, and Cf) and standard housingmice (SH; Cc, Cd, Cg, Ch). Size and abun-dance of thioflavine-positive structures inenriched (a = low power; b = high power) isreduced compared to standard housingmice (c = low power; d = high power). For(Ca) and (Cc), scale bar, 250



m. For (Cb)and (Cd), scale bar, 120



m. Double labelingwith thioflavine S and anti-A

3D6 antibodiesreveals overlap staining at the core of theamyloid deposits, while the periphery of thedeposit is stained mostly with anti-A

3D6antibodies (Cg and Ch). In contrast, the vastmajority of amyloid deposits in brain sec-tions of enriched mice had little 3D6-positiveperipheral staining (Ce and Cf). Scale bar,60



Environmental Enrichment and Amyloid Deposition703Figure 2. Amyloid Deposition as a Function of Activity Level(A) Activity level of mice during exposure to enriched environment. Activity level of the mice was observed and recorded periodically. Thetime spent by the mice for each activity group is expressed as a percentage of total observation time.(B) Amyloid deposition in the brain of enriched mice as a function of their activity level. Amyloid deposition in the brains of enriched micewas detected and analyzed as described above (seeFigures 1 A and 1B). Levels of amyloid deposition were found to be inversely correlatedwith the activity level of the mice (mean ± SE; ANOVA, p

0.0116).

scripts encoding polypeptides involved in A

seques- immunoreactive brain sections confirmed that enrichedmice exhibited significantly less amyloid burden in thetration, endothelial function, and phospholipid metabo-lism were also elevated. This study provides evidence hippocampus and cortex compared to standard hous-ing mice(Figure 1B). Thioflavine S staining revealed athat steady-state levels of cerebral A

peptides andamyloid deposition can be modulated by environmen- reduced abundance and size of deposits with fibrillar A

in enriched mice(Figures 1Ca and1Cb) comparedtal factors. to standard housing mice(Figures 1Cc and 1Cd). Co- staining of brain sections with thioflavine S and 3D6

Results

antibodies revealed overlap in staining at the core ofthe amyloid deposits in sections fromeither enriched

Environmental Enrichment Leadsto Reduced A



Deposition

or standard mice (compareFigures 1Ce and 1Cf to 1Cgand 1Ch, respectively). However, 3D6 immunoreactivity At 1 month of age, an experimental group of nine male APPswe X PS1



E9 mice were exposed to enriched en- in the plaque periphery in enriched mice was reducedcompared to standard housing mice (compareFiguresvironment conditions for 5 months. During the last month, we documented the behavior and activity of a subset1Ce and 1Cf to 1Cg and 1Ch, respectively).To examine a possible correlation between the extentof these animals in the “enrichment” cage. Seven malemice at the age of 1 month were maintained in standard of amyloid deposition and activity of the mice in theenriched environment, we documented the behavior ofhousing conditions for 5 months, and these served asthe control group. Animals were euthanized and brain six enriched mice during the last month prior to sacri-fice. Some mice were highly active, spending more thansections were probed with 3D6 antibodies, specific foran epitope at or near the amino terminus of A

(Kim et40% of their enrichment time running on the runningwheels, while others had low activity(Figure 2 A). Re-al., 2001 ). Bound antibodies were detected by fluores- cently labeled secondary antibodies and visualized by markably, enriched mice exhibiting high activity levelsshowed the most significant reductions in amyloid bur-confocal microscopy. We observed a dramatic reduc-tion in amyloid deposition in the cortex and hippocam- den(Figure 2B). Thus, at least in this small cohort of animals, exercise appears to play a significant role inpus of enriched mice compared to standard housingcounterparts(Figure 1 A). Morphometric analysis of 3D6- modulating amyloid deposition.

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