2006 AFAR Research Grant: Memory Recovery as a Function of Aging and Tau Transgene Suppression

Please give a brief summary of your AFAR research project.
"A man is but what he knoweth," wrote Sir Francis Bacon. This phrase defines one of our traits we most value in being human. Aging can severely compromise our cognition, and although the decline in memory function is typically a gentle one, it can be greatly affected by age-related neurodegenerative diseases like Alzhiemer's disease or fronto-temporal dementia with Parkinsonism, for example. Although cognitive evaluation is indicative, a definitive diagnosis related to a particular disease is reached only post-mortem, and is defined by a combination of pathological changes in the patient's brain. Despite a considerable scientific progress, our understanding of the pathogenesis of specific forms of dementia is still poorly understood, and it is not surprising that effective treatments are at present purely symptomatic.

The identification of genes associated with neurodegenerative diseases provided an opportunity of creating mouse models designed to replicate the relevant features found in these diseases, including both brain pathology and associated cognitive changes. The proposed research capitalizes on this novel technology, and using a mouse model attempts to elucidate the causes of cognitive decline in the fronto-temporal dementia. This mouse model, denoted technically Tg4510, is unique in a sense that it carries a mutated human tau gene implicated in the fronto-temporal dementia which can be conditionally switched on and off (made active or inactive in a live animal). Such system will allow us to investigate how fast memory declines when the gene causing the disease is turned on, and which signs of the disease change when we turn the gene off. We plan to use such system to investigate the interaction between the effects of aging and the presence of the mutated human gene on memory decline. Switching the gene on or off at various ages of the mice life we will attempt to determine how the severity of dementia depends on the onset of the disease, which types of memory (knowledge of facts or memory of different environments) are most affected, and how much the memory can recover when we switch the gene off at early or late stage of the disease. Such findings will considerably help us to design future experiments which would test therapeutic approaches potentially ameliorating dementia caused by neurodegeneration and/or aging.

What problems are you addressing and what specific questions will your research seek to answer?
The problem addressed in this study focuses on the neural mechanism of dementia.

What aspects of your project are most interesting from a scientific point of view?
The most interesting scientifically aspect of the study is the fact that memory can be improved irrespectively of progressing brain pathology. Studying this dissociation should broaden our understanding of mechanisms underlying dementia.

What are the implications of your research for age-related diseases and disorders?
Intraneuronal tau deposition is a key feature of normal aging. Aging is also one of the major risk factors in neurodegenerative disorders. The project will elucidate the patho-psychologic consequences of tau accumulation in the brain and will provide a stage for therapeutic attempts to ameliorate dementia.

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