Neurodegenerative Diseases
Neurodegenerative disorders rob people of their ability to remember, speak, write, ambulate, and control their lives. These diseases are on the rise because people live longer and aging strongly increases one’s risk of being afflicted by these conditions. The enormous costs associated with the care for individuals with these diseases threaten our health care system. A medical breakthrough is clearly needed, and the surest way to such a breakthrough is to determine how exactly these diseases result in the dysfunction and degeneration of brain cells. Alzheimer’s disease is the leading cause of cognitive impairment in the elderly. It now afflicts an estimated four million Americans and its prevalence is expected to rise steeply during the next 20-30 years if no cure is found. Parkinson’s disease, the second most frequent neurodegenerative disease, causes a disabling movement disorder. Huntington’s disease and related trinucleotide-repeat diseases also result in incapacitating movement disorders and, like Parkinson’s disease, can also be associated with dementia.

Cerebrovascular Disease
Strokes and other cerebrovascular events are the main neurological reasons for hospital admission in most parts of the developed world. Strokes often result in permanent paralysis, loss of vision, or speech impairments. Evidence is also increasing that cerebrovascular disease can contribute to the development of dementia and to more subtle age-related cognitive impairments.

Mental Retardation
Conditions resulting in mental retardation are an important cause of long-term disability and suffering among children and adults. Some of these conditions overlap with neurodegenerative disorders and all of them raise important neurodevelopmental questions.

Amyloidogenic Proteins
Amyloidogenic molecules, such as the amyloid protein precursor (APP) and a-synuclein, may normally function primarily to protect the brain or to facilitate learning and other CNS functions. However, they can be broken down into peptides that form neurotoxic aggregates in cells and tissues. Understanding how the toxic protein fragments form and act could allow the design of better treatments for Alzheimer’s disease and other neurodegenerative disorders. Defining the normal function of the precursor molecules is of fundamental neuroscientific interest.

Apolipoprotein E
The apolipoprotein (apo) E4 allele is the main known genetic risk factor for the common form of Alzheimer’s disease and for poor outcome after head injury. Characterizing the effects of human apoE isoforms (E2, E3, E4) on brain cells should provide insights into central apoE functions and help elucidate how the E4 variant promotes neurodegeneration and impairs cognition in aging. The study of apoE structure-function relationships may result in the development of novel apoE-targeted drug treatments for Alzheimer’s disease and related conditions.

Huntington and Other Polyglutamine-Repeat Proteins
Huntingtin’s disease is the most common inherited neurodegenerative disorder and is caused by an abnormally long stretch of the amino acid glutamine within the protein called huntingtin. Abnormal polyglutamine stretches within other proteins are responsible for several midlife neurodegenerative disorders, including spinocerebellar ataxias and Kennedy’s disease. Determining how abnormal polyglutamine stretches cause neurons to die may make it possible to develop specific therapies for these disorders. It may also reveal general mechanisms of neurodegeneration that are relevant to other neurological diseases.

Cognition and Behavior
Cognitive deficits are at the very core of the dementing illnesses we study and provide intriguing insights into the human mind. The detailed behavioral characterization of transgenic models designed to simulate aspects of these diseases can elucidate the effect of transgene products on basic cognitive functions. These models can also be used to assess novel therapeutic strategies at the preclinical level.

Neural Plasticity
Plasticity is the property of the nervous system that enables it to undergo long-lasting, sometimes permanent adaptive responses to brief stimuli. Plasticity is believed to be important for establishing precise patterns of synaptic connections during early neuronal development and for learning and memory in adults. Disturbances in plasticity and synaptic function could contribute significantly to neurological deficits characteristic of mental retardation and neurodegenerative diseases. An understanding of the molecular mechanisms that regulate the formation, activity, degeneration, and regeneration of synapses and neuronal dendrites could form the basis for therapeutic strategies to prevent memory loss and cognitive decline in diverse diseases.

Proteopathies
A basic premise that connects several projects in this institute is that the structure and biophysical properties of a protein determine whether it functions normally or abnormally. We use a multidisciplinary team approach to address the hypothesis that many, if not all, aging-related neurodegenerative disorders are caused by the intracellular or extracellular accumulation of specific proteins that have assumed pathogenic conformational states (proteopathies). Although different proteins accumulate in different neurodegenerative disorders, the ways in which they damage nerve cells may overlap. Thus, it may be feasible to develop treatments that can prevent, stall or even reverse more than one of these conditions.

Inflammation and Gliosis
Astrocytes and microglia are specialized brain cells that support the health and function of neurons. In response to brain injuries, these cells produce a large number of molecules that participate in inflammation and wound repair. While acute glial responses may help prevent neuronal damage, prolonged or aberrant activation of these cells may contribute to neurological disease. Genetic and pharmacological strategies are used to assess whether glial cells and their products contribute to cerebral amyloidosis and neurodegeneration.