Alzheimer's disease (AD), a neurodegenerative disease of unknown etiology, is the most common cause of dementia in the elderly, affecting an estimated 10% of the population over 65 years of age. An invariant feature in the brains of patients with AD is the extaneuronal deposition of a specific amyloidogenic peptide (beta-amyloid or Abeta) derived from a transmembrane glycoprotein of unknown physiologic function called the beta-amyloid precursor protein or APP. The goal of this research is to gain further insight into the molecular pathogenesis of AD by studying APP processing by the endocytotic pathway in central neurons. The principal hypothesis of this work is that APP processing by the endocytotic pathway in neurons contributes to Abeta release and cerebral Abeta deposition, and, hence to the pathogenesis of AD. It is also postulated that endocytosis of APP is a stress-related response that, possibly in concert with other endocytosed plasmalemmal proteins (e.g., the low-affinity neurotrophin receptor or p75NTR), further mediates cytotoxic responses in central neurons. This hypothesis will be examined by addressing four specific aims. First, to study APP processing by the endocytotic pathway, adenoviral vectors will be used to modulate gene expression in cultured central neurons. Second, to identify intraneuronal compartments that participate in trafficking of endocytosed APP, morphological studies will be carried out using transfected neurons. Third, to determine whether APP processing by the endocytotic pathway increases in response to stress, metabolic labelling studies will be carried out using transfected neurons. Fourth, to determine whether p75NTR plays a role in APP processing by the endocytotic pathway, biochemical and cell biological studies will be carried out using vesicular fractions prepared from mammalian brain and cultured neurons, respectively. The results of these studies will provide greater understanding of cellular mechanisms involved in the pathogenesis of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AG015066-02
Application #
6043097
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Oliver, Eugene J
Project Start
1998-08-01
Project End
2003-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611