The Physiological Parameters and Behavioral Outcomes Associated with Environmental Enrichment-Induced Reduction in Aß Peptide Levels and Deposition in FAD Transgenic Mice
2005 Seed Grant
Orly Lazarov, Ph.D.
The University of Chicago
Alzheimer’s disease (AD) is characterized by memory loss and cognitive deterioration. Human subjects affected with the disease exhibit amyloid deposits in specific brain areas. Amyloid deposits are aggregates of small peptides termed 13-amyloid (Ap), derived from a larger membrane proteins, tem1ed amyloid precursor protein (APP). The familial, early onset form of the disease (FAD) is caused by mutations in APP, presenilin 1 (PSI) and presenilin 2 (PS2). We have previously shown that exposure of transgenic mice expressing FAD-linked mutant polypeptides to environmental enrichment induced a dramatic reduction in amyloid deposition in their brains. Our analysis also revealed an important inverse relation between physical activity level of the mice and extent of amyloid deposition, as well as upregulation of genes associated with neuroprotection, neurogenesis, Al3 sequestration and learning and memory processes. Encouraged by these exciting observations, in the current proposal, we propose to identify the stimuls that accounts for reduction of amyloid deposition, to examine whether environmental enrichment ameliorates amyloid deposition in old transgenic mice with preexisting amyloid deposits, and to examine whether exposure to enriched environment affects cognitive function. Our study will unravel an important and novel link between environmental factors and AD. The implications of this study are far-reaching concerning our ability to prevent AD as well as to treat human subjects with late onset AD.
Alzheimer’s disease (AD), the leading cause of adult onset dementia, is now the fourth major cause of death in the developed world after heart disease, cancer and stroke. It is estimated that 4.5 million people in the United States of America are affected with the disease. Affected individuals experience difficulties in memory, learning, speed of performance, recall accuracy, and problem solving. A large proportion of these individuals eventually develop progressively severe cognitive impairments, and some show evidence of psychoses. Since the vast majority of AD cases are the sporadic late onset form of the disease, it is reasonable to assume that environmental factors in the individual’s lifestyle may have an accumulative effect, contributing to either formation or prevention of the disease. Indeed, we have shown, for the first time, that exposure to environmental enrichment dramatically reduces amyloid deposition in the brains of transgenic mice harboring Familial Alzheimer’s Disease-linked mutant polypeptides. Further examination of this important and exciting breakthrough may lead to a conceptual revolution in our lifestyle, by providing a natural, acquired and noninvasive way to slow down or prevent AD.